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  • Insulin Resistance in Patients With Major Depression Not Recruiting

    The purpose of this study is to study the relationship between insulin and glucose action and neuropsychological functioning (memory, attention, general thinking abilities) in persons with depression.

    Stanford is currently not accepting patients for this trial. For more information, please contact Norma Costello, (650) 736 - 2182.

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Publications

All Publications


  • Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116
  • Fasting plasma triglyceride concentration: A possible approach to identify increased risk of statin-induced type 2 diabetes DIABETES & VASCULAR DISEASE RESEARCH Sung, K., Reaven, G. 2015; 12 (5): 373-376

    Abstract

    To evaluate the hypothesis that measurement of fasting plasma triglyceride concentration identifies individuals at enhanced risk of statin-induced type 2 diabetes mellitus.A retrospective analysis of data collected from routine health examinations in non-diabetic, East Asian individuals (n = 5790) with low-density lipoprotein cholesterol concentrations of ⩾3.4 mmol/L. Subjects were stratified into those with or without a triglyceride concentration of ⩾1.7 mmol/L, and comparisons made of risk factors for type 2 diabetes mellitus.Approximately 40% of men and 20% of women with elevations of both low-density lipoprotein cholesterol and triglyceride concentrations were more insulin resistant (homeostatic model assessment of insulin resistance), associated with higher plasma concentrations of HbA1c, glucose and insulin.Apparently, healthy, non-diabetic East Asian men and women with combined elevations of low-density lipoprotein cholesterol and triglyceride concentrations are glucose intolerant and insulin resistant, and thereby at enhanced risk of type 2 diabetes mellitus. Measurement of plasma triglyceride concentration can identify within a hypercholesterolemic population a subset of individuals at enhanced risk of statin-induced type 2 diabetes mellitus.

    View details for DOI 10.1177/1479164115584275

    View details for Web of Science ID 000359399600009

    View details for PubMedID 25966738

  • Circulating microRNA-320a and microRNA-486 predict thiazolidinedione response: Moving towards precision health for diabetes prevention METABOLISM-CLINICAL AND EXPERIMENTAL Flowers, E., Aouizerat, B. E., Abbasi, F., Lamendola, C., Grove, K. M., Fukuoka, Y., Reaven, G. M. 2015; 64 (9): 1051-1059
  • Usefulness of Fetuin-A to Predict Risk for Cardiovascular Disease Among Patients With Obstructive Sleep Apnea AMERICAN JOURNAL OF CARDIOLOGY Liu, A., Lamendola, C., Ariel, D., Abbasi, F., Kim, S. H., Cardell, J., Tomasso, V., Xu, S., Patel, S., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 116 (2): 219-224

    Abstract

    Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases (CVDs). Fetuin-A, a novel hepatokine, has been associated with the metabolic syndrome (MetS), insulin resistance, and type 2 diabetes mellitus, all of which are highly prevalent in patients with OSA and associated with increased CVD risk. The goal of this study was to determine whether fetuin-A could be involved in the pathogenesis of CVD risk in patients with OSA, through relations of fetuin-A with MetS components and/or insulin resistance. Overweight or obese, nondiabetic volunteers (n = 120) were diagnosed with OSA by in-laboratory nocturnal polysomnography. Steady-state plasma glucose concentrations derived during the insulin suppression test were used to quantify insulin-mediated glucose uptake; higher steady-state plasma glucose concentrations indicated greater insulin resistance. Fasting plasma fetuin-A and lipoprotein concentrations were measured. Whereas neither the prevalence of MetS nor the number of MetS components was associated with tertiles of fetuin-A concentrations, the lipoprotein components of MetS, triglycerides and high-density lipoprotein cholesterol, increased (p <0.01) and decreased (p <0.05), respectively, across fetuin-A tertiles. Additionally, comprehensive lipoprotein analysis revealed that very low density lipoprotein (VLDL) particles and VLDL subfractions (VLDL1+2 and VLDL3) were increased across fetuin-A tertiles. In contrast, neither insulin resistance nor sleep measurements related to OSA were found to be modified by fetuin-A concentrations. In conclusion, abnormalities of lipoprotein metabolism, but not MetS or insulin resistance per se, may represent a mechanism by which fetuin-A contributes to increased CVD risk in patients with OSA.

    View details for DOI 10.1016/j.amjcard.2015.04.014

    View details for Web of Science ID 000357548100008

    View details for PubMedID 25960379

  • Abnormalities of lipoprotein concentrations in obstructive sleep apnea are related to insulin resistance. Sleep Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-799

    Abstract

    Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

    View details for DOI 10.5665/sleep.4678

    View details for PubMedID 25348129

  • Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Xie, W., Zhang, Z., Chennemsetty, I., Assimes, T. L., Paananen, J., Hansson, O., Pankow, J., Goodarzi, M. O., Carcamo-Orive, I., Morris, A. P., Chen, Y. I., Maekinen, V., Ganna, A., Mahajan, A., Guo, X., Abbasi, F., Greenawalt, D. M., Lum, P., Molony, C., Lind, L., Lindgren, C., Raffel, L. J., Tsao, P. S., Schadt, E. E., Rotter, J. I., Sinaiko, A., Reaven, G., Yang, X., Hsiung, C. A., Groop, L., Cordell, H. J., Laakso, M., Hao, K., Ingelsson, E., Frayling, T. M., Weedon, M. N., Walker, M., Quertermous, T. 2015; 125 (4): 1739-1751

    Abstract

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

    View details for DOI 10.1172/JCI74592

    View details for Web of Science ID 000352248600037

  • Low Circulating 25-Hydroxyvitamin D Concentrations Are Associated with Defects in Insulin Action and Insulin Secretion in Persons with Prediabetes JOURNAL OF NUTRITION Abbasi, F., Blasey, C., Feldman, D., Caulfield, M. P., Hantash, F. M., Reaven, G. M. 2015; 145 (4): 714-719

    Abstract

    Individuals with prediabetes mellitus (PreDM) and low circulating 25-hydroxyvitamin D [25(OH)D] are at increased risk of type 2 diabetes mellitus (T2DM).We aimed to determine whether low 25(OH)D concentrations are associated with defects in insulin action and insulin secretion in persons with PreDM.In this cross-sectional study, we stratified 488 nondiabetic subjects as having PreDM or normal fasting glucose (NFG) and a 25(OH)D concentration ≤20 ng/mL (deficient) or >20 ng/mL (sufficient). We determined insulin resistance by steady state plasma glucose (SSPG) concentration and homeostasis model assessment of insulin resistance (HOMA-IR) and insulin secretion by homeostasis model assessment of β-cell function (HOMA-β). We compared insulin resistance and secretion measures in PreDM and NFG groups; 25(OH)D-deficient and 25(OH)D-sufficient groups; and PreDM-deficient, PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups, adjusting for age, sex, race, body mass index, multivitamin use, and season.In the PreDM group, mean SSPG concentration and HOMA-IR were higher and mean HOMA-β was lower than in the NFG group (P < 0.001 for all comparisons). In the 25(OH)D-deficient group, mean SSPG concentration was higher (P < 0.001), but neither mean HOMA-IR nor HOMA-β was significantly different from that in the 25(OH)D-sufficient group. In the PreDM-deficient subgroup, mean (95% CI) SSPG concentration was higher (P < 0.01) than in the PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups [192 (177-207) mg/dL vs. 166 (155-177) mg/dL, 148 (138-159) mg/dL, and 136 (127-144) mg/dL, respectively]. Despite greater insulin resistance, mean HOMA-β was not significantly higher in the PreDM-deficient subgroup than in the PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups [98 (85-112) vs. 91 (82-101), 123 (112-136), and 115 (106-124), respectively].Subjects with PreDM and low circulating 25(OH)D concentrations are the subgroup of nondiabetic individuals who are the most insulin resistant and have impaired β-cell function, attributes that put them at enhanced risk of T2DM.

    View details for DOI 10.3945/jn.114.209171

    View details for Web of Science ID 000352180500007

  • Relationship Among 25-Hydroxyvitamin D Concentrations, Insulin Action, and Cardiovascular Disease Risk in Patients With Essential Hypertension AMERICAN JOURNAL OF HYPERTENSION Abbasi, F., Feldman, D., Caulfield, M. P., Hantash, F. M., Reaven, G. M. 2015; 28 (2): 266-272

    Abstract

    Although low plasma 25-hydroxyvitamin D (25(OH)D) concentrations have been shown to predict risk of hypertension and associated cardiovascular disease (CVD), vitamin D repletion has not consistently lowered blood pressure or decreased CVD. One possibility for this discrepancy is the presence of considerable metabolic heterogeneity in patients with hypertension. To evaluate this possibility, we quantified relationships among insulin resistance, 25(OH)D concentration, and CVD risk factor profile in patients with essential hypertension.Measurements were made of 25(OH)D concentrations, multiple CVD risk factors, and insulin resistance by the steady-state plasma glucose concentration during the insulin suppression test in 140 otherwise healthy patients with essential hypertension.As a group, the patients were overweight/obese and insulin resistant and had low 25(OH)D concentrations. The more insulin resistant the patients were, the worse the CVD risk profile was. In addition, the most insulin-resistant quartile had significantly lower 25(OH)D concentrations than the most insulin-sensitive quartile (20.3±1.4 vs. 25.8±1.4ng/ml; P = 0.005). In the entire group, 25(OH)D concentration significantly correlated with magnitude of insulin resistance (steady-state plasma glucose concentration; r = -0.20; P = 0.02).There was considerable metabolic heterogeneity and substantial difference in magnitude of conventional CVD risk factors in patients with similar degrees of blood pressure elevation. The most insulin-resistant quartile of subjects had the lowest 25(OH)D concentration and the most adverse CVD risk profile, and they may be the subset of patients with essential hypertension most likely to benefit from vitamin D repletion.

    View details for DOI 10.1093/ajh/hpu136

    View details for Web of Science ID 000349559300015

    View details for PubMedID 25138785

  • Use of plasma triglyceride/high-density lipoprotein cholesterol ratio to identify increased cardio-metabolic risk in young, healthy South Asians INDIAN JOURNAL OF MEDICAL RESEARCH Flowers, E., Molina, C., Mathur, A., Reaven, G. M. 2015; 141: 68-74

    Abstract

    Prevalence of insulin resistance and associated dyslipidaemia [high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations] are increased in South Asian individuals; likely contributing to their increased risk of type-2 diabetes and cardiovascular disease. The plasma concentration ratio of TG/HDL-C has been proposed as a simple way to identify apparently healthy individuals at high cardio-metabolic risk. This study was carried out to compare the cardio-metabolic risk profiles of high-risk South Asian individuals identified by an elevated TG/HDL-C ratio versus those with a diagnosis of the metabolic syndrome.Body mass index, waist circumference, blood pressure, and fasting plasma glucose, insulin, TG, and HDL-C concentrations were determined in apparently healthy men (n=498) and women (n=526). The cardio-metabolic risk profile of "high risk" individuals identified by TG/HDL-C ratios in men (≥ 3.5) and women (≥2.5) was compared to those identified by a diagnosis of the metabolic syndrome.More concentrations of all cardio-metabolic risk factors were significantly higher in "high risk" groups, identified by either the TG/HDL-C ratio or a diagnosis of the metabolic syndrome. TG, HDL-C, and insulin concentrations were not significantly different in "high risk" groups identified by either criterion, whereas plasma glucose and blood pressure were higher in those with the metabolic syndrome.Apparently healthy South Asian individuals at high cardio-metabolic risk can be identified using either the TG/HDL-C ratio or the metabolic syndrome criteria. The TG/HDL-C ratio may be used as a simple marker to identify such individuals.

    View details for Web of Science ID 000352904600010

  • Effect of liraglutide administration and a calorie-restricted diet on lipoprotein profile in overweight/obese persons with prediabetes NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES Ariel, D., Kim, S. H., Abbasi, F., Lamendola, C. A., Liu, A., Reaven, G. M. 2014; 24 (12): 1317-1322

    Abstract

    To evaluate the effects of 14 weeks of liraglutide plus modest caloric restriction on lipid/lipoprotein metabolism in overweight/obese persons with prediabetes.Volunteers with prediabetes followed a calorie-restricted diet (-500 Kcal/day) plus liraglutide (n = 23) or placebo (n = 27) for 14 weeks. The groups were similar in age (58 ± 7 vs. 58 ± 8 years) and body mass index (31.9 ± 2.8 vs. 31.9 ± 3.5 kg/m(2)). A comprehensive lipid/lipoprotein profile was obtained before and after intervention using vertical auto profile (VAP). Weight loss was greater in the liraglutide group than in the placebo group (6.9 vs. 3.3 kg, p < 0.001), as was the fall in fasting plasma glucose concentration (9.9 mg/dL vs. 0.3 mg/dL, p < 0.001). VAP analysis revealed multiple improvements in lipid/lipoprotein metabolism in liraglutide-treated compared with placebo-treated volunteers, including decreases in concentrations of total cholesterol, low-density lipoprotein cholesterol and several of its subclasses, triglyceride, and non-high-density cholesterol. The liraglutide-treated group also had a significant shift away from small, dense low-density lipoprotein-particles, as well as decreases in apolipoprotein B concentration and ratio of apolipoprotein B/apolipoprotein A-1. There were no significant changes in the lipoprotein profile in the placebo-treated group.Treatment with liraglutide plus modest calorie restriction led to enhanced weight loss, a decrease in fasting plasma glucose concentration, and improvement in multiple aspects of lipid/lipoprotein metabolism associated with increased cardiovascular disease (CVD) risk. The significant clinical benefit associated with liraglutide-assisted weight loss in a group at high risk for CVD - obese/overweight individuals with prediabetes - as seen in our pilot study, suggests that this approach deserves further study.

    View details for DOI 10.1016/j.numecd.2014.06.010

    View details for Web of Science ID 000348043200008

  • Ability of the plasma concentration ratio of triglyceride/high-density lipoprotein cholesterol to identify increased cardio-metabolic risk in an east Asian population DIABETES RESEARCH AND CLINICAL PRACTICE Sung, K., Reaven, G., Kim, S. 2014; 105 (1): 96-101
  • Fasting urine pH is independent of insulin sensitivity AMERICAN JOURNAL OF CLINICAL NUTRITION Workeneh, B., Abbasi, F., Reaven, G. 2010; 91 (3): 586-588

    Abstract

    It has recently been suggested that a low urine pH be added to the abnormalities linked to insulin resistance. This conclusion is based on the finding of a low urine pH in individuals with clinical syndromes associated with insulin resistance and not on studies in which a direct measure of insulin sensitivity was shown to be significantly related to differences in urine pH.To address this issue, we quantified insulin-mediated glucose uptake (IMGU) by using the insulin suppression test in 96 apparently healthy, nondiabetic individuals and defined its relation to fasting urine pH.Urine samples were collected and analyzed from a cohort of healthy subjects within a narrow body mass index range who were recruited to determine insulin sensitivity.There was an approximate 6-fold variation in values for IMGU in this population, with no relation to urine pH (r = 0.02). Furthermore, there was no relation between body mass index, as a surrogate estimate of insulin resistance, and urine pH (r = 0.06).On the basis of these findings, we question the view that a low urine pH be added to the abnormalities linked to insulin resistance in low-risk populations.

    View details for DOI 10.3945/ajcn.2009.28830

    View details for Web of Science ID 000274706500013

    View details for PubMedID 20032494

  • Utility of Homeostasis Model Assessment of beta-Cell Function in Predicting Diabetes in 12,924 Healthy Koreans DIABETES CARE Sung, K., Reaven, G. M., Kim, S. H. 2010; 33 (1): 200-202

    Abstract

    It is unclear how well homeostasis model assessment of beta-cell function (HOMA-beta) predicts diabetes development beyond its components, especially glucose.We identified 12,924 nondiabetic Koreans who had fasting plasma glucose and insulin concentrations measured in 2003 and again in 2008. To minimize the impact of differences in baseline glucose concentration, individuals were divided into three glucose categories: normal fasting glucose (NFG, glucose <5.6 mmol/l), impaired fasting glucose (IFG-100) (5.6-6.0 mmol/l), and IFG-110 (6.1-6.9 mmol/l).Diabetes developed in 29% of individuals in the IFG-110 group, compared with 5% in IFG-100 and 0.3% in NFG groups. Within each glucose category, those who progressed to diabetes had higher baseline glucose concentrations (P < or = 0.04). Baseline HOMA-beta, however, was not lower but higher in individuals who developed diabetes in the NFG group (P = 0.009) and similar in the IFG-100 and IFG-110 groups.These data question the utility of using HOMA-beta to predict the development of diabetes.

    View details for DOI 10.2337/dc09-1070

    View details for Web of Science ID 000273622200040

    View details for PubMedID 19808927

  • The role of membrane glycoprotein plasma cell antigen 1 ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities ENDOCRINE REVIEWS Goldfine, I. D., Maddux, B. A., Youngren, J. F., Reaven, G., Accili, D., Trischitta, V., Vigneri, R., Frittitta, L. 2008; 29 (1): 62-75

    Abstract

    Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.

    View details for DOI 10.1210/er.2007-0004

    View details for Web of Science ID 000252969900003

    View details for PubMedID 18199690

  • Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo DIABETES CARE Beysen, C., Turner, H. C., Murphy, E. J., Awada, M., McLaughlin, T., Turner, S. M., Riiff, T., Reaven, G., Lamendola, C., Hellerstein, M. K. 2007; 30 (5): 1143-1149

    Abstract

    The purpose of this study was to compare an in vivo test of whole-body glycolysis, the deuterated-glucose disposal test (2H-GDT), with insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp and the steady-state plasma glucose (SSPG) test.The 2H-GDT consists of an oral glucose challenge containing deuterated glucose, followed by measurement of heavy water (2H2O) production, which represents whole-body glycolytic disposal of the glucose load. 2H2O production is corrected for ambient insulin concentration as an index of tissue insulin sensitivity. The 2H-GDT was compared with euglycemic-hyperinsulinemic glucose clamps in healthy lean subjects (n = 8) and subjects with the metabolic syndrome (n = 9) and with the SSPG test in overweight (n = 12) and obese (n = 6) subjects.A strong correlation with the clamp was observed for the 75-g and 30-g 2H-GDT (r = 0.95, P < 0.0001 and r = 0.88, P < 0.0001, respectively). The 2H-GDT and clamp studies revealed marked insulin resistance in subjects with metabolic syndrome compared with lean control subjects. The correlation with the clamp was maintained in each group (lean, r = 0.86, P < 0.01; metabolic syndrome, r = 0.81, P < 0.01) for the 75-g test. The 2H-GDT also correlated strongly with the SSPG test (r = -0.87, P < 0.0001) in overweight and obese subjects.The 2H-GDT, which measures whole-body glycolysis in humans in a quantitative manner, correlates highly with the euglycemic-hyperinsulinemic glucose clamp and the SSPG test. Impaired insulin-mediated whole-body glycolysis is a feature of insulin resistance, which provides a means of assessing insulin sensitivity in vivo.

    View details for DOI 10.2337/dc06-1809

    View details for Web of Science ID 000246291400019

    View details for PubMedID 17259480

  • Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Allison, G., Abbasi, F., Lamendola, C., Reaven, G. 2004; 53 (4): 495-499

    Abstract

    Obese individuals tend to be both insulin resistant and at increased risk to develop cardiovascular disease (CVD). Given the increased prevalence of obesity in the US population, we thought it important to define the relationship between degree of obesity and insulin-mediated glucose disposal in the population at large, as well as the relationship between obesity, insulin resistance, and CVD risk in these individuals. To do this we quantified insulin-mediated glucose disposal in 465 healthy volunteers by determining the steady-state plasma glucose (SSPG) concentrations at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Adiposity was estimated by body mass index (BMI) and the relationship between BMI and SSPG defined. In addition, a series of CVD risk factors were measured, including blood pressure, plasma glucose, and insulin concentrations, before and after 75 g of oral glucose, and fasting plasma lipid and lipoprotein concentrations. The results indicated that SSPG concentration and BMI were significantly correlated (r = 0.54, P >.001), and 36% of individuals in the most insulin-resistant tertile were obese (BMI >/= 30.0 kg/m(2)). However, 16% of those in the most insulin-resistant tertile were of normal weight (BMI < 25.0 kg/m(2)). Although CVD risk factors were accentuated in general with progressive increases in either BMI or SSPG concentration, important differences were noted. Thus, the higher the SSPG concentration, the more the increase in plasma glucose, insulin, and triglyceride (TG) concentrations, whereas the greater the BMI, the higher the low-density lipoprotein concentration. Furthermore, while CVD risk factors increased significantly with each tertile of insulin resistance, significant differences in CVD risk were only apparent when the lowest BMI tertile was compared with the other 2, with the values in the middle and upper BMI differing from each other. These results show that while BMI and insulin resistance are related, they are not synonymous, and that they make independent and different contributions to increasing CVD risk.

    View details for Web of Science ID 000220581500016

    View details for PubMedID 15045698

  • Use of metabolic markers to identify overweight individuals who are insulin resistant ANNALS OF INTERNAL MEDICINE McLaughlin, T., Abbasi, F., Cheal, K., Chu, J., Lamendola, C., Reaven, G. 2003; 139 (10): 802-809

    Abstract

    Insulin resistance is more common in overweight individuals and is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Given the current epidemic of obesity and the fact that lifestyle interventions, such as weight loss and exercise, decrease insulin resistance, a relatively simple means to identify overweight individuals who are insulin resistant would be clinically useful.To evaluate the ability of metabolic markers associated with insulin resistance and increased risk for cardiovascular disease to identify the subset of overweight individuals who are insulin resistant.Cross-sectional study.General clinical research center.258 nondiabetic, overweight volunteers.Body mass index; fasting glucose, insulin, lipid and lipoprotein concentrations; and insulin-mediated glucose disposal as quantified by the steady-state plasma glucose concentration during the insulin suppression test. Overweight was defined as body mass index of 25 kg/m2 or greater, and insulin resistance was defined as being in the top tertile of steady-state plasma glucose concentrations. Receiver-operating characteristic curve analysis was used to identify the best markers of insulin resistance; optimal cut-points were identified and analyzed for predictive power.Plasma triglyceride concentration, ratio of triglyceride to high-density lipoprotein cholesterol concentrations, and insulin concentration were the most useful metabolic markers in identifying insulin-resistant individuals. The optimal cut-points were 1.47 mmol/L (130 mg/dL) for triglyceride, 1.8 in SI units (3.0 in traditional units) for the triglyceride-high-density lipoprotein cholesterol ratio, and 109 pmol/L for insulin. Respective sensitivity and specificity for these cut-points were 67%, 64%, and 57% and 71%, 68%, and 85%. Their ability to identify insulin-resistant individuals was similar to the ability of the criteria proposed by the Adult Treatment Panel III to diagnose the metabolic syndrome (sensitivity, 52%, and specificity, 85%).Three relatively simple metabolic markers can help identify overweight individuals who are sufficiently insulin resistant to be at increased risk for various adverse outcomes. In the absence of a standardized insulin assay, we suggest that the most practical approach to identify overweight individuals who are insulin resistant is to use the cut-points for either triglyceride concentration or the triglyceride-high-density lipoprotein cholesterol concentration ratio.

    View details for Web of Science ID 000186663500002

    View details for PubMedID 14623617

  • Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance AMERICAN JOURNAL OF CARDIOLOGY Tuan, C. Y., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. 2003; 92 (5): 606-610

    Abstract

    In this study, a specific measurement of insulin-mediated glucose disposal was used in 490 healthy volunteers to classify subjects as being insulin resistant. We then made standard measurements of plasma glucose and insulin concentrations to see how useful they would be as surrogate markers of insulin resistance.

    View details for DOI 10.1016/S0002-9149(03)00735-5

    View details for Web of Science ID 000185060700024

    View details for PubMedID 12943888

  • Differentiation between obesity and insulin resistance in the association with C-reactive protein CIRCULATION McLaughlin, T., Abbasi, F., Lamendola, C., Liang, L., Reaven, G., Schaaf, P., Reaven, P. 2002; 106 (23): 2908-2912

    Abstract

    Plasma C-reactive protein (CRP) concentrations are increased in obese and/or hyperinsulinemic individuals. The goal of this study was to determine if the relation between insulin resistance and CRP was independent of obesity.Plasma CRP concentrations were measured before and after 3 months of calorie restriction in 38 healthy, obese women. Steady-state plasma glucose (SSPG) concentration during a 180-minute infusion of octreotide, glucose, and insulin was used to stratify participants into insulin-resistant (IR, n=20) or insulin-sensitive (n=18) groups, similar in terms of mean age (46+/-2 versus 44+/-2 years), body mass index (32.0+/-0.4 versus 31.4+/-0.3 kg/m2), and waist circumference (96+/-2 versus 95+/-2 cm). Mean CRP (0.39+/-0.08 versus 0.12+/-0.03 mg/dL, P=0.003) concentrations were higher in the IR group, as were day-long plasma glucose and insulin responses (P<0.001). There was a significant correlation at baseline between CRP and day-long plasma integrated insulin response (r=0.47, P=0.001) but not between CRP and body mass index (r=0.14) or waist circumference (r=0.10). Weight loss was similar in the two groups (8.7+/-0.9 versus 8.4+/-0.8 kg) but was associated with significant (P<0.001) decreases in SSPG and CRP concentrations in the IR group only. Regression analysis showed that SSPG and day-long plasma insulin response were the only significant predictors of CRP concentration.CRP concentrations are elevated predominantly in obese individuals who are also insulin resistant and fall in parallel with weight loss-associated improvements in insulin resistance. The relation between CRP concentrations and insulin resistance is independent of obesity.

    View details for DOI 10.1161/01.CIR.0000041046.32962.86

    View details for Web of Science ID 000179698600011

    View details for PubMedID 12460870

  • Do coronary heart disease risk factors change over time? METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, L., Ardigo, D., Massironi, P., Gasparini, P., Barilli, A. L., Vetrugno, E., Sartori, E., Baroni, M. C., Delsignore, R., Reaven, G. 2002; 51 (8): 1022-1026

    Abstract

    The stability over a 12-year period of several coronary heart disease (CHD) risk factors was evaluated in 348 individuals who had remained healthy following baseline measurements made of the same variables in 1981. CHD risk factors evaluated were fasting and post-glucose challenge (120-minute) plasma glucose and insulin concentrations, plasma triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) concentrations, and the ratio of LDL/HDL cholesterol concentrations. Approximately 40% to 60% of individuals in the highest CHD risk quartile (or lowest in the case of HDL cholesterol concentrations) in 1981 were still at highest risk in 1993. A similar proportion of individuals at lowest risk in 1981 were still in that category in 1993. At least 50% of the participants in this prospective analysis experienced a change by 1 quartile or more in each of the metabolic CHD risk factors measured, and these differences were highly statistically significant for all variables measured with the exception of the TG and HDL cholesterol concentrations. These results demonstrate that the implicit assumption in epidemiological studies that CHD risk factors at baseline remain stable may require examination.

    View details for DOI 10.1053/meta.2002.34031

    View details for Web of Science ID 000177138000013

    View details for PubMedID 12145776

  • Metabolic syndrome - Pathophysiology and implications for management of cardiovascular disease CIRCULATION Reaven, G. 2002; 106 (3): 286-288
  • Relationship between insulin resistance, weight loss, and coronary heart disease risk in healthy, obese women METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Abbasi, F., Kim, H. S., Lamendola, C., Schaaf, P., Reaven, G. 2001; 50 (7): 795-800

    Abstract

    Several popular books have recently been published stating that being insulin-resistant favors weight gain and/or prevents weight loss. Because this view seems to have gained widespread support in the general population, we thought it important to perform the current study testing the hypothesis that differences in insulin-mediated glucose disposal do not affect weight loss in response to calorie-restricted diets. For this purpose, we studied the change in weight and risk factors for coronary heart disease (CHD) in healthy women volunteers, defined as being obese on the basis of a body mass index (BMI) greater than 30.0 kg/m(2). The insulin suppression test was used to stratify obese women at baseline into insulin-resistant and insulin-sensitive subgroups on the basis of their steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of octreotide, exogenous insulin, and glucose. They were then instructed on a calorie-restricted diet plus sibutraminine (15 mg/day) for a total period of 4 months. Baseline measurements also included determination of fasting lipid and lipoprotein concentrations, and hourly (8 AM to 4 PM) determinations of plasma glucose and insulin concentrations before and after breakfast and lunch. Twenty-four women completed the 4-month period of calorie restriction: 13 classified as insulin-resistant (SSPG = 219 +/- 7 mg/dL) and 11 as insulin-sensitive (SSPG = 69 +/- 6 mg/dL). The insulin-resistant group also had higher (P =.03) plasma triglyceride (TG) concentrations and a higher ratio of total to high-density lipoprotein (HDL) cholesterol concentration (P =.02) at baseline. Both groups lost a significant amount of weight during the study, and there was no difference between the weight loss in the insulin-resistant (8.6 +/- 1.3 kg) and insulin-sensitive (7.9 +/- 1.4 kg) groups. Weight loss in the insulin-resistant group was also associated with a significant decrease in SSPG concentration (219 +/- 7 to 144 +/- 14 mg/dL), associated with significantly lower fasting TG concentrations (P <.001) and day-long concentrations of plasma glucose and insulin (P <.005). None of these variables changed in the insulin-sensitive group. These results indicate that: (1) CHD risk factors in obese women vary as a function of being insulin-resistant or insulin-sensitive; (2) dramatic variations in insulin-mediated glucose disposal do not modulate weight loss in response to calorie-restricted diets, and (3) weight loss is effective in reducing CHD risk in insulin-resistant, obese women. Given these data, it seems obvious that attempts to reduce CHD risk factors by weight loss should focus on obese individuals who are also insulin-resistant.

    View details for DOI 10.1053/meta.2001.24210

    View details for Web of Science ID 000169829600010

    View details for PubMedID 11436184

  • Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease - A prospective study CIRCULATION Valantine, H., Rickenbacker, P., Kemna, M., Hunt, S., CHEN, Y. D., Reaven, G., Stinson, E. B. 2001; 103 (17): 2144-2152

    Abstract

    This study examines the hypothesis that metabolic abnormalities of dysmetabolic syndrome are risk factors for transplant coronary artery disease (TxCAD).Sixty-six patients without overt diabetes, 2 to 4 years after surgery, underwent intracoronary ultrasound (ICUS), measurement of plasma glucose and insulin after oral glucose (75 g), and fasting lipid and lipoproteins. TxCAD incidence by angiography or autopsy was prospectively determined during subsequent follow-up (8 years). Coronary artery intimal thickness (IT) and subsequent outcomes were compared in patients stratified as having "high" versus "low" plasma glucose (>8.9 mmol/L) and insulin (>760 pmol/L) 2 hours after glucose challenge; and "abnormal" versus "normal" fasting lipid and lipoprotein concentrations as defined by the National Cholesterol EducationPatients with high glucose or insulin concentrations had greater IT: 0.38+/-0.05 versus 0.22+/-0.02 mm, P0.3 mm than with IT

    View details for Web of Science ID 000168583700005

    View details for PubMedID 11331254

  • Effect of orlistat-assisted weight rose in decreasing coronary heart disease risk in patients with syndrome X AMERICAN JOURNAL OF CARDIOLOGY Reaven, G., Segal, K., Hauptman, J., Boldrin, M., Lucas, C. 2001; 87 (7): 827-831

    Abstract

    This study describes the changes in risk factors for coronary heart disease in obese persons with syndrome X after orlistat-assisted weight loss. Data were available for 1,700 patients who completed 52 weeks of weight loss; 128 were defined as having syndrome X by being in the quintile with the highest plasma triglyceride levels (>2.2 mM/L) and the lowest high-density lipoprotein cholesterol (HDL, <1.0 mM/L) concentrations. Initial characteristics of those with syndrome X were similar to the 119 subjects (non-syndrome X) in the lowest quintile of plasma triglyceride (<0.975 mM/L) and highest quintile of HDL cholesterol (>1.5 mM/L). Subjects were placed on a calorie-restricted diet, and randomized to receive orlistat or placebo. Initial values were higher in those with syndrome X for diastolic blood pressure (p = 0.03), plasma insulin (p = 0.0001), triglyceride (p = 0.0001) concentrations, and ratio of low-density lipoprotein cholesterol to HDL cholesterol (p = 0.0001), and were lower for HDL cholesterol (p = 0.001) concentrations. Weight loss was greater in both groups of orlistat-treated patients (p = 0.026); in those with syndrome X, it was associated with a significant reduction in plasma insulin (p = 0.019) and triglyceride (p = 0.0001) concentrations, an increase in HDL cholesterol concentration, and a decrease in low-density lipoprotein/HDL cholesterol ratio (p = 0.0001). There were no significant changes in plasma insulin, triglycerides, or HDL cholesterol concentration in the non-syndrome X group. In conclusion, weight loss attenuates coronary heart disease risk factors in obese persons with syndrome X, and the risk factor reduction is enhanced with administration of orlistat.

    View details for Web of Science ID 000167741300003

    View details for PubMedID 11274935

  • Alterations in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with type 2 diabetes JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Piatti, P. M., Monti, L. D., Zavaroni, I., Valsecchi, G., Van Phan, C., Costa, S., Conti, M., Sandoli, E. P., Solerte, B., Pozza, G., Pontiroli, A. E., Reaven, G. 2000; 85 (7): 2416-2420

    Abstract

    In this study, we have compared resistance to insulin-mediated glucose disposal and plasma concentrations of nitric oxide (NO) and cyclic-GMP in healthy volunteers with (n = 35) or without (n = 27) at least one sibling and one parent with type 2 diabetes. The 62 volunteers were further divided into groups of those with normal glucose tolerance or impaired glucose tolerance. Insulin-mediated glucose disposal was quantified by determining the insulin sensitivity index (ISI) in response to a low-dose, constant infusion of insulin (25 mU/kg x h) and glucose (4 mg/kg x min) for 150 min. The mean (+/-SEM) ISI [(mL kg(-1) min(-1)/pmol/L) x 10(3)] was significantly greater in those without a family history (30.3 +/- 2.3) as compared with nondiabetic volunteers with a family history of type 2 diabetes, whether they had normal glucose tolerance (17.0 +/- 7.2) or impaired glucose tolerance (9.5 +/- 1.4). In addition, basal NO levels, evaluated by the measurement of its stable end products [i.e. nitrite and nitrate levels (NO2-/ NO3-)], were significantly higher, and cyclic-GMP levels, its effector messenger, were significantly lower in those with a family history, irrespective of their degree of glucose tolerance, when compared with healthy volunteers without a family history of type 2 diabetes. Furthermore, when the 62 volunteers were analyzed as one group, there was a negative correlation between ISI and NO2-/NO3- levels (r = -0.35; P < 0.005) and a positive correlation between ISI and cyclic-GMP levels (r = 0.30; P < 0.02). These results have shown that alterations of the NO/cyclic-GMP pathway seem to be an early event in nondiabetic individuals with a family history of type 2 diabetes and these changes are correlated with the degree of insulin resistance.

    View details for Web of Science ID 000088387500010

    View details for PubMedID 10902787

  • Effect of variations in plasma magnesium concentration on resistance to insulin-mediated glucose disposal in nondiabetic subjects JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Rosolova, H., Mayer, O., Reaven, G. 1997; 82 (11): 3783-3785

    Abstract

    Eighteen nondiabetic volunteers were selected for these studies on the basis of their plasma magnesium (Mg) concentrations defined as being either high (> 0.83 mmol/L) or low (< 0.80 mmol/L). Although different in Mg concentration (0.90 +/- 0.02 vs. 0.73 +/- 0.01 mmol/L), the 2 groups were comparable in terms of age, gender distribution, body mass index, and waist to hip girth. Measurements were made of their plasma glucose and insulin concentrations in response to a 75-g oral glucose load and the steady state plasma insulin and glucose (SSPG) concentrations at the end of an 180-min infusion of octreotide, insulin, and glucose. The low Mg group had significantly higher plasma glucose (P < 0.001) and insulin (P < 0.002) concentrations after the oral glucose challenge. Although the steady state plasma insulin concentrations were similar during the infusion study, the SSPG concentration was significantly (P < 0.001) greater in the low Mg group (11.9 +/- 0.9 vs. 6.6 +/- 0.9 mmol/L). Finally, when the 18 patients were analyzed together, there were significant (P < 0.05 to P < 0.01) inverse correlations between Mg concentrations and glucose (r = -0.68) and insulin (r = -0.51) areas and SSPG concentrations (r = -0.60). Thus, a low Mg concentration in nondiabetic subjects was associated with relative insulin resistance, glucose intolerance, and hyperinsulinemia.

    View details for Web of Science ID A1997YF27100042

    View details for PubMedID 9360541

  • HYPERINSULINEMIA, OBESITY, AND SYNDROME-X JOURNAL OF INTERNAL MEDICINE Zavaroni, I., Bonini, L., FANTUZZI, R., DALLAGLIO, E., Passeri, M., Reaven, G. M. 1994; 235 (1): 51-56

    Abstract

    The major aim of this study was to compare various aspects of carbohydrate, insulin, and lipoprotein metabolism, serum uric acid concentration, and blood pressure in normal subjects stratified on the basis of both plasma insulin concentration and degree of obesity. The hypothesis to be tested was that hyperinsulinaemia, per se, was associated with relative glucose intolerance, higher triglyceride and uric acid concentrations, lower high-density lipoprotein cholesterol concentration and higher blood pressure, irrespective of degree of obesity.This represents a case-control study, in which normal volunteers were subdivided into four equal groups based upon degree of obesity and plasma insulin response to a 74 g oral glucose challenge.The study was performed in the out-patient clinic of a university hospital.Sixty-four individuals were recruited for this study, subdivided into four groups based upon their plasma insulin concentration and body mass index. Subjects were classified as hyperinsulinaemic if their plasma insulin concentrations in response to an oral glucose challenge were more than two standard deviations above the mean of 732 volunteers previously studied [1]. Obesity was defined as a body mass index of > 30 kg m-2, and individuals were classified as non-obese if their body mass index was < 27.0 kg m-2. Based upon these criteria, four experimental groups were created: (i) non-obese hyperinsulinaemic (NOB hyper); (ii) obese hyperinsulinaemic (OB hyper); (iii) non-obese normoinsulinaemic (NOB normo); and (iv) obese normoinsulinaemic (OB normo).Subject groups were compared on the basis of the integrated plasma glucose response to a 75 g oral glucose challenge, fasting plasma triglyceride, cholesterol, high-density lipoprotein cholesterol, and uric acid concentrations, and blood pressure.Mean (+/- standard error of the mean) integrated plasma glucose response area for 2 h following a 75 g oral glucose load was significantly higher (13.4 +/- 0.4 vs. 11.0 +/- 0.4 mmol l-1, P < 0.001) in the hyperinsulinaemic group, as were the fasting triglyceride levels (2.4 +/- 0.2 vs. 1.4 +/- 0.1 mmol l-1, P < 0.001) and uric acid (5.3 +/- 0.2 vs. 4.4 +/- 0.2 mmol l-1, P < 0.05) concentrations. In contrast, high-density lipoprotein concentrations were lower in the hyperinsulinaemic group (1.06.0.05 vs. 1.32 +/- 0.05 mmol l-1, P < 0.001). In addition, blood pressure was higher in the hyperinsulinaemic group (136 +/- 5/87 +/- 2 vs. 123 +/- 2/82 +/- 1 mmHg, P < 0.05). Furthermore, when each of the two groups were divided into obese (n = 16) and non-obese (n = 16) groups, all of the differences outlined above persisted. These changes were independent of age, gender distribution, generalized and abdominal obesity, cigarette smoking, and estimated physical activity.The cluster of changes subsumed under the heading of syndrome X are closely associated with hyperinsulinaemia (and presumably insulin resistance), and can be discerned irrespective of degree of obesity.

    View details for Web of Science ID A1994MR01000006

    View details for PubMedID 8283160

  • INSULIN-RESISTANCE, GLUCOSE-INTOLERANCE, AND HYPERINSULINEMIA IN PATIENTS WITH MICROVASCULAR ANGINA METABOLISM-CLINICAL AND EXPERIMENTAL Fuh, M. M., Jeng, C. Y., Young, M. M., Sheu, W. H., CHEN, Y. D., Reaven, G. M. 1993; 42 (9): 1090-1092

    Abstract

    Plasma glucose and insulin responses to oral glucose and insulin-mediated glucose disposal were determined in 20 patients with microvascular angina and 20 normal volunteers who were similar in terms of age, gender distribution, and degree of obesity. Plasma glucose and insulin responses to a 75-g oral glucose challenge were significantly higher in those with microvascular angina (P < .001), as were steady-state plasma glucose concentrations after a 180-minute infusion of somatostatin, glucose, and insulin (12.2 +/- 1.0 v 7.6 +/- 0.6 mmol/L, P < .001). Since steady-state plasma insulin concentrations were similar in the two groups (627 +/- 32 v 631 +/- 29 pmol/L), these data indicate that patients with microvascular angina are insulin-resistant, glucose-intolerant, and hyperinsulinemic compared with a matched group of normal volunteers.

    View details for Web of Science ID A1993LZ80900005

    View details for PubMedID 8412759

  • CHANGES IN INSULIN AND LIPID-METABOLISM IN MALES WITH ASYMPTOMATIC HYPERURICEMIA JOURNAL OF INTERNAL MEDICINE Zavaroni, I., Mazza, S., Fantuzzi, M., DALLAGLIO, E., Bonora, E., Delsignore, R., Passeri, M., Reaven, G. M. 1993; 234 (1): 25-30

    Abstract

    To define the effect of asymptomatic hyperuricaemia on various facets of glucose, insulin, and lipoprotein metabolism.Case control study in health volunteers.The volunteers for this study were selected on the basis of their laboratory results from a larger population participating in a general survey in one large factory.The study population consisted of 40 healthy males: 20 with asymptomatic hyperuricaemia (serum uric acid concentration equal to or greater than 420 mmol l-1) and 20 with normal serum uric acid concentrations (180-320 mmol l-1). The two groups were similar in terms of age, general obesity (estimated by body mass index), smoking and alcohol intake, and estimate of work and leisure time activity.All subjects received a 75 g oral glucose challenge, with blood taken before and at frequent intervals thereafter.Fasting plasma glucose, insulin, and lipid concentrations and plasma glucose and insulin responses to the oral glucose challenge.By selection, mean (+/- SEM) serum uric acid concentration was higher in the hyperuricaemic individuals (454 +/- 7 vs. 274 +/- 12 mmol l-1). In addition, the plasma insulin response to oral glucose was increased in individuals with asymptomatic hyperuricaemia (P < 0.005) as were both systolic (136 +/- 3 vs. 126 +/- 3 mmHg, P < 0.05) and diastolic (91 +/- 1 vs. 82 +/- 1, P < 0.01) blood pressure. Furthermore, subjects with asymptomatic hyperuricaemia were dyslipidaemic (higher plasma TG and cholesterol and lower HDL-cholesterol concentrations) as compared to the normouricaemic control group (P < 0.07-0.005).These results provide a possible explanation for the well-known association of hyperuricaemia with coronary heart disease, as well as suggesting that hyperuricaemia be added to the cluster of metabolic and haemodynamic abnormalities associated with insulin resistance and/or hyperinsulinaemia and designated as Syndrome X.

    View details for Web of Science ID A1993LL70900005

    View details for PubMedID 8326285

  • GLUCAGON DOES NOT INCREASE PLASMA-FREE FATTY-ACID AND GLYCEROL CONCENTRATIONS IN PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Jeng, C. Y., Sheu, W. H., Jaspan, J. B., Polonsky, K. S., CHEN, Y. D., Reaven, G. M. 1993; 77 (1): 6-10

    Abstract

    The study was initiated to determine whether physiological elevations of plasma glucagon would increase plasma FFA or glycerol concentrations in patients with noninsulin-dependent diabetes mellitus (NIDDM). To do this, patients were infused for 6 h with somatostatin (SRIF) alone or with SRIF plus glucagon. Furthermore, these studies were performed with an insulin infusion rate that maintains basal insulin levels or without any insulin infusion. Infusion of SRIF alone was associated with an increase in plasma FFA and glycerol concentrations, whereas hepatic glucose production and plasma glucose concentrations fell somewhat. When glucagon was added to SRIF, plasma FFA and glycerol concentrations were again increased, but to a significantly lesser extent. In addition, the addition of glucagon was associated with a modest increase in hepatic plasma glucose production and plasma glucose concentrations. In contrast, plasma FFA and glycerol concentrations fell when SRIF was infused in the presence of basal insulin levels. The decrease in FFA and glycerol levels tended to be accentuated when glucagon was also infused. It should be noted that the increases in hepatic glucose production and plasma glucose concentration after glucagon was added to SRIF were prevented when basal insulin levels were replaced. These results demonstrate that an increase in the plasma glucagon level comparable to that seen in patients with NIDDM was associated with lower, not higher, plasma FFA and glycerol concentrations in patients with NIDDM. Furthermore, these changes were seen in the absence of insulin or when basal insulin levels were replaced. Thus, the higher ambient plasma FFA and glycerol concentrations in patients with NIDDM do not appear to be secondary to increased plasma glucagon levels.

    View details for Web of Science ID A1993LL82800003

    View details for PubMedID 8100832

  • INHIBITORS OF INSULIN-RECEPTOR TYROSINE KINASE IN FIBROBLASTS FROM DIVERSE PATIENTS WITH IMPAIRED INSULIN ACTION - EVIDENCE FOR A NOVEL MECHANISM OF POSTRECEPTOR INSULIN-RESISTANCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Maddux, B. A., Sbraccia, P., Reaven, G. M., Moller, D. E., Goldfine, I. D. 1993; 77 (1): 73-79

    Abstract

    Insulin resistance is a major feature of noninsulin-dependent diabetes mellitus. This resistance appears to involve molecules, apart from the insulin receptor, that are capable of altering its function. Previously, we reported that dermal fibroblasts from a female patient with insulin resistance and noninsulin-dependent diabetes produced an inhibitor of insulin receptor tyrosine kinase activity. We have now studied inhibitors in fibroblasts from four additional patients (one male and three females) with severe insulin resistance. Although clinical features were diverse, these patients had in common normal fasting glucose values, with fasting and postprandial hyperinsulinemia. The fibroblast insulin receptor content was within the normal range, but both basal and insulin-stimulated tyrosine kinase activity in fibroblast extracts were markedly decreased compared to those in extracts of fibroblasts from nondiabetic subjects. Studies revealed that these fibroblasts contained a glycoprotein inhibitor of insulin receptor tyrosine kinase activity. This inhibitor was not found in extracts of either similar insulin-resistant patients with normal insulin receptors or insulin-resistant patients with insulin receptor abnormalities. The inhibitor was not adsorbed with antiserum to either tyrosine phosphatases or fetuin. These studies thus suggest that one or more unique inhibitors of insulin receptor tyrosine kinase are present in fibroblasts of certain patients with severe insulin resistance. The presence of insulin receptor tyrosine kinase inhibitors in target cells, therefore, may constitute a novel mechanism of postreceptor insulin resistance.

    View details for Web of Science ID A1993LL82800016

    View details for PubMedID 7686917

  • INSULIN RESISTANCE, GLUCOSE-INTOLERANCE, AND HYPERINSULINEMIA - HYPERTRIGLYCERIDEMIA VERSUS HYPERCHOLESTEROLEMIA ARTERIOSCLEROSIS AND THROMBOSIS Sheu, W. H., Shieh, S. M., Fuh, M. M., SHEN, D. D., Jeng, C. Y., CHEN, Y. D., Reaven, G. M. 1993; 13 (3): 367-370

    Abstract

    Plasma glucose and insulin responses to oral glucose and mixed meals and the ability of insulin to stimulate glucose disposal were quantified in normal volunteer subjects and patients with types IIA, IIB, and IV hyperlipoproteinemia (HLP). The results indicated that patients with either type IIB or IV HLP had higher plasma glucose (p < 0.05-< 0.001) and insulin (p < 0.001) responses to both oral glucose and mixed meals compared with the normal subjects and patients with type IIA HLP. Steady-state plasma glucose concentrations (mmol/L) were also higher (p < 0.001) in patients with types IIB (13.3 +/- 0.6) and IV (12.8 +/- 1.2) HLP during a continuous infusion of somatostatin, glucose, and insulin than either the control group (volunteer subjects) (6.2 +/- 0.9) or patients with type IIA HLP (5.6 +/- 1.0). Because the steady-state plasma insulin concentrations were similar in all four groups, patients with either type IIB or IV HLP were resistant to insulin-mediated glucose uptake. These data indicate that patients with hypertriglyceridemia are insulin resistant, glucose intolerant, and hyperinsulinemic, irrespective of the plasma cholesterol concentration. The results further demonstrate that hypercholesterolemic patients with normal triglyceride concentrations do not have any abnormalities of glucose and insulin metabolism.

    View details for Web of Science ID A1993KQ56000005

    View details for PubMedID 8443140

  • ACUTE METABOLIC EFFECTS OF CLONIDINE AND ADENOSINE IN MAN HORMONE AND METABOLIC RESEARCH Swislocki, A. L., Vestal, R. E., Reaven, G. M., Hoffman, B. B. 1993; 25 (2): 90-95

    Abstract

    Insulin resistance may contribute to non-insulin-dependent diabetes mellitus, hypertension, and dyslipidemia; increased free fatty acid concentrations could both promote and maintain this state of insulin resistance. Therefore, agents that inhibit lipolysis and decrease plasma concentrations of free fatty acids could be of therapeutic interest. We have measured metabolic effects of clonidine, an alpha 2 adrenergic agonist, and adenosine in healthy human subjects since human fat cells have alpha 2 and adenosine A1 receptors, which inhibit lipolysis in vitro. Clonidine, as expected, significantly lowered systolic and diastolic blood pressure; clonidine also decreased the plasma concentration of free fatty acids. Although clonidine caused a transient mild increase in plasma glucose, insulin and triglyceride concentrations were unchanged. The metabolic effects of adenosine were examined with two protocols. In the first study, volunteers received a graded infusion of adenosine (at 0, 10, 20, 50 and 100 micrograms/kg.min for 30 min/dose), and glucose, insulin, free fatty acids, as well as respiratory rate, systolic and diastolic blood pressures, and heart rate were measured. There was no change in glucose, insulin, or free fatty acid concentrations. In the second study a graded infusion was used and was maintained at 100 micrograms/kg/min for 120 minutes. Heart rate and respiratory rate significantly increased. Glucose and free fatty acid concentrations were unchanged, while insulin concentrations were significantly increased. All subjects had significant symptomatic complaints (dyspnea, chest pressure) during the adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993KR38100005

    View details for PubMedID 8458615

  • PREVALENCE OF HYPERINSULINEMIA IN PATIENTS WITH HIGH BLOOD-PRESSURE JOURNAL OF INTERNAL MEDICINE Zavaroni, I., Mazza, S., DALLAGLIO, E., Gasparini, P., Passeri, M., Reaven, G. M. 1992; 231 (3): 235-240

    Abstract

    A total of 41 patients with hypertension were identified in a survey of 732 healthy factory workers. Twenty-three of these individuals were receiving antihypertensive medication, whereas 18 cases were newly discovered. Plasma glucose and insulin responses to oral glucose and fasting plasma triglyceride (TG), cholesterol, and high-density-lipoprotein (HDL) cholesterol concentrations of these 41 individuals were compared with those of 41 other factor workers, with normal blood pressure, matched with the hypertensive group in terms of gender, age, degree of obesity, job in the factory, and leisure-time activity. Patients with hypertension had significantly higher plasma glucose (P less than 0.05) and insulin (P less than 0.05) concentrations in response to oral glucose, as well as a higher plasma TG concentration (P less than 0.05). Similar findings were obtained when the treated and untreated hypertensive groups were analysed separately and compared with their respective control groups. However, there were no differences between the treated and untreated hypertensive groups. Ninety per cent of the normotensive group had a plasma insulin concentration of less than 500 pmol l-1 2 h after the glucose load. Using this value as the criterion for definition of hyperinsulinaemia, 41% of the patients with high blood pressure were hyperinsulinaemic. In addition to meeting this cut-off point, the patients with hypertension and hyperinsulinaemia were also glucose intolerant and dyslipidaemic. In conclusion, approximately 50% of an unselected group of patients with hypertension were hyperinsulinaemic. Insulin levels were comparable in treated and untreated patients with high blood pressure, and hyperinsulinaemic patients also tended to be glucose intolerant and dyslipidaemic.

    View details for Web of Science ID A1992HK80400007

    View details for PubMedID 1556520

  • Insulin-resistance and associated risk factors for coronary heart disease as seen in families. Diabe`te & me´tabolisme Zavaroni, I., Reaven, G. 1991; 17 (1): 109-111

    Abstract

    Recent reports have shown that resistance to insulin-stimulated glucose uptake, increased plasma glucose and insulin response to oral glucose, and hypertriglyceridemia can be seen in first degree relatives of patients with type 2 diabetes. We have recently shown that very similar metabolic changes can be seen in hyperinsulinemic individuals who have either normal or impaired glucose tolerance (IGT). Given these data, we thought it would be of interest to compare the plasma glucose and insulin response to an oral glucose challenge, plasma lipid concentrations, and blood pressure in offspring of parents with IGT as compared to offspring of parents with normal glucose tolerance. Parents with IGT had higher plasma insulin and triglyceride levels and blood pressure than those with normal glucose tolerance. The two groups of offspring were young, non-obese and similar in terms of age, gender distribution and body mass index. Statistically significant increases in plasma insulin response to oral glucose and in systolic and diastolic blood pressure were present in the offspring of parents with IGT. Demonstration of similar abnormalities in plasma insulin response to glucose and blood pressure regulation in patients with IGT and in their offspring is consistent with the view that individual differences in insulin metabolism and blood pressure are modulated by genetic factors and that both may be related to variations in insulin-stimulated glucose uptake and/or plasma insulin concentration.

    View details for PubMedID 1936465

  • INSULIN-RESISTANCE AND ASSOCIATED RISK-FACTORS FOR CORONARY HEART-DISEASE AS SEEN IN FAMILIES DIABETES & METABOLISM Zavaroni, I., Reaven, G. 1991; 17 (1BIS): 109-111
  • CORONARY-ARTERY DISEASE IN CHINESE MALES WITHOUT HYPERCHOLESTEROLEMIA JOURNAL OF INTERNAL MEDICINE Shieh, S. M., Fuh, M. M., Shen, D. C., CHEN, Y. D., Reaven, G. M. 1990; 228 (5): 471-475

    Abstract

    The aim of this study was to determine the frequency of various metabolic risk factors for coronary artery disease (CAD) in 246 male patients studied over a 2-year period. CAD was diagnosed on the basis of a history indicative of angina pectoris, an electrocardiogram diagnostic of myocardial ischaemia, and a positive coronary angiogram. Thirty-eight per cent of this population had diabetes, hypertension or both. Of the remaining individuals, 39% had a plasma cholesterol concentration greater than 5.2 mmol l-1, whereas 23% had a cholesterol concentration less than 5.2 mmol l-1. Plasma lipid and lipoprotein levels of a non-smoking subset of those subjects with a total cholesterol concentration less than 5.2 mmol l-1 were compared with values of a matched group of individuals who did not have significant vessel disease as revealed by angiography. The results of these investigations indicated that patients with CAD and a plasma cholesterol concentration less than 5.2 mmol l-1 exhibited an increase in plasma triglyceride concentration and a decrease in plasma HDL-cholesterol concentration. Since these subjects were not diabetic, hypertensive or hypercholesterolaemic, it is suggested that the observed changes in triglyceride and HDL metabolism made a major contribution to the CAD in these individuals.

    View details for Web of Science ID A1990EJ09700010

    View details for PubMedID 2254717

  • HABITUAL LEISURE-TIME PHYSICAL-ACTIVITY IS ASSOCIATED WITH DIFFERENCES IN VARIOUS RISK-FACTORS FOR CORONARY-ARTERY DISEASE JOURNAL OF INTERNAL MEDICINE Zavaroni, I., Bonati, P. A., Luchetti, L., Bonora, E., Buonanno, G., BERGONZANI, M., Pagliara, M., Gnudi, L., BUTTURINI, L., Passeri, M., Reaven, G. M. 1989; 226 (6): 417-421

    Abstract

    Various risk factors for coronary artery disease (CAD) were compared in 100 healthy, male factory workers, divided into two groups of 50 each on the basis of their leisure-time activity. The two groups, designated as sedentary and physically active, were similar in terms of age and body mass index, but the physically active group had a significantly slower pulse rate. In addition, the plasma glucose and insulin responses to an oral glucose load were significantly lower in physically active individuals. Furthermore, fasting plasma triglyceride concentration was significantly lower and the high-density lipoprotein-cholesterol concentration was higher in the physically active individuals. Thus, substantial benefits in terms of CAD risk were associated with increased leisure-time physical activity.

    View details for Web of Science ID A1989CD53500005

    View details for PubMedID 2489226

  • RISK-FACTORS FOR CORONARY-ARTERY DISEASE IN HEALTHY-PERSONS WITH HYPERINSULINEMIA AND NORMAL GLUCOSE-TOLERANCE NEW ENGLAND JOURNAL OF MEDICINE Zavaroni, I., Bonora, E., Pagliara, M., DALLAGLIO, E., Luchetti, L., Buonanno, G., Bonati, P. A., BERGONZANI, M., Gnudi, L., Passeri, M., Reaven, G. 1989; 320 (11): 702-706

    Abstract

    We studied the relation of serum insulin levels to plasma lipid levels and blood pressure in two groups drawn from among 247 healthy, normotensive nonobese subjects with normal glucose tolerance. One group of 32 subjects was defined as having hyperinsulinemia (serum insulin, greater than 2 SD above the mean) and then compared with 32 normoinsulinemic subjects (serum insulin within 1 SD of the mean) matched for age (mean, 39 years), sex (22 men and 10 women), and body-mass index (24.7). The two groups had similar patterns of smoking, drinking, and physical exercise. Plasma glucose levels after an oral glucose challenge were significantly higher (P less than 0.05) in the hyperinsulinemic group. In addition, the mean (+/- SEM) fasting plasma triglyceride levels in subjects with hyperinsulinemia were significantly higher (1.73 +/- 0.2 vs. 1.24 +/- 0.1 mmol per liter) and the plasma high-density lipoprotein cholesterol concentrations were lower (1.21 +/- 0.06 vs. 1.43 +/- 0.06 mmol per liter) than in subjects with normoinsulinemia. Both systolic (126 vs. 119 mm Hg; P less than 0.05) and diastolic (85 vs. 78 mm Hg; P less than 0.01) blood pressures were significantly elevated in the group with hyperinsulinemia. We conclude that healthy persons with hyperinsulinemia and normal glucose tolerance have an increase in risk factors for coronary artery disease, as compared with a well-matched group of healthy subjects with normal insulin levels.

    View details for Web of Science ID A1989T654400005

    View details for PubMedID 2646537

  • ABNORMAL LIPID-METABOLISM IN TREATED HYPERTENSIVE PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS AMERICAN JOURNAL OF MEDICINE DALLAGLIO, E., Strata, A., Reaven, G. 1988; 84 (5): 899-903

    Abstract

    Plasma lipid, lipoprotein, and apoprotein concentrations were measured in 169 patients with non-insulin-dependent diabetes mellitus (NIDDM), 78 with normal blood pressure, and 91 diagnosed and receiving drug treatment for hypertension. Plasma triglyceride, cholesterol, low-density lipoprotein-cholesterol, and apoprotein B concentrations were significantly higher (p = less than 0.05 to less than 0.001) in the hypertensive group. In addition, the ratios of high-density to low-density lipoprotein-cholesterol and of apoprotein A-1 to apoprotein B were significantly reduced (p less than 0.01) in patients with hypertension. The changes noted were independent of differences in sex distribution, degree of obesity, and level of glycemic control. These results indicate that substantial differences in plasma lipid, lipoprotein, and apoprotein concentrations are seen when normotensive patients with NIDDM are compared with patients who are also being treated for hypertension, and that all of the changes noted would increase the risk of coronary artery disease in the hypertensive group. Since all patients with hypertension were receiving anti-hypertensive medications, it is not clear if it is hypertension per se, or its treatment, that is responsible for the observed changes in lipid metabolism.

    View details for Web of Science ID A1988N262600014

    View details for PubMedID 3364449

  • EFFECT OF A LOW FAT DIET ON CARBOHYDRATE-METABOLISM IN PATIENTS WITH HYPERTENSION HYPERTENSION Parillo, M., Coulston, A., Hollenbeck, C., Reaven, G. 1988; 11 (3): 244-248

    Abstract

    Plasma glucose and insulin responses to both a 75-g oral glucose challenge and to conventional meals were determined in eight patients with hypertension and compared with values of a control population. The results indicated that patients with hypertension had significantly higher than normal plasma glucose and insulin concentrations in both situations. Furthermore, when dietary carbohydrate was increased by 16% of total calories (with a reciprocal reduction in dietary fat), the hyperglycemia and hyperinsulinemia present in patients with hypertension were accentuated. Since low fat-high carbohydrate diets are usually recommended for patients with hypertension, these data suggest that abnormalities of glucose and insulin metabolism associated with hypertension would be increased if patients with high blood pressure followed conventional dietary advice. Since hyperglycemia and hyperinsulinemia have been shown to be associated with an increased risk of developing coronary artery disease, it may be appropriate to reevaluate the clinical utility of low fat-high carbohydrate diets in the treatment of hypertension.

    View details for Web of Science ID A1988M858000006

    View details for PubMedID 3280483

  • EVIDENCE THAT MULTIPLE RISK-FACTORS FOR CORONARY-ARTERY DISEASE EXIST IN PERSONS WITH ABNORMAL GLUCOSE-TOLERANCE AMERICAN JOURNAL OF MEDICINE Zavaroni, I., DALLAGLIO, E., Bonora, E., ALPI, O., Passeri, M., Reaven, G. M. 1987; 83 (4): 609-612

    Abstract

    Multiple risk factors for coronary artery disease were determined in 50 healthy, non-diabetic persons with an oral glucose tolerance test result that could not be classified as normal by current criteria and 50 sex-, age-, and weight-matched persons with normal oral glucose tolerance. The results indicated that persons with abnormal oral glucose tolerance were hyperinsulinemic, as well as hypercholesterolemic and hypertriglyceridemic. In addition, patients with abnormal results in glucose tolerance tests had significantly elevated systolic blood pressure and heart rates. These data suggest that a cluster of risk factors for coronary artery disease exists in non-diabetic persons with abnormal oral glucose tolerance.

    View details for Web of Science ID A1987K590600001

    View details for PubMedID 3674049

  • HIGH-DENSITY-LIPOPROTEIN (HDL) METABOLISM IN NONINSULIN-DEPENDENT DIABETES-MELLITUS - MEASUREMENT OF HDL TURNOVER USING TRITIATED HDL JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Golay, A., ZECH, L., Shi, M. Z., CHIOU, Y. A., Reaven, G. M., CHEN, Y. D. 1987; 65 (3): 512-518

    Abstract

    High density lipoprotein (HDL) kinetics were studied by injecting [3H]apoprotein A-I (apoA-I)/HDL into 12 subjects with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM). The results indicate that the mean fractional catabolic rate (FCR) of apoA-I/HDL was significantly faster [0.63 +/- 0.07 (+/- SEM) vs. 0.39 +/- 0.02 1/day; P less than 0.001] and the apoA-I/HDL synthetic rate greater (29.4 +/- 2.9 vs. 22.9 +/- 1.3 mg/kg X day; P less than 0.02) in patients with NIDDM than in normal subjects. Furthermore, there were statistically significant inverse relationships between apoA-I/HDL FCR and plasma levels of both HDL cholesterol (r = -0.71; P less than 0.001) and apoA-I (r = -0.63; P less than 0.001). In addition, the increase in apoA-I/HDL FCR was directly related to fasting plasma glucose (r = 0.78; P less than 0.001) and insulin (r = 0.76; P less than 0.001) concentrations. These data support the view that the decrease in plasma HDL cholesterol and apoA-I levels commonly found in patients with noninsulin-dependent diabetes is due to an increase in the catabolic rate of apoA-I/HDL secondary to the defects in carbohydrate metabolism present in these patients.

    View details for Web of Science ID A1987J694700020

    View details for PubMedID 3114304

  • EFFECT OF SOURCE OF DIETARY CARBOHYDRATE ON PLASMA-GLUCOSE AND INSULIN RESPONSES TO MIXED MEALS IN SUBJECTS WITH NIDDM DIABETES CARE Coulston, A. M., Hollenbeck, C. B., Swislocki, A. L., Reaven, G. M. 1987; 10 (4): 395-400

    Abstract

    It has been demonstrated that carbohydrate-rich foods result in different plasma glucose responses when eaten alone by normal subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). This study was designed to test if the glycemic response to mixed meals can be altered by selecting carbohydrate-rich foods based on their glycemic potency. Consequently, three test meals were developed that should have yielded high-, intermediate-, and low-glycemic responses based on the published glycemic index of all the carbohydrate foods in the meals. The test meals were consumed by normal individuals and patients with NIDDM, and the resultant plasma glucose and insulin responses were determined. The results indicated that the plasma glucose responses after the meals did not vary as a function of their glycemic potency in either the normal or NIDDM subjects. There were no significant differences in the plasma insulin responses for either group. These results indicate that the plasma glucose response to mixed meals did not vary as a function of the calculated glycemic potencies. Therefore, the glycemic response to a mixed meal was not predicted on the basis of the published values of the glycemic index of the individual carbohydrate foods included in the meal.

    View details for Web of Science ID A1987J422600002

    View details for PubMedID 3304893

  • VARIATIONS IN INSULIN-STIMULATED GLUCOSE-UPTAKE IN HEALTHY-INDIVIDUALS WITH NORMAL GLUCOSE-TOLERANCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Hollenbeck, C., Reaven, G. M. 1987; 64 (6): 1169-1173

    Abstract

    Measurements were made of both glucose disposal (M) during hyperinsulinemic clamp studies and plasma glucose and insulin responses to an oral glucose challenge in 100 individuals with normal glucose tolerance. The subjects were divided into 4 quartiles on the basis of M values, ranging from a low mean (+/- SEM) value of 140 +/- 3 mg/m2 X min (quartile 1) to a high of 349 mg/m2 X min (quartile 4). The plasma insulin response to oral glucose inversely correlated with the M value (r = -0.60; P less than 0.001), being highest in those with the lowest M (quartile 1) and lowest in those with the highest M (quartile 4). On the other hand, the plasma glucose responses of the 4 quartiles were virtually identical. These results document that insulin-stimulated glucose uptake varies widely in subjects with normal glucose tolerance, and that these differences are independent of any change in the plasma glucose response to oral glucose. Furthermore, the results indicate that insulin resistance in normal individuals is associated with hyperinsulinemia.

    View details for Web of Science ID A1987H318300011

    View details for PubMedID 3553221

  • CAN INSULIN RESISTANCE EXIST AS A PRIMARY DEFECT IN NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Swislocki, A. L., DONNER, C. C., FRAZE, E., CHEN, Y. D., Reaven, G. M. 1987; 64 (4): 778-782

    Abstract

    In this study we have attempted to quantify the plasma insulin response to glucose and insulin action in 22 nonobese subjects: 11 with normal glucose tolerance and 11 with mild [mean fasting plasma glucose concentration, 128 +/- (+/- SEM) 5 mg/dL] noninsulin-dependent diabetes mellitus (NIDDM). Estimates of the plasma insulin response were made by determining the plasma insulin concentration at hourly intervals from 0800-1600 h, before and after mixed meals consumed at 0800 h (breakfast) and 1200 h (lunch). Insulin action was assessed by measuring glucose uptake during insulin clamp studies performed at steady state plasma insulin levels of approximately 10 and 60 microU/mL, with the difference between the 2 values defined as insulin-stimulated glucose uptake. Plasma glucose (P less than 0.001) and insulin (P less than 0.001) concentrations were significantly higher in patients with NIDDM throughout the 8-h period (by two-way analysis of variance). However, mean (+/- SEM) insulin-stimulated glucose uptake was markedly reduced (P less than 0.001) in patients with type 2 diabetes mellitus (112 +/- 72 vs. 336 +/- 44 mg/m2 min-1). Thus, patients with NIDDM and mild fasting hyperglycemia were both insulin resistant and hyperinsulinemic compared to normal individuals. These data indicate that a defect in insulin-stimulated glucose uptake can occur in NIDDM in the absence of significant hyperglycemia and/or hypoinsulinemia.

    View details for Web of Science ID A1987G463100022

    View details for PubMedID 3546354

  • AGE-RELATED-CHANGES IN POSTPRANDIAL PLASMA-GLUCOSE, INSULIN, AND FREE FATTY-ACID CONCENTRATIONS IN NONDIABETIC INDIVIDUALS JOURNAL OF THE AMERICAN GERIATRICS SOCIETY FRAZE, E., CHIOU, Y. A., CHEN, Y. D., Reaven, G. M. 1987; 35 (3): 224-228

    Abstract

    Plasma glucose, insulin, and free fatty acid (FFA) concentrations were measured from 0800 to 1600 hours in 40 nondiabetic individuals, separated into younger (38 +/- 1.4 years) and older (64 +/- 1.5 years) age groups. Meals were served at 0800 (20% total daily calories) and 1200 h (40% of total daily calories), and blood drawn just before the 0800 hours meal and at hourly intervals thereafter until 1600 hours. Statistical evaluation of the results of these measurements indicated that day-long plasma glucose and insulin levels were higher in the older individuals. In contrast, the day-long FFA response was reduced in this age group. These data suggest that the ability of insulin to maintain normal plasma glucose levels deteriorates with age, whereas regulation of FFA levels does not.

    View details for Web of Science ID A1987G369500006

    View details for PubMedID 3546468

  • AGE-RELATED-CHANGES IN RAT MUSCLE GLYCOGEN-SYNTHASE ACTIVITY JOURNALS OF GERONTOLOGY DALLAGLIO, E., Chang, H., Reaven, G. M., Azhar, S. 1987; 42 (2): 168-172

    Abstract

    This study was designed to evaluate effects of aging on glycogen synthase activity in rat skeletal muscle. Total enzyme activity was shown to be significantly, (p less than .001) lower in tensor fascia latae, biceps femoris, and soleus muscle obtained from 24-month-old compared with 2-month-old rats. Similarly, values for the active form of enzyme were significantly lower, (p less than .001) in all three muscle types of 24-month-old compared with 2-month-old rats. This age-related decline in glycogen synthase activity was not due to a reduction in the affinity of the enzyme for its activator (glucose-6-phosphate) and was independent of the concentration of substrate (UDP-glucose) in the assay system. Because similar age-related changes were seen when enzyme activity was expressed per milligram of muscle protein or per gram of muscle tissue, the fall in enzyme activity was not a simple function of an age-related decline in muscle mass. Glycogen levels also were reduced significantly in tensor fascia latae, biceps femoris, and soleus of 24-month-old rats compared with 2-month-old rats, p less than .001. These results document an age-related change in a key enzyme regulating glycogen metabolism in muscle.

    View details for Web of Science ID A1987G289800009

    View details for PubMedID 3102591

  • DELETERIOUS METABOLIC EFFECTS OF HIGH-CARBOHYDRATE, SUCROSE-CONTAINING DIETS IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS AMERICAN JOURNAL OF MEDICINE Coulston, A. M., Hollenbeck, C. B., Swislocki, A. L., CHEN, Y. D., Reaven, G. M. 1987; 82 (2): 213-223

    Abstract

    The effects of variations in dietary carbohydrate and fat intake on various aspects of carbohydrate and lipid metabolism were studied in patients with non-insulin-dependent diabetes mellitus (NIDDM). Two test diets were utilized, and they were consumed in random order over two 15-day periods. One diet was low in fat and high in carbohydrate, and corresponded closely to recent recommendations made by the American Diabetes Association (ADA), containing (as percent of total calories) 20 percent protein, 20 percent fat, and 60 percent carbohydrate, with 10 percent of total calories as sucrose. The other diet contained 20 percent protein, 40 percent fat, and 40 percent carbohydrate, with sucrose accounting for 3 percent of total calories. Although plasma fasting glucose and insulin concentrations were similar with both diets, incremental glucose and insulin responses from 8 a.m. to 4 p.m. were higher (p less than 0.01), and mean (+/- SEM) 24-hour urine glucose excretion was significantly greater (55 +/- 16 versus 26 +/- 4 g/24 hours p less than 0.02) in response to the low-fat, high-carbohydrate diet. In addition, fasting and postprandial triglyceride levels were increased (p less than 0.001 and p less than 0.05, respectively) and high-density lipoprotein (HDL) cholesterol concentrations were reduced (p less than 0.02) when patients with NIDDM ate the low-fat, high-carbohydrate diet. Finally, since low-density lipoprotein (LDL) concentrations did not change with diet, the HDL/LDL cholesterol ratio fell in response to the low-fat, high-carbohydrate diet. These results document that low-fat, high-carbohydrate diets, containing moderate amounts of sucrose, similar in composition to the recommendations of the ADA, have deleterious metabolic effects when consumed by patients with NIDDM for 15 days. Until it can be shown that these untoward effects are evanescent, and that long-term ingestion of similar diets will result in beneficial metabolic changes, it seems prudent to avoid the use of low-fat, high-carbohydrate diets containing moderate amounts of sucrose in patients with NIDDM.

    View details for Web of Science ID A1987F979500004

    View details for PubMedID 3544839

  • DOCUMENTATION OF HYPERGLUCAGONEMIA THROUGHOUT THE DAY IN NONOBESE AND OBESE PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Reaven, G. M., CHEN, Y. D., Golay, A., Swislocki, A. L., Jaspan, J. B. 1987; 64 (1): 106-110

    Abstract

    Plasma glucose, insulin, FFA, glucagon, and GH concentrations were measured over an 8-h period in normal subjects and patients with noninsulin-dependent diabetes mellitus (NIDDM). Meals were consumed at 0800 h (20% of daily calories) and noon (40% of daily calories), and measurements were made hourly from 0800-1600 h. Day-long plasma glucose, insulin, and FFA concentrations were higher than normal (by two-way analysis of variance) in patients with NIDDM, whether obese or nonobese. In addition, day-long plasma glucagon concentrations were also higher than normal (by two-way analysis of variance) in both nonobese and obese patients with NIDDM. Furthermore, direct relationships were found between the total plasma glucagon response from 0800-1600 h and total plasma glucose (r = 0.57; P less than 0.001) and FFA (r = 0.30; P less than 0.06) responses. In contrast, plasma GH levels were not increased in patients with NIDDM. These data demonstrate that ambient plasma concentrations of both glucose and FFA are higher in patients with NIDDM, despite the fact that coexisting plasma insulin levels are equal to or higher than normal. The higher day-long plasma glucagon levels in patients with NIDDM may contribute to their higher plasma glucose and FFA concentrations.

    View details for Web of Science ID A1987F431800018

    View details for PubMedID 3536980

  • ROLE OF INSULIN IN REGULATION OF HIGH-DENSITY-LIPOPROTEIN METABOLISM JOURNAL OF LIPID RESEARCH Golay, A., ZECH, L., Shi, M. Z., Jeng, C. Y., CHIOU, Y. A., Reaven, G. M., CHEN, Y. D. 1987; 28 (1): 10-18

    Abstract

    The effect of alloxan-induced insulin deficiency on high density lipoprotein (HDL) metabolism was studied in rabbits. Rabbits with alloxan-induced diabetes had significantly higher (P less than 0.001, mean +/- SEM) plasma concentrations of glucose (541 +/- 13 vs. 130 +/- 2 mg/dl), triglyceride (2851 +/- 332 vs. 101 +/- 10 mg/dl), and total plasma cholesterol (228 +/- 55 vs. 42 +/- 4 mg/dl) than did normal control rabbits. However, diabetic rabbits had lower plasma HDL-cholesterol (7.2 +/- 1 vs. 51.3 +/- 1.3 mg/dl, P less than 0.001) and HDL apoA-I (38.3 +/- 6.0 vs. 87.2 +/- 4.3 mg/dl, P less than 0.001) concentrations. HDL kinetics were compared in diabetic and normal rabbits, using either 125I-labeled HDL or HDL labeled with 125I-labeled apoA-I, and it was demonstrated that HDL fractional catabolic rate (FCR) was slower and residence time was longer in the diabetic rabbits when either tracer was used. The slow FCR and the low apoA-I pool size led to reduced apoA-I/HDL synthetic rate in diabetic rabbits (0.97 +/- 0.11 vs. 0.34 +/- 0.07 mg per kg per hr). Thus, the reduced plasma HDL-cholesterol concentrations seen in rabbits with alloxan-induced insulin deficiency was associated with a lower total apoA-I/HDL synthetic rate. Since insulin treatment restored to normal all of the changes in plasma lipoprotein concentration and kinetics seen in diabetic rabbits, it is unlikely that the phenomena observed were secondary to a nonspecific toxic effect of alloxan. These data strongly support the view that insulin plays an important role in regulation of HDL metabolism.

    View details for Web of Science ID A1987F711900002

    View details for PubMedID 3549953

  • RESISTANCE TO INSULIN SUPPRESSION OF PLASMA-FREE FATTY-ACID CONCENTRATIONS AND INSULIN STIMULATION OF GLUCOSE-UPTAKE IN NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM CHEN, Y. D., Golay, A., Swislocki, A. L., Reaven, G. M. 1987; 64 (1): 17-21

    Abstract

    The ability of insulin to stimulate tissue glucose uptake and lower plasma FFA concentrations was quantified in 12 individuals with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM), further subdivided into obese and nonobese subjects. Measurements were made during 5-h glucose clamp studies, carried out at plasma insulin concentrations of about 10 microU/ml (0-150 min) and about 60 microU/ml (150-300 min). Differences between the patient groups were compared by two-way analysis of variance. The ability of insulin to either suppress plasma FFA concentrations or stimulate glucose uptake was significantly reduced (P less than 0.001) in patients with NIDDM, and this was true of both the obese and nonobese groups. The defect in the ability of insulin to suppress plasma FFA concentrations in patients with NIDDM was more apparent at the lower insulin concentration, whereas resistance to insulin-stimulated glucose uptake in NIDDM was more dramatic at the high insulin concentration. Finally, a significant correlation (r = -0.67; P less than 0.001) between insulin-stimulated glucose uptake and plasma FFA concentration was found in the entire group. These data emphasize the fact that patients with NIDDM are resistant to multiple actions of insulin, and that the magnitudes of the defect in insulin suppression of plasma FFA levels and stimulation of tissue glucose uptake are roughly comparable.

    View details for Web of Science ID A1987F431800003

    View details for PubMedID 3782431

  • SUPPRESSION OF FREE FATTY-ACIDS AND TRIGLYCERIDES IN NORMAL AND HYPERTRIGLYCERIDEMIC RATS BY THE ADENOSINE RECEPTOR AGONIST PHENYLISOPROPYLADENOSINE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Hoffman, B. B., DALLAGLIO, E., Hollenbeck, C., Chang, H., Reaven, G. M. 1986; 239 (3): 715-718

    Abstract

    Activation of adenosine receptors leads to the inhibition of lipolysis in the fat cells of several species including humans. We have examined the effects of the adenosine analog phenylisopropyladenosine (PIA) on lipolysis in vivo in intact rats. PIA suppresses markedly serum-free fatty acid (FFA) concentrations when injected s.c. (-)-PIA is more potent than (+)-PIA in suppressing FFA concentrations; also, this effect of (-)-PIA is blocked by the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline. (-)-PIA also suppressed plasma triglyceride (TG) concentrations by approximately 50% in these rats. Utilizing Triton WR1339 injections, we found that the decrease in serum TG concentrations was associated with a marked fall in very low density lipoprotein secretion rate. We also examined the effects of (-)-PIA on FFA and TG concentrations in two models of hypertriglyceridemia in rats: stretozotocin-induced diabetes and sucrose feeding. Both groups had elevated FFA and TG concentrations compared with controls. An injection of (-)-PIA suppressed markedly FFA concentrations and essentially normalized the serum concentration of TG in these rats. We conclude that (-)-PIA suppresses markedly lipolysis and triglyceride secretion in control and hypertriglyceridemic rats suggesting that the activation of adenosine receptors may have major metabolic effects in vivo.

    View details for Web of Science ID A1986F424700014

    View details for PubMedID 3795036

  • GLYCEMIC EFFECTS OF CARBOHYDRATES - A DIFFERENT PERSPECTIVE DIABETES CARE Hollenbeck, C. B., Coulston, A. M., Reaven, G. M. 1986; 9 (6): 641-647

    View details for Web of Science ID A1986F080000015

    View details for PubMedID 3803155

  • THE EFFECT OF EXERCISE TRAINING ON INSULIN RESISTANCE IN SEDENTARY YEAR OLD RATS JOURNALS OF GERONTOLOGY Mondon, C. E., Sims, C., DOLKAS, C. B., REAVEN, E. P., Reaven, G. M. 1986; 41 (5): 605-610

    Abstract

    The purpose of this study was to determine if exercise training of 12-month-old Sprague-Dawley rats could reverse the resistance to insulin-induced glucose uptake that has been shown to occur in these animals. Twelve-month-old rats were trained to run 1 1/2 miles/day in motorized exercise wheel cages, and the ability of insulin to stimulate glucose uptake in these rats was compared with values observed in two groups of similar aged sedentary rats--one fed rat chow ad libitum and the other a calorie-restricted diet for 4 months. Body weight increased and insulin-stimulated glucose uptake decreased as rats fed chow ad libitum grew from 12 to 16 months of age. In contrast, 4 months of either exercise training or calorie restriction prevented weight gain and loss of insulin-stimulated glucose uptake. Thus, the intensity of exercise training attained in this study did not result in an improvement in insulin action in older rats above and beyond that related to the reduction in rate of body weight gain.

    View details for Web of Science ID A1986D960700008

    View details for PubMedID 3745815

  • EFFECT OF OBESITY ON AMBIENT PLASMA-GLUCOSE, FREE FATTY-ACID, INSULIN, GROWTH-HORMONE, AND GLUCAGON CONCENTRATIONS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Golay, A., Swislocki, A. L., CHEN, Y. D., Jaspan, J. B., Reaven, G. M. 1986; 63 (2): 481-484

    Abstract

    Fasting and postprandial plasma concentrations of glucose, FFA, insulin, glucagon, and GH concentrations were determined in 10 nonobese and 10 obese subjects with normal glucose tolerance. Measurements were made at 0800 h (after a 14-h fast) and at hourly intervals from then until 1600 h. During this time period all individuals ate breakfast at 0800 h (20% of total daily calories) and lunch (40% of total daily calories). Although plasma glucose concentrations were similar throughout the 8-h period in the 2 groups, plasma insulin concentrations were significantly (P less than 0.001) higher in the obese individuals. However, despite the presence of hyperinsulinemia, the obese group also had higher (P less than 0.001) plasma FFA concentration throughout the day. On the other hand, both the absolute and the relative declines in plasma FFA concentration after meals were similar in the 2 groups. Since plasma glucagon and GH concentrations were similar in the 2 groups, altered production of these lipolytic hormones was not responsible for the elevated plasma FFA levels in the obese individuals. These data document the presence in obese individuals of a disassociation in their ability to maintain normal plasma glucose as opposed to plasma FFA homeostasis, and indicate that the increase in plasma FFA concentrations in obesity occurs in the presence of hyperinsulinemia and is not related to abnormalities of either glucagon or GH secretion.

    View details for Web of Science ID A1986D236100033

    View details for PubMedID 3522620

  • DESENSITIZATION OF ADENOSINE RECEPTOR-MEDIATED INHIBITION OF LIPOLYSIS - THE MECHANISM INVOLVES THE DEVELOPMENT OF ENHANCED CYCLIC ADENOSINE-MONOPHOSPHATE ACCUMULATION IN TOLERANT ADIPOCYTES JOURNAL OF CLINICAL INVESTIGATION Hoffman, B. B., Chang, H., DALLAGLIO, E., Reaven, G. M. 1986; 78 (1): 185-190

    Abstract

    Adipocytes contain adenosine receptors, termed A1 receptors, which inhibit lipolysis by decreasing adenylate cyclase activity. The inhibition of lipolysis by adenosine agonists in vivo acutely suppresses the plasma concentrations of free fatty acids (FFA) and triglycerides. We have found that infusions of the adenosine receptor agonist phenylisopropyladenosine (PIA) initially decreases plasma FFA concentrations; however, with prolonged exposure (6 d), rats become very tolerant to the effects of the drug. Adipocytes isolated from epididymal fat pads from PIA-infused rats have altered lipolytic responses. When lipolysis is stimulated with a relatively high concentration of isoproterenol (10(-7) M), PIA does not inhibit lipolysis in adipocytes from the infused animals. However, PIA inhibits isoproterenol-stimulated cyclic AMP (cAMP) accumulation in adipocytes from the infused rats although with decreased sensitivity compared with controls. The explanation for the impaired antilipolytic effect appears to be due to the fact that isoproterenol-stimulated cAMP accumulation is markedly increased in cells from infused rats. Indeed, basal lipolysis and lipolysis stimulated with lower concentrations of isoproterenol (10(-9), 10(-8) M) are effectively inhibited by PIA. cAMP accumulation is greatly increased in adipocytes from infused rats when stimulated by isoproterenol, ACTH, and forskolin. The results have some striking analogies to changes induced in nerve cells by prolonged exposure to narcotics. These data suggest that tolerance to PIA develops in adipocytes as a consequence of enhanced cAMP accumulation.

    View details for Web of Science ID A1986C980700027

    View details for PubMedID 3013937

  • INSULIN METABOLISM BY LIVER, MUSCLE, AND KIDNEYS FROM SPONTANEOUSLY DIABETIC RATS AMERICAN JOURNAL OF PHYSIOLOGY Rabkin, R., Reaven, G. M., Mondon, C. E. 1986; 250 (5): E530-E537

    Abstract

    The in vivo metabolism of insulin is a complex process in which liver, kidney, and muscle are major participants. In this study we evaluated the effect of spontaneous hyperglycemic nonketoacidotic diabetes (DH) and ketoacidotic diabetes (DKA) on insulin clearance and degradation by these organs. Livers, hindlimbs, and kidneys from nondiabetic controls and DH and DKA Bio-Breed rats were isolated and perfused with artificial media. Liver clearance of immunoreactive insulin (ml/min) was significantly higher in DH rats, 6.0 +/- 0.2, but significantly lower in DKA rats, 3.4 +/- 0.5, compared with controls, 4.6 +/- 0.2. Acidosis alone induced by ammonium chloride loading, did not impair liver insulin clearance (4.8 +/- 0.4 ml/min). Muscle responded differently to the diabetic state in that insulin clearance was not altered by DH and DKA. Renal (organ) clearance of insulin was significantly depressed in the DKA state when compared with controls (0.52 +/- 0.04 and 0.75 +/- 0.07 ml X min-1 X g-1, respectively). This could largely be explained by a lower glomerular filtration rate. Fractional urinary insulin clearance was increased twofold above control values in DH kidneys and fourfold in DKA kidneys, indicating that tubular luminal absorption of insulin was impaired in both states. By contrast contraluminal uptake (peritubular clearance) did not differ significantly from controls. 125I-insulin degrading activity of the 100,000 g supernate fraction from muscle homogenates was similar in the diabetic and control groups. However in liver and kidney, degrading activity did not correspond to whole organ insulin clearance in a consistent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986C334800025

    View details for PubMedID 3085515

  • COMPARISON OF METABOLIC EFFECTS OF WHITE BEANS PROCESSED INTO 2 DIFFERENT PHYSICAL FORMS DIABETES CARE Golay, A., Coulston, A. M., Hollenbeck, C. B., Kaiser, L. L., Wursch, P., Reaven, G. M. 1986; 9 (3): 260-266

    Abstract

    In the present study eight control subjects and eight patients with non-insulin-dependent diabetes mellitus (NIDDM) consumed single portions of processed beans equivalent to 50 g of carbohydrate. The beans were processed by different methods into two physical forms; one maintained the integrity of the bean cells (undamaged bean cells, UC) and the other ruptured the bean cells (damaged bean cells, DC). Incremental glucose response areas after ingestion of either UC or DC were not significantly different in control subjects, while incremental insulin response areas (49 +/- 7 vs. 26 +/- 4 microU X ml-1 X h-1, P less than .05) were significantly lower after eating UC-processed beans. In patients with NIDDM both incremental glucose (150 +/- 14 vs. 73 +/- 25 mg X dl-1 X h-1, P less than .001) and insulin (67 +/- 16 vs. 46 +/- 11 microU X ml-1 X h-1, P less than .05) response areas were significantly lower after UC administration. To test the effectiveness of the UC-processed bean when incorporated into mixed meals, nine patients with NIDDM consumed mixed meals containing either DC or UC on two separate mornings. The test meals represented a typical Mexican American use of pureed beans wrapped in a flour tortilla topped with melted cheese. Incremental glucose responses were significantly lower after the UC meal (171 +/- 42 mg X dl-1 X h-1, P less than .05) when compared with the DC meal (212 +/- 34 mg X dl-1 X h-1). Incremental insulin areas were also lower after the UC (91 +/- 19 microU X ml-1 X h-1) when compared with the DC meal (120 +/- 22 microU X ml-1 X h-1).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986C742200009

    View details for PubMedID 3525056

  • EVIDENCE THAT INSULIN DEFICIENCY IN THE RAT HAS DISPARATE EFFECTS ON FRUCTOSE 2,6-BISPHOSPHATE LEVELS IN MUSCLE AND LIVER ENDOCRINOLOGY DALLAGLIO, E., Reaven, G. M., Azhar, S. 1986; 118 (1): 108-111

    Abstract

    The level of fructose 2,6-bisphosphate (F2,6P2), a potent stimulator of 6-phosphofructo-1-kinase and inhibitor of fructose 1,6-bisphosphatase, was measured in three different muscle types (tensor fascia latae, biceps femoris, and soleus) and in the liver of normal and diabetic rats. The mean (+/- SEM) content of F2,6P2 (nanomoles per g tissue) varied among the three types of skeletal muscle in normal rats, with the biceps femoris having the highest (0.97 +/- 0.15) and the soleus the lowest (0.57 +/- 0.03) levels. However, these differences were unrelated to simultaneous estimates of skeletal muscle activity of 6-phosphofructo-1-kinase activity. The total concentration of F2,6P2 was more than 8-fold higher (8.5 +/- 0.9) in the liver, and this value fell to 5.3 +/- 0.8 (P less than 0.05) after the induction of diabetes with streptozotocin. In contrast, F2,6P2 levels did not fall in skeletal muscle of rats with streptozotocin-induced diabetes, and the concentration actually increased. Thus, the fall in hepatic F2,6P2 concentration associated with insulin deficiency was not observed in skeletal muscle.

    View details for Web of Science ID A1986AWR7000017

    View details for PubMedID 2934240

  • TO WHAT EXTENT DOES INCREASED DIETARY FIBER IMPROVE GLUCOSE AND LIPID-METABOLISM IN PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS (NIDDM) AMERICAN JOURNAL OF CLINICAL NUTRITION Hollenbeck, C. B., Coulston, A. M., Reaven, G. M. 1986; 43 (1): 16-24

    Abstract

    The present study assesses the impact of variations in the amount of fiber in high carbohydrate diets on carbohydrate and lipid metabolism in NIDDM. The amount and source of carbohydrate, and source of dietary fiber, were held constant. Two 4-wk diet periods were randomly assigned and all subjects completed both dietary periods. Diets were identical in the proportion of carbohydrate, fat, protein, P/S ratio, and cholesterol. The normal fiber diet contained 11 g/1000 kcal, while the high fiber diet contained 27 g/1000 kcal. The results showed no significant difference in fasting plasma glucose and insulin, day-long glucose and insulin, fasting hemoglobin AIc, or 24 h urinary glucose. Fasting plasma triglyceride and VLDL-triglyceride, as well as fasting plasma cholesterol, LDL-cholesterol, and HDL-cholesterol were also unchanged. In conclusion, an increase in the fiber content from 11 to 27 g/1000 kcal did not lead to measurable improvements in overall plasma glucose, insulin, or lipid metabolism.

    View details for Web of Science ID A1986A408600003

    View details for PubMedID 3002163

  • ESTIMATES OF INVIVO INSULIN ACTION IN HUMANS - COMPARISON OF THE INSULIN CLAMP AND THE MINIMAL MODEL TECHNIQUES HORMONE AND METABOLIC RESEARCH Foley, J. E., CHEN, Y. D., LARDINOIS, C. K., Hollenbeck, C. B., Liu, G. C., Reaven, G. M. 1985; 17 (8): 406-409

    Abstract

    The insulin clamp technique, which is often assumed to measure the ability of insulin to stimulate glucose uptake, actually measures both insulin-independent and insulin-dependent glucose uptake. In contrast, the minimal model technique, recently introduced by Bergman, Philips and Cobelli (1981), attempts to directly estimate insulin sensitivity (insulin-dependent glucose uptake = S1) by measurement of plasma glucose and insulin values during a 3 hour intravenous glucose tolerance test (IVGTT). In the present study estimates of insulin action derived from the insulin clamp and the minimal model technique were compared in 20 humans with varying degrees of glucose tolerance. The insulin response during the IVGTT was too low to permit calculation of S1 in 5 subjects - 4 with Type II diabetes and 1 with normal glucose tolerance. Although the correlation coefficient between the two tests in the other 15 patients was statistically significant (r = 0.53, P less than 0.05), this statement is somewhat misleading. Thus, S1 in the 4/7 patients with Type II diabetes in whom it could be measured was zero, and the correlation between estimates of insulin action with the two techniques in the 11 non-diabetic patients was not statistically significant (r = 0.41, P = NS) when these 4 patients were removed from the analysis. In conclusion, these data indicate that there was only a weak correlation between estimates of insulin action assessed with the insulin clamp and the minimal model techniques. One explanation for this observation is that the insulin-independent component of total glucose disposal both varies widely among patients and contributes significantly to glucose uptake as assessed by the insulin clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1985APE2400007

    View details for PubMedID 3902605

  • QUANTITATION OF INSULIN-STIMULATED GLUCOSE DISPOSAL IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS DIABETES DONNER, C. C., FRAZE, E., CHEN, Y. D., Reaven, G. M. 1985; 34 (9): 831-835

    Abstract

    Glucose disposal rates (Rd) during an insulin clamp study reflect both basal and insulin-stimulated Rd. To quantify the amount of glucose taken up in response to a known increase in insulin concentration, two consecutive studies were performed on 10 patients with mild to moderate NIDDM (mean fasting glucose = 146 mg/dl) and 10 normal subjects. Endogenous insulin secretion was inhibited by somatostatin and plasma glucose level maintained at 180 mg/dl for 5. Rd (mg/m2/min) was determined isotopically for 2.5 h at insulin concentrations approximately 6 microU/ml and during 2.5 h of physiologic hyperinsulinemia at approximately 60 microU/ml (total glucose disposal), with the increase in Rd resulting from the approximate 10-fold elevation of plasma insulin concentration defined as insulin-stimulated glucose disposal. Results showed that the increment in Rd resulting from the elevation of plasma insulin concentration was relatively minor in NIDDM (38 +/- 6), increasing from a mean (+/- SEM) value of 83 +/- 8 to 121 +/- 12. Similar values in normal subjects were 90 +/- 7 and 274 +/- 26 with an increment of 183 +/- 21. Thus, insulin-stimulated glucose uptake in patients with NIDDM was only one-fifth of that in normals, and accounted for only 31% (38 divided by 121) of total glucose disposal during the clamp study. These data indicate that the majority of previous insulin clamp studies of in vivo insulin action in patients with NIDDM, in which total glucose disposal and insulin-stimulated glucose disposal have been equated, have underestimated the magnitude of insulin resistance present in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1985AQC2600001

    View details for PubMedID 2863188

  • SPONTANEOUS RUNNING ACTIVITY IN MALE-RATS - EFFECT OF AGE JOURNAL OF APPLIED PHYSIOLOGY Mondon, C. E., DOLKAS, C. B., Sims, C., Reaven, G. M. 1985; 58 (5): 1553-1557

    Abstract

    Alterations in the intensity and pattern of spontaneous running activity as rats increase in age from 7 wk to 1 yr was studied in male rats placed in exercise wheel cages. Daily running records were obtained on 27 rats for periods up to 12 mo, and 24-h activity recordings were made of selected runners to study the variation in activity during the day. The data indicate that for rats running over 2,940 revolutions (or 2 miles/day), the maximum intensity of running attained can be divided into a group of high achievers (approximately 8 miles/day) and moderate achievers (averaging 4.5 miles/day). For both groups, spontaneous running activity reached maximal rates after 4-5 wk. This maximal rate was sustained for 7-8 wk, then fell to levels approximately 60% of maximum for 4-5 mo, and then fell again to levels approximately 25% of maximum from 8 to 12 mo of age. The hourly pattern of running activity during the day was defined in rats of increasing age, who averaged 13,280, 6,662, 3,874, and 1,755 rev/day, corresponding to 9.0, 4.5, 2.6, and 1.2 miles/day, respectively. The overall patterns at each level indicated that the major running period occurred between 6:00 P.M. and 6:00 A.M., the greater activity of younger rats was paralleled by faster speeds and longer duration at each hour of the day, and the peak running activity for each group generally occurred between 7:00 and 9:00 P.M. In summary, there is a progressive loss in speed and duration of spontaneous running activity as male rats increase in age, with intensity of exercise falling below 2 miles/day after 7-8 mo of age.

    View details for Web of Science ID A1985AHF5900023

    View details for PubMedID 3997720

  • GLYBURIDE IN NON-INSULIN-DEPENDENT DIABETES - ITS THERAPEUTIC EFFECT IN PATIENTS WITH DISEASE POORLY CONTROLLED BY INSULIN ALONE ARCHIVES OF INTERNAL MEDICINE LARDINOIS, C. K., Liu, G. C., Reaven, G. M. 1985; 145 (6): 1028-1032

    Abstract

    Glyburide, a second-generation sulfonylurea compound, was combined with insulin to evaluate its therapeutic effectiveness in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM), poorly controlled by insulin alone. Patients were studied before and three months after the addition of glyburide to their insulin program. Fasting plasma glucose concentration fell an average of 57 mg/dL, associated with an approximately 25% reduction in postprandial glucose response. Therapeutic responses varied widely from patient to patient; the greatest improvement in diabetic control was seen in heavier patients, who had retained the ability to secrete insulin in response to meals and who were not excessively insulin resistant. The glyburide-induced fall in plasma glucose concentration was associated with improvements in both insulin secretion and insulin action, but only the enhanced insulin action correlated with the reduction in fasting and postprandial glucose levels. Thus, diabetic control was significantly improved by glyburide. Combined insulin-sulfonylurea therapy may be useful in the treatment of NIDDM that cannot be easily controlled with either agent alone.

    View details for Web of Science ID A1985AJU8900009

    View details for PubMedID 3923961

  • EFFECT OF HABITUAL PHYSICAL-ACTIVITY ON REGULATION OF INSULIN-STIMULATED GLUCOSE DISPOSAL IN OLDER MALES JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Hollenbeck, C. B., Haskell, W., Rosenthal, M., Reaven, G. M. 1985; 33 (4): 273-277

    Abstract

    The goal of this study was to evaluate the effect of differences in habitual level of physical activity on insulin action in healthy males between 60 and 75 years of age. The study population consisted of 20 non-obese individuals with normal glucose tolerance: 13 older subjects (68 +/- 4 years) not exercising regularly and 7 older subjects (66 +/- 3 years) who exercised regularly. Measurements were made of body mass index (BMI), percentage body fat by underwater weighing, maximal O2 consumption by bicycle ergometry (VO2max), and insulin-stimulated glucose disposal by the insulin clamp technique. The results demonstrated that insulin-stimulated glucose disposal was significantly increased (P less than 0.001) in the normal older subjects who exercised regularly. Furthermore, a direct relationship (r = 0.74, P less than 0.001) existed between maximal aerobic capacity and in vivo insulin action, which was independent of either BMI or percentage body fat. These data are consistent with the view that the extensive variation previously noted in in vivo insulin-stimulated glucose disposal of older subjects is related to differences in habitual physical activity.

    View details for Web of Science ID A1985AFY3000010

    View details for PubMedID 3886766

  • MODERATE WEIGHT-LOSS AND SULFONYLUREA TREATMENT OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS - COMBINED EFFECTS ARCHIVES OF INTERNAL MEDICINE Liu, G. C., Coulston, A. M., LARDINOIS, C. K., Hollenbeck, C. B., MOORE, J. G., Reaven, G. M. 1985; 145 (4): 665-669

    Abstract

    Hypocaloric liquid formula diets were given for one month to 20 moderately obese patients with non-insulin-dependent diabetes mellitus divided into two equal groups; group 1 was treated with weight loss alone; group 2 received glipizide in addition to the hypocaloric diet. Mean weight loss was similar in the two groups (6.5 +/- 0.6 v 6.4 +/- 0.5 kg) and was associated with a statistically significant fall in mean fasting plasma glucose values from 293 +/- 15 to 232 +/- 24 mg/dL (group 1) and from 281 +/- 15 to 152 +/- 7 mg/dL (group 2). This was associated with 13% (group 1) and 36% (group 2) decrements in total postprandial glucose response. Neither fasting nor postprandial insulin levels changed significantly with weight loss, but estimates of insulin-stimulated glucose disposal demonstrated a 15% (group 1) and 42% (group 2) improvement. Finally, fasting plasma cholesterol and triglyceride concentrations fell significantly in both groups.

    View details for Web of Science ID A1985AEV4200015

    View details for PubMedID 3885889

  • HOW INSULIN RESISTANT ARE PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Reaven, G. M., CHEN, Y. D., DONNER, C. C., FRAZE, E., Hollenbeck, C. B. 1985; 61 (1): 32-36

    Abstract

    The study was carried out to quantify the ability of physiological increases in the plasma insulin concentration to stimulate glucose disposal above basal levels in 25 normal subjects and 25 patients with noninsulin-dependent diabetes mellitus (NIDDM). Patients were sex, age, and weight matched, and glucose disposal was determined under basal conditions (plasma insulin, approximately 10 microU/ml) and after plasma insulin levels had been increased to approximately 90 microU/ml. The mean (+/- SEM) glucose disposal rate was significantly greater (P less than 0.001) under basal conditions in patients with NIDDM (110 +/- 5 mg/m2 X min) than in individuals with normal glucose tolerance (77 +/- 4 mg/m2 X min). Glucose disposal rates increased in both normal subjects and NIDDM patients when plasma insulin concentrations were increased to about 90 microU/ml; however, the increment was much greater in normal subjects. Thus, glucose disposal only rose to a mean (+/- SEM) value of 145 +/- 7 mg/m2 X min in patients with NIDDM, representing an approximate 30% increase due to insulin. In contrast, a similar elevation of plasma insulin in normal subjects resulted in an increase in glucose disposal of approximately 300%, reaching a mean (+/- SEM) value of 310 +/- 24 mg/m2 X min. These results indicate that the defect in insulin-stimulated glucose uptake is significantly greater in patients with NIDDM than has previously been found.

    View details for Web of Science ID A1985AKM5300007

    View details for PubMedID 3889039

  • PRESENTATION OF A NEW METHOD FOR SPECIFIC MEASUREMENT OF INVIVO INSULIN-STIMULATED GLUCOSE DISPOSAL IN HUMANS - COMPARISON OF THIS APPROACH WITH THE INSULIN CLAMP AND MINIMAL MODEL TECHNIQUES JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM DONNER, C. C., FRAZE, E., CHEN, Y. D., Hollenbeck, C. B., Foley, J. E., Reaven, G. M. 1985; 60 (4): 723-726

    Abstract

    This study was initiated to compare the abilities of two alternative approaches to the measurement of insulin-dependent glucose disposal in normal humans. The ability of insulin to stimulate glucose disposal was measured in 12 normal subjects by determining glucose disposal rates during insulin clamp studies carried out at both basal insulin concentrations (approximately 6 microU/ml) and during a period of sustained hyperinsulinemia (approximately 60 microU/ml). The increment in glucose disposal was defined as insulin-dependent disposal and compared to estimates of insulin action generated by both the conventional insulin clamp approach and the minimal model technique. The results documented an extremely close correlation (r = 0.99; P less than 0.001) between the direct determination of insulin-dependent glucose disposal and insulin-stimulated glucose disposal as estimated by the insulin clamp technique. In contrast, there was a poor correlation (r = 0.44; P = NS) between insulin sensitivity as estimated by the minimal model technique and insulin-dependent glucose disposal. These results indicate that the value of glucose disposal determined by the insulin clamp approach, which includes both insulin-independent and insulin-dependent glucose disposal, provides an excellent estimate of insulin-dependent glucose disposal in subjects with normal glucose tolerance. Unfortunately, this does not appear to be true of the minimal model technique. However, it must be emphasized that these conclusions are only applicable to normal humans, and may not apply to normal subjects of other species or to humans under different physiological or pathological situations.

    View details for Web of Science ID A1985ADU0900016

    View details for PubMedID 3882738

  • METABOLIC EFFECTS OF ADDED DIETARY SUCROSE IN INDIVIDUALS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS (NIDDM) METABOLISM-CLINICAL AND EXPERIMENTAL Coulston, A. M., Hollenbeck, C. B., DONNER, C. C., WILLIAMS, R., CHIOU, Y. A., Reaven, G. M. 1985; 34 (10): 962-966

    Abstract

    This study addresses the metabolic effects of sucrose in the diets of 11 individuals with noninsulin-dependent diabetes mellitus (NIDDM). Each of two dietary periods were 15 days in length, and contained 50% of the calories as carbohydrate, 30% as fat, and 20% as protein. The only variable between the two periods was the percentage of total calories as sucrose, 16% v 1%. Fasting blood samples were analyzed for plasma glucose and insulin as well as total plasma VLDL-, LDL- and HDL-cholesterol and triglyceride concentrations. In addition, postprandial blood samples were obtained for the measurement of plasma glucose, insulin and triglyceride concentrations. Fasting plasma glucose, insulin, and day-long insulin concentrations were similar between the two diets. However, the addition of sucrose in amounts comparable to those typically consumed by the general population resulted in significantly elevated day-long glucose (P less than 0.05) and triglyceride (P less than 0.05) responses, as well as elevated fasting total plasma cholesterol (P less than 0.001), triglyceride (P less than 0.05), VLDL-cholesterol (P less than 0.01), and VLDL-triglyceride (P less than 0.05) concentrations. LDL-cholesterol and HDL-cholesterol concentrations were unchanged during the added sucrose diet. It is clear that the consumption of diets containing moderate amounts of sucrose resulted in changes to plasma lipid and postprandial glucose concentrations that have been identified as risk factors for coronary artery disease. Therefore, it seems prudent at this time to advise patients with NIDDM to avoid added dietary sucrose.

    View details for Web of Science ID A1985ARL6100014

    View details for PubMedID 3900632

  • THE EFFECTS OF VARIATIONS IN PERCENT OF NATURALLY-OCCURRING COMPLEX AND SIMPLE CARBOHYDRATES ON PLASMA-GLUCOSE AND INSULIN-RESPONSE IN INDIVIDUALS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS DIABETES Hollenbeck, C. B., Coulston, A. M., DONNER, C. C., Williams, R. A., Reaven, G. M. 1985; 34 (2): 151-155

    Abstract

    In the present study, 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) consumed eucaloric, mixed food diets on three consecutive days. Diets provided 50% of the calories as carbohydrate, 35% as fat, and 15% as protein. The percent of carbohydrate fed as complex (starches) and simple (mono- and disaccharides) varied among the 3 days. On day 1, the diet contained 80% of the carbohydrate as complex and 20% as simple (80/20); another contained 50% complex and 50% simple (50/50); and the final diet contained 20% of the carbohydrate as complex and 80% as simple (20/80). All simple carbohydrates represent naturally occurring sugars in fruits, vegetables, and dairy products. No refined sugars were added to any of the diets. The three experimental diets were randomly assigned using a 3 X 3 Latin square design. Blood was obtained hourly from 0800 to 1700 h for day-long glucose and insulin concentrations, and 24-h urine collections were made for the measurement of urine glucose. Mean (+/- SEM) day-long glucose concentrations were significantly greater for the 80/20 diet (2245 +/- 199 mg/dl X h, P less than 0.05) than for either the 50/50 (2030 +/- 157 mg/dl X h) or the 20/80 diets (2008 +/- 160 mg/dl X h). No significant differences were noted between the 50/50 and the 20/80 diets. In contrast, day-long insulin concentrations were not significantly different with 401 +/- 62, 370 +/- 50, and 369 +/- 60 mu U/ml X h on the 80/20, 50/50, and 20/80 diets, respectively. Twenty-four-hour urinary glucose excretion paralleled plasma glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1985AAV3700010

    View details for PubMedID 3881303

  • GLUCOSE-INDUCED INSULIN-SECRETION BY PERFUSED PANCREAS OF 2-MO-OLD AND 12-MO-OLD FISCHER-344 RATS AMERICAN JOURNAL OF PHYSIOLOGY Curry, D. L., Reaven, G., Reaven, E. 1984; 247 (3): E385-E388

    Abstract

    Previous studies have shown that cells from older Sprague-Dawley rats secrete insulin less efficiently in response to a maximal glucose challenge than do beta-cells from young animals. In the current study we have asked whether this change in beta-cell response occurs in another strain of rat, and, if so, whether the secretory defect occurs at submaximal as well as maximal glucose stimulatory levels. Pancreas perfusions were carried out on 2- and 12-mo-old Fischer 344 rats at perfusate glucose concentrations of 150 and 300 mg/dl. The secretory data for each pancreas was subsequently corrected for differences in islet cell mass and expressed as insulin secretion per unit islet cell. The results show that 12-mo-old Fischer rats release more insulin per total pancreas than do 2-mo-old animals at both glucose concentrations. However when corrected for islet cell mass, the amount of insulin secretion per islet cell is actually reduced in the older Fischer rat. These data are comparable to those seen previously in the 12-mo-old Sprague-Dawley rat and indicate that the insulin secretory defect seen as rats grow older is not species specific.

    View details for Web of Science ID A1984TN96100037

    View details for PubMedID 6383072

  • INSULIN-STIMULATED GLUCOSE DISPOSAL INCREASES WITH TIME IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS DIABETES Liu, G., CHEN, Y. D., Hollenbeck, C. B., LARDINOIS, C. K., Reaven, G. M. 1984; 33 (7): 643-647

    Abstract

    The relative effects of time versus ambient glucose concentration on insulin-stimulated glucose uptake was estimated by performing 5-h insulin clamp studies in patients with NIDDM. Each experimental subject was studied three times, at steady-state plasma insulin levels approximately 2000 microU/ml, but at different steady-state plasma glucose concentrations (studies A, B, and C). Study A consisted of a 5-h clamp, with plasma glucose level maintained at the basal level of fasting hyperglycemia; study B differed in that the basal level of fasting hyperglycemia was reduced during the first hour to approximately 80 mg/dl, and maintained there for the next 4 h; and study C was carried out by clamping the patient at the basal glucose level for 2 h, lowering the glucose concentration to approximately 80 mg/dl during the third hour, and then clamping at this level for the last 2 h. The glucose metabolic clearance rate (MCR) was calculated from 60 to 120 min and from 240 to 300 min during each study, and the results indicated that values for glucose MCR were time dependent, being significantly greater (20-60%) in the fifth than in the second hour in two (studies A and B) of the three studies. In contrast, glucose MCR was independent of plasma glucose concentration, and relatively constant in each subject, as long as it was measured during the same time period. The time-dependent increase in glucose MCR was associated with an approximate 30% increase in steady-state plasma insulin concentrations when comparing the second and fifth hours.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1984SY22600007

    View details for PubMedID 6376220

  • INSULIN RESISTANCE IN OLDER RATS AMERICAN JOURNAL OF PHYSIOLOGY Narimiya, M., Azhar, S., DOLKAS, C. B., Mondon, C. E., Sims, C., Wright, D. W., Reaven, G. M. 1984; 246 (5): E397-E404

    Abstract

    Insulin-stimulated glucose utilization was estimated in vivo in 1.5-, 4-, and 12-mo-old rats with an insulin suppression test wherein the height of the steady-state plasma glucose ( SSPG ) concentration, at similar steady-state plasma insulin levels, provides a direct reflection of the efficiency of insulin-stimulated glucose disposal. In parallel studies, the effect of age on in vitro insulin-stimulated glucose uptake was assessed in perfused hindlimb preparations. In addition, changes in the activity of enzymes that regulate muscle glycolysis, glycogenesis, and glycogenolysis were determined in isolated soleus muscle. The results indicated that rats got heavier as they became older, and changes in weight were associated with parallel increases in mean (+/- SE) SSPG concentrations as rats grew from 1.5 (56 +/- 3 mg/dl) to 4 (172 +/- 6 mg/dl) to 12 mo of age (194 +/- 8 mg/dl). The age-related decline in in vivo insulin action was associated with a reduction in insulin action on muscle, and maximal insulin-stimulated glucose uptake by perfused hindlimbs of 12-mo-old rats was approximately 50% of the value seen with perfused hindlimbs from 1.5-mo-old rats. Soleus muscle enzyme activity also varied with age, with significant increases in glycogen synthase and decreases in glycogen phosphorylase documented. Furthermore, muscle glycogen phosphorylase activity, which fell during an insulin infusion in 1.5-mo-old rats, did not change when 12-mo-old rats were infused at comparable insulin levels. Finally, glycogen content was significantly increased (P less than 0.01) in soleus muscle from 12-mo-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1984ST74700026

    View details for PubMedID 6426315

  • A COMPARISON OF THE RELATIVE EFFECTS OF OBESITY AND NON-INSULIN-DEPENDENT DIABETES-MELLITUS ON INVIVO INSULIN-STIMULATED GLUCOSE-UTILIZATION DIABETES Hollenbeck, C. B., CHEN, Y. D., Reaven, G. M. 1984; 33 (7): 622-626

    Abstract

    Insulin clamp studies were carried out in 50 individuals, 25 with normal glucose tolerance and 25 with non-insulin-dependent diabetes mellitus (NIDDM). Both diagnostic groups were further subdivided on the basis of body mass index (BMI) into an obese (BMI greater than 28 kg/m2) or nonobese group (BMI less than 28 kg/m2). The obese and nonobese subjects in each diagnostic category had similar plasma glucose levels in response to an oral glucose challenge. In addition, insulin-stimulated glucose utilization, as assessed by determination of glucose metabolic clearance rate (MCR), was not different as a function of obesity. Glucose MCR (mean +/- SEM) in obese subjects (mean BMI = 32.1) with normal glucose tolerance was 162 ml/min/m2, as compared with a value of 205 ml/min/m2 in nonobese individuals (mean BMI = 23.8). This difference was not statistically significant. Similarly, glucose MCR in obese patients (mean BMI = 34.7) with NIDDM was 55 ml/min/m2, as compared with a value of 80 ml/min/m2 in nonobese subjects (mean BMI = 24.9) with NIDDM. However, as can be seen from the above data, glucose MCR in patients with NIDDM, either nonobese or obese, was markedly reduced (P less than 0.001) when compared with that of normal subjects. These data emphasize the profound effect of NIDDM on reducing in vivo insulin action, and point out that the impact of obesity on insulin resistance is minor in comparison.

    View details for Web of Science ID A1984SY22600004

    View details for PubMedID 6376218

  • CAUSES OF THE TRIGLYCERIDE-LOWERING EFFECT OF EXERCISE TRAINING IN RATS JOURNAL OF APPLIED PHYSIOLOGY Mondon, C. E., DOLKAS, C. B., TOBEY, T., Reaven, G. M. 1984; 57 (5): 1466-1471

    Abstract

    Serum triglyceride (TG) levels are lower in exercise-trained (ET) compared with control rats throughout a 24-h period (P less than 0.01-0.001). To understand this phenomenon, the relationship between serum TG concentration and hepatic very low density lipoprotein (VLDL)-TG secretion rate was studied in intact rats. In addition, hepatic TG secretion was measured in isolated perfused liver and TG removal by isolated perfused hindlimbs at rest and during simulated exercise. In vivo, low TG levels are consistently associated with decreased serum insulin concentration and periodic decrease in free fatty acid (FFA) levels. At rest, with comparable FFA levels, VLDL-TG secretion was 50% lower in ET rats, proportionate to the reduction in serum TG levels. Hepatic TG secretion by perfused livers of ET and control rats was similar when studied at comparable FFA and insulin levels suggesting the fall in VLDL-TG secretion with exercise training was not the result of intrinsic change in the ability of the liver to esterify and secrete TG. Perfused muscle of ET and control rats remove TG at equal rates when perfused at rest. However, during simulated exercise, TG removal was increased only in hindlimbs from ET rats. Thus, low serum TG levels in ET rats seem to be due to a combined effect of decreased hepatic TG secretion, secondary to reduced substrate and insulin supply to the liver, and increased TG removal by muscle during exercise.

    View details for Web of Science ID A1984TT17600027

    View details for PubMedID 6394563

  • ACARBOSE TREATMENT OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS ARCHIVES OF INTERNAL MEDICINE LARDINOIS, C. K., GREENFIELD, M. S., Schwartz, H. C., Vreman, H. J., Reaven, G. M. 1984; 144 (2): 345-347

    Abstract

    Acarbose is a newly developed inhibitor of intestinal alpha-glucosidase, and in the current study its ability to lower plasma glucose levels was studied in 12 patients with non-insulin-dependent diabetes mellitus, poorly controlled on diet plus sulfonylurea drugs. Patients were studied before and three months after the addition of acarbose to their treatment program, and there was a notable fall in postprandial plasma glucose concentrations that approximated 60 mg/dL. When acarbose therapy was discontinued in five patients, plasma glucose levels rapidly returned toward pretreatment levels. In addition to the improvement in glycemia, acarbose treatment also led to a notable reduction in Hb A1c and triglyceride concentrations. Finally, considerable individual variation was noted in the response to acarbose, and the results in four patients were quite dramatic, with striking reductions in both fasting and postprandial glucose concentrations. These data suggest that acarbose may be a useful addition in the treatment of patients with non-insulin-dependent diabetes mellitus.

    View details for Web of Science ID A1984SC31600021

    View details for PubMedID 6696573

  • EFFECT OF INVIVO PLASMA-INSULIN LEVELS ON THE RELATIONSHIP BETWEEN PERFUSATE FREE FATTY-ACID CONCENTRATION AND TRIGLYCERIDE SECRETION BY PERFUSED RAT LIVERS HORMONE AND METABOLIC RESEARCH Reaven, G. M., Mondon, C. E. 1984; 16 (5): 230-232

    Abstract

    Previous evidence has indicated that plasma concentrations of insulin and free fatty acid (FFA) play crucial roles in regulation of hepatic triglyceride (TG) secretion. To further define the relationship between these variables, we have assessed the effect of pre-existing ambient insulin levels on the ability of perfusate FFA concentrations to stimulate TG secretion by perfused livers from five groups of rats. The groups and their mean plasma in vivo insulin concentrations were as follows: sucrose-fed (49 microU/ml), control (35 microU/ml), moderate streptozotocin-induced insulin deficiency (24 microU/ml), semi-starved control (11 microU/ml), and severe streptozotocin-induced insulin deficiency (6 microU/ml). Hepatic TG secretion by perfused rat livers from all five groups was stimulated by increments in perfusate FFA concentration. However, the magnitude of the stimulation of hepatic TG secretion by any given perfusate FFA concentration varied considerably among the groups, and appeared to be directly related to the height of the in vivo insulin concentrations. These results indicate that TG secretion by perfused rat livers is related to perfusate FFA concentrations, but emphasize the importance that pre-existing ambient insulin levels have in modulating the quantitative nature of this relationship.

    View details for Web of Science ID A1984SU95800004

    View details for PubMedID 6376309

  • EFFECT OF AGE AND DIET ON INSULIN-SECRETION AND INSULIN ACTION IN THE RAT DIABETES Reaven, E., Wright, D., Mondon, C. E., Solomon, R., Ho, H., Reaven, G. M. 1983; 32 (2): 175-180

    Abstract

    The effects of aging on various aspects of insulin secretion and action were studied in male Sprague-Dawley rats, maintained from 1 1/2 to 12 mo of age on conventional rat chow, sucrose-rich, or calorie-restricted diets. In chow-fed rats, islet volume increased as the animals grew from 1 1/2 to 12 mo of age, but glucose-stimulated insulin secretion (per volume islet) declined over the same interval. In addition, in vivo insulin-stimulated glucose utilization fell in these rats. However, the plasma insulin response to an oral glucose challenge was sufficient to prevent frank decompensation of glucose tolerance (presumably due to an increase in total pancreatic endocrine cell mass). All these changes, with the exception of the decline in glucose-stimulated insulin secretion per volume islet, were accentuated by feeding sucrose. Thus, 12-mo-old sucrose-fed rats had larger islets and higher plasma insulin levels in response to an oral glucose challenge, and the rats were more insulin-resistant than chow-fed rats. However, glucose-stimulated insulin release per volume islet was similar in 12-mo-old chow-fed and sucrose-fed rats. In contrast, calorie restriction led to an amelioration in all but one of the age-related changes, i.e., islets from calorie-restricted rats were comparable in size to those of 2-mo-old rats, the animals had lower plasma insulin levels in response to an oral glucose load, and they were less insulin resistant than the other two groups of 12-mo-old rats. On the other hand, glucose-stimulated insulin secretion per volume islet was similar to that of the other 12-mo-old rats. These results suggest that aging leads to marked changes in both insulin secretion and insulin action. The decline in glucose-stimulated insulin secretion per unit endocrine pancreas appears to be an inevitable consequence of the aging process. In contrast, the age-related changes in islet size, insulin response to a glucose load, and in vivo insulin-stimulated glucose uptake are extremely responsive to variations in amount and kind of calories. DIABETES 32:175-180, February 1983.

    View details for Web of Science ID A1983QD46700013

    View details for PubMedID 6337897

  • EFFECT OF EXERCISE TRAINING AND SUCROSE FEEDING ON INSULIN-STIMULATED GLUCOSE-UPTAKE IN RATS WITH STREPTOZOTOCIN-INDUCED INSULIN-DEFICIENT DIABETES DIABETES DALLAGLIO, E., Chang, F., Chang, H., Wright, D., Reaven, G. M. 1983; 32 (2): 165-168

    Abstract

    The effect of exercise training and a sucrose-rich diet on insulin-stimulated glucose disposal was studied in rats with streptozotocin-induced insulin deficiency. Rats were injected with streptozotocin (40 mg/kg), and 3 days later divided into three groups with equal degrees of hyperglycemia. One group of rats was allowed to run spontaneously on exercise wheels, another group remained sedentary but ate a sucrose-rich diet (66% sucrose), and the third also remained sedentary but consumed conventional rat chow. Three weeks later, we determined the effect of these various programs on postabsorptive plasma glucose and insulin levels, as well as on the ability of exogenous insulin to stimulate disposal of a glucose load during a period in which endogenous insulin was suppressed by epinephrine and propanolol. Basal plasma insulin levels were the same in all three groups, but plasma glucose levels were significantly lower (P less than 0.001) in exercise-trained rats, and significantly higher (P less than 0.05) in sucrose-fed rats, than in chow-fed diabetic rats. The inference that exercise training markedly enhanced insulin action in rats with insulin deficiency was borne out by direct estimation of insulin-stimulated glucose disposal. In contrast, sucrose-fed diabetic rats seemed to be more insulin-resistant than chow-fed diabetic rats. These results provide direct evidence that spontaneous exercise can dramatically attenuate the severity of diabetes in insulin-deficient rats by enhancing insulin action. DIABETES 32:165-168, February 1983.

    View details for Web of Science ID A1983QD46700011

    View details for PubMedID 6219028

  • EFFECT OF AGE AND ENVIRONMENTAL-FACTORS ON INSULIN RELEASE FROM THE PERFUSED PANCREAS OF THE RAT JOURNAL OF CLINICAL INVESTIGATION Reaven, E., Curry, D., Moore, J., Reaven, G. 1983; 71 (2): 345-350

    Abstract

    In this study we examined the effect of age and various age-related environmental factors on maximal glucose-stimulated insulin release by the intact perfused pancreas. Male Sprague-Dawley rats were maintained from 40 d to 12 mo of age on standard chow, or on a sucrose-rich or calorie-restricted diet. At 12 mo, studies were carried out on the isolated pancreas of each animal to determine maximal (300 mg/ml) glucose-stimulated insulin secretion. After these studies were completed, each pancreas was perfused with formalin fixative and processed for morphometric estimation of the mass of the endocrine pancreas. Data from these older animals were compared with data from 2-mo-old control rats. The results indicate that maximal glucose-stimulated insulin secretion per unit endocrine pancreas was markedly reduced in all three groups of 12-mo-old rats, and was only 25-33% of that of 2-mo-old rats. Thus, aging led to a decline in insulin secretion per beta cell that was not modifiable by environmental manipulation. On the other hand, environmental factors can influence the development of endocrine tissue within the pancreas, and in so doing, modify total pancreatic insulin secretion. The mass of the endocrine pancreas of 12-mo-old rats fed either sucrose or chow was between three and four times that of 2-mo-old control rats, and these older rats were able to maximally secrete as much insulin per total pancreas as the young rats. In contrast, the endocrine cell mass of the calorie-restricted rats had not enlarged to this extent, and the maximally stimulated perfused pancreas from these rats secreted less insulin. These data suggest that the aging animal, challenged in vivo to secrete insulin, can overcome the loss of the beta cell response by expanding its pancreatic pool of beta cells. Although this compensation is successful in the 12-mo-old, obese, middle-aged rat, it is not yet clear what effect further aging would have on these events.

    View details for Web of Science ID A1983QD89700019

    View details for PubMedID 6337185

  • EFFECT OF CONFINEMENT IN SMALL SPACE-FLIGHT SIZE CAGES ON INSULIN SENSITIVITY OF EXERCISE-TRAINED RATS AVIATION SPACE AND ENVIRONMENTAL MEDICINE Mondon, C. E., DOLKAS, C. B., Reaven, G. M. 1983; 54 (10): 919-922

    Abstract

    Previous studies on men under conditions of total bed rest, and laboratory animals under limited physical activity, have shown resistance to insulin-induced glucose uptake and, conversely, increased sensitivity to insulin with exercise training. To determine whether the beneficial effects of exercise training on increasing insulin sensitivity are lost following end of exercise and confinement in small cages, oral glucose tolerance tests (OGTT) were given to control and exercise-trained rats before and after placement in small space flight size cages (11 X 4 X 4 1/2 in) for 7 d. The product of the area of the insulin and glucose curves of the OGTT (IG index) provides a measure of insulin resistance. Values obtained, before confinement, were one-half as high in exercise-trained rats as those in control rats (p less than 0.001), reflecting increased sensitivity to insulin with exercise training. After 7 d confinement, the IG index was not significantly different from initial values for both control and exercise-trained rats. These findings indicate that increased insulin sensitivity in exercise-trained rats persists 7 d after cessation of running activity. Furthermore, the data suggest that exercise training, before flight, may be beneficial in minimizing the loss of insulin sensitivity expected with decreased use of gravity dependent muscles during exposure to hypogravity in space flight.

    View details for Web of Science ID A1983RK65300007

    View details for PubMedID 6651715

  • DISPARATE EFFECTS OF PRAZOSIN AND PROPRANOLOL ON LIPID-METABOLISM IN A RAT MODEL METABOLISM-CLINICAL AND EXPERIMENTAL DALLAGLIO, E., Chang, H., Reaven, G. 1983; 32 (5): 510-513

    Abstract

    The effects of 14 days of daily intraperitoneal injections of prazosin hydrochloride (3.0 or 0.3 mg/kg) or propranolol (5 mg/kg) on various aspects of the lipid metabolism of normal rats was studied. The results indicate that plasma triglyceride and cholesterol concentrations were lower and the ratio of plasma HDL-cholesterol to total cholesterol concentration higher in prazosin-treated rats compared with propranolol-treated rats. The decline in plasma triglyceride levels in prazosin-treated rats was associated with a commensurate reduction in triglyceride secretion rates. Plasma free fatty acid levels were also lower in prazosin-treated rats, and this change may have contributed to the fall in triglyceride secretion rates. These data demonstrate that the disparate effects of alpha and beta receptor antagonists, previously shown to occur in hypertensive humans, can be duplicated in normal rats.

    View details for Web of Science ID A1983QQ02700015

    View details for PubMedID 6843362

  • EFFECT OF HIGH-CARBOHYDRATE-LOW-FAT DIETS ON PLASMA-GLUCOSE, INSULIN AND LIPID RESPONSES IN HYPERTRIGLYCERIDEMIC HUMANS METABOLISM-CLINICAL AND EXPERIMENTAL Liu, G. C., Coulston, A. M., Reaven, G. M. 1983; 32 (8): 750-753

    Abstract

    Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical US diets and fed for 15 days each to eight patients with endogenous hypertriglyceridemia. Fasting blood samples were drawn on days 13, 14, and 15 of each dietary period, and analyzed for glucose, insulin, cholesterol, and triglyceride concentrations, as well as for triglyceride and cholesterol content of the various lipoprotein classes. In addition, these same measurements were made before and for three hours after the noon meal on days 14 and 15. Fasting plasma triglyceride (TG) and very-low-density lipoprotein (VLDL)-TG concentrations were significantly increased (P less than 0.005) on the low-fat-high-carbohydrate diet. In addition, integrated postprandial insulin, TG, and VLDL-TG responses to the noon meal were significantly (P less than 0.01-0.001) elevated on the low-fat-high-carbohydrate diet. No dietary-induced changes were noted in either the fasting or postprandial values of glucose cholesterol, chylomicron-TG, low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, HDL2-cholesterol, or HDL3-cholesterol. These results indicate that low-fat-high-carbohydrate diets accentuate the metabolic risk factors for coronary artery disease that are already present in patients with endogenous hypertriglyceridemia.

    View details for Web of Science ID A1983RB28700003

    View details for PubMedID 6346001

  • DOES DAY-LONG ABSOLUTE HYPOINSULINEMIA CHARACTERIZE THE PATIENT WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS METABOLISM-CLINICAL AND EXPERIMENTAL Liu, G., Coulston, A., CHEN, Y. D., Reaven, G. M. 1983; 32 (8): 754-756

    Abstract

    Plasma glucose and insulin responses to a standard oral glucose tolerance test (75 g of glucose) and to mixed meals were compared in 15 normal subjects and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting plasma glucose levels were above 140 mg/dL in all patients with NIDDM, and the two groups were weight matched. Plasma glucose levels were significantly higher in patients with NIDDM throughout the glucose tolerance test, and this was associated with a marked reduction in plasma insulin response. Plasma glucose levels were also higher in patients with NIDDM when measured hourly from 8 AM to 5 PM (mixed meals were consumed at 8 AM and 12 PM), but the plasma insulin concentration of the two groups were similar. Thus, the day-long circulating insulin levels of patients with NIDDM are not reduced. Consequently, these patients cannot be considered to be absolutely insulin deficient.

    View details for Web of Science ID A1983RB28700004

    View details for PubMedID 6346002

  • EVIDENCE OF AN AGE-RELATED DECLINE IN MITOCHONDRIAL GLYCEROPHOSPHATE DEHYDROGENASE-ACTIVITY OF ISOLATED RAT ISLETS METABOLISM-CLINICAL AND EXPERIMENTAL Azhar, S., Ho, H., REAVEN, E. P., Reaven, G. M. 1983; 32 (11): 1019-1021

    Abstract

    The activities of three enzymes--two mitochondrial and one microsomal--were measured in isolated islets of Langerhans from 2-month-old and 12-month-old rats. Mitochondrial glycerophosphate dehydrogenase activity (expressed as nanomoles of iodonitrotetrazolium reduced per minute per milligram of protein), decreased (P less than 0.01) from a mean (+/- SEM) of 73.2 +/- 11.2 (2-month-old) to 34.7 +/- 5.9 (12-month-old). In contrast, activities of neither mitochondrial monoamine oxidase nor microsomal NADH cytochrome-c reductase changed with age. These results demonstrate that the activity of the glycerophosphate shuttle decreases as rats grow older, and it raises the possibility that the consequent difficulty in regenerating cytosolic NAD+ may play a role in the insulin secretory defect associated with aging.

    View details for Web of Science ID A1983RP46600001

    View details for PubMedID 6353135

  • PLASMA-GLUCOSE, INSULIN AND LIPID RESPONSES TO HIGH-CARBOHYDRATE LOW-FAT DIETS IN NORMAL HUMANS METABOLISM-CLINICAL AND EXPERIMENTAL Coulston, A. M., Liu, G. C., Reaven, G. M. 1983; 32 (1): 52-56

    Abstract

    Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical U.S. diets and fed for 10 days each to 11 healthy volunteers. Fasting blood samples were drawn on days 8, 9, and 10 of each dietary period and analyzed for glucose, insulin, cholesterol, triglyceride (TG) and high density lipoprotein (HDL)-cholesterol concentrations. In addition, plasma glucose, insulin and TG concentrations were determined before, and for 3 hr after the noon meal on days 8 and 10. No differences were observed in fasting plasma glucose, insulin or cholesterol concentrations. However, fasting plasma TG levels were significantly elevated on the 60% carbohydrate diet, and HDL-cholesterol concentrations were significantly decreased. Furthermore, the plasma insulin and triglyceride responses to the meal tolerance test during the 60% carbohydrate dietary period were significantly elevated. These results indicate that high-carbohydrate diets lead to changes in insulin, TG, and HDL-cholesterol concentrations which have been associated with an increase in incidence of coronary artery disease.

    View details for Web of Science ID A1983PZ73400010

    View details for PubMedID 6336816

  • SUCROSE-INDUCED INSULIN RESISTANCE IN THE RAT - MODULATION BY EXERCISE AND DIET AMERICAN JOURNAL OF CLINICAL NUTRITION Wright, D. W., Hansen, R. I., Mondon, C. E., Reaven, G. M. 1983; 38 (6): 879-883

    Abstract

    Isocaloric substitution of sucrose for starch results in hyperinsulinemia and deterioration of glucose tolerance, suggesting a loss of insulin sensitivity. In this study we have quantitated the insulin resistance which develops with sucrose feeding, and evaluated the ability of dietary fiber, or an increase in skeletal muscle activity, to inhibit, or even prevent, the detrimental effect of sucrose feeding on in vivo insulin action. Thus, 6-wk-old rats were fed one of the following regimens for three weeks: a 64% cornstarch diet (C), a 32% cornstarch + 32% sucrose diet (S), the (S) diet containing added wheat bran fiber (S/F), and the (S) diet given to rats running spontaneously in exercise wheel cages (S/ET). Insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels approximately 70 microU/ml attained during the continuous infusion of epinephrine (0.08 micrograms/kg/min), propranolol (1.7 micrograms/kg/min), glucose (8 mg/kg/min), and insulin (2.5 mU/kg/min) to each experimental group. The results show that rats fed the S diet had a significant increase (p less than 0.01) in mean (+/- SEM) SSPG concentration compared with rats fed the C diet (255 +/- 14 versus 165 +/- 3 mg/dl). SSPG concentrations, although lower (p less than 0.05) in rats fed S/F (205 +/- 8 mg/dl), were still higher (p less than 0.05) than the C levels (165 +/- 3 mg/dl). However, S/ET completely inhibited the increase in SSPG concentration seen in rats fed S and the values were actually lower (p less than 0.05) than in rats fed C (100 +/- 10 versus 165 +/- 3 mg/dl). In conclusion 1) sucrose feeding results in a loss of insulin sensitivity in normal rats; 2) addition of fiber attenuates, but does not completely prevent, the loss of insulin sensitivity associated with feeding sucrose; 3) exercise training prevents the loss of insulin sensitivity seen in sucrose-fed rats, and actually improves glucose uptake beyond that seen in the control group. These results document the profound effect of environmental factors on in vivo insulin action.

    View details for Web of Science ID A1983RV09200007

    View details for PubMedID 6316774

  • STUDIES OF THE MECHANISM OF FRUCTOSE-INDUCED HYPERTRIGLYCERIDEMIA IN THE RAT METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., CHEN, Y. D., Reaven, G. M. 1982; 31 (11): 1077-1083

    Abstract

    Carbohydrate-induced hypertriglyceridemia is easily produced in the rat, and fructose has been shown to be particularly potent in this regard. In this study we have compared the effects of feeding rats diets high (66% of total calories) in fructose or glucose on various aspects of carbohydrate and lipid metabolism. The results confirmed previous observations that fructose (456 +/- 276 mg/dl) was more potent (p less than 0.001) in raising plasma TG concentration than was glucose (242 +/- 13 mg/dl), and indicated that the difference in magnitude of hypertriglyceridemia produced by the two carbohydrates was closely related to the ability of the test diets to increase VLDL-TG secretion (r = 0.85, p less than 0.001). Both glucose and fructose feeding led to comparable degrees of hyperinsulinemia, and plasma TG concentrations increased before hyperinsulinemia evolved in fructose-fed rats. Therefore, it was concluded that fructose can act directly on the liver to increase VLDL-TG secretion, and that fructose-induced hypertriglyceridemia can occur in the absence of hyperinsulinemia. On the other hand, the rise in plasma TG concentration produced by fructose was reduced dramatically in exercise-trained rats, and this was associated with a decrease in plasma insulin concentration. Based upon these observations, we suggest that fructose feeding produces hypertriglyceridemia by directly stimulating hepatic VLDL-TG secretion, as well as by producing insulin resistance and hyperinsulinemia, and that it is the combined effect of these two separate actions which accounts for the magnitude of fructose-induced hypertriglyceridemia.

    View details for Web of Science ID A1982PQ13100002

    View details for PubMedID 6752639

  • EFFECTS OF MODERATE INCREASES IN DIETARY POLY-UNSATURATED - SATURATED FAT ON PLASMA TRIGLYCERIDE AND CHOLESTEROL LEVELS IN MAN BRITISH JOURNAL OF NUTRITION Kraemer, F. B., Greenfield, M., TOBEY, T. A., Reaven, G. M. 1982; 47 (2): 259-266

    Abstract

    1. The effects of two isoenergetic diets differing only in the values for polyunsaturated: saturated fat (P:S values of 0.2 v. 2.0) were studied in twenty adult human volunteers. 2. A period of 14 d on the high P:S diet failed to produce significant changes in fasting triglyceride levels, though there were individual variations. On the other hand, fasting cholesterol levels dropped by 10% (P less than 0.005). High-density-lipoprotein-cholesterol concentrations were not influenced by changes in the P:S value. 3. Investigations into the mechanism by which changes in the P:S value might affect plasma triglyceride values revealed no consistent effects on very-low-density-lipoprotein kinetics, insulin secretion, insulin sensitivity or free fatty acid concentrations. 4. The results of this study suggest that the largest increase in dietary P:S values that is likely to be obtained on a long-term basis may have only a small effect on plasma triglyceride and cholesterol concentrations.

    View details for Web of Science ID A1982NH29300011

    View details for PubMedID 7066289

  • LIPID-METABOLISM IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS - EFFECT OF GLIPIZIDE THERAPY ARCHIVES OF INTERNAL MEDICINE GREENFIELD, M. S., DOBERNE, L., Rosenthal, M., Vreman, H. J., Reaven, G. M. 1982; 142 (8): 1498-1500

    Abstract

    Plasma lipid concentration and lipoprotein composition were studied before and after several months of glipizide treatment in 23 patients with non-insulin-dependent diabetes mellitus. The mean (+/- SEM) plasma glucose level fell 87 mg/dL, and the fall in plasma glucose concentration was correlated with a reduction in plasma triglyceride, very low-density lipoprotein triglyceride, cholesterol, and low-density lipoprotein cholesterol levels. Furthermore, there was a statistically significant increase in the plasma high-density lipoprotein cholesterol to total cholesterol ratio. Thus, improved diabetic control in patients treated with glipizide with non-insulin-dependent diabetes mellitus leads to changes in lipoprotein metabolism thought to be beneficial in terms of known cardiovascular risk factors.

    View details for Web of Science ID A1982PA57400015

    View details for PubMedID 7103631

  • PRAZOSIN LOWERS PLASMA TRIGLYCERIDE CONCENTRATION IN RATS - A PRELIMINARY-REPORT JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Reaven, G. M., DALLAGLIO, E. 1982; 4: S248-S250

    Abstract

    Prazosin was administered by intraperitoneal injection (0.3 or 3.0 mg/kg) to normal chow-fed male rats for 14 days. Mean +/- SEM plasma triglyceride levels were lower (p less than 0.001) in the prazosin-treated rats (74 +/- 12 mg/dl and 72 +/- 9 mg/dl) than in saline-injected control rats (115 +/- 11 mg/dl). This effect was associated with commensurate reductions in very low density lipoprotein-triglyceride secretion in prazosin-treated rats. No changes were noted in either plasma total or high density lipoprotein cholesterol concentrations. In addition, prazosin was capable of reducing by approximately 50% the elevation in plasma triglyceride concentration produced by a high glucose diet in control rats. The mechanism of the observed effect of prazosin on very low density lipoprotein metabolism in the rat remains to be defined.

    View details for Web of Science ID A1982NL71800014

    View details for PubMedID 6177967

  • DOES INSULIN REMOVAL RATE FROM PLASMA DECLINE WITH AGE DIABETES Reaven, G. M., GREENFIELD, M. S., Mondon, C. E., Rosenthal, M., Wright, D., REAVEN, E. P. 1982; 31 (8): 670-673

    Abstract

    The effect of age on the rate of insulin removal from plasma was studied in both rat and man. The experimental approach was based on measurement of the steady-state plasma insulin concentration achieved during a period in which endogenous insulin secretion was suppressed and exogenous insulin infused. Rats, 1 1/2 and 12 mo of age, were infused with 2.5, 5.0, and 10.0 mU/kg of insulin during a 180-min period in which endogenous insulin secretion was suppressed by epinephrine and propranolol. Steady-state plasma insulin concentrations were approximately twice as high in the older rats at every insulin infusion rate. Similar results were seen in man; significant correlations were observed between height of steady-state plasma insulin concentration and advancing age during infusion of exogenous insulin and suppression of endogenous insulin with either exogenous insulin (r = 0.66, P less than 0.001) or epinephrine and propranolol (r = 0.47, P less than 0.01). Since infusion rates of exogenous insulin were identical in all studies, these results suggest that there is an age-related decrease in insulin catabolism.

    View details for Web of Science ID A1982PA28200002

    View details for PubMedID 6761206

  • MECHANISM OF INSULIN RESISTANCE IN FRUCTOSE-FED RATS METABOLISM-CLINICAL AND EXPERIMENTAL TOBEY, T. A., Mondon, C. E., Zavaroni, I., Reaven, G. M. 1982; 31 (6): 608-612

    Abstract

    Previous results from our laboratory demonstrated that chronic administration of fructose to normal rats led to both hyperinsulinemia and in vivo insulin resistance. To localize the major tissue site of insulin resistance in fructose-fed animals, we compared glucose uptake by perfused hindlimb skeletal muscle and liver from rats fed either a 60% fructose diet or laboratory chow. Glucose uptake by perfused muscle from chow and fructose-fed rats was comparable at perfusate insulin levels of 0 microunit/ml (15.2 versus 15.5 microliters/min/g muscle), 100 microunits/ml (18.3 versus 19.8), and greater than 500 microunits/ml (35.5 versus 33.4). In contrast, glucose outflow from livers of fructose-fed rats was significantly greater (p less than .02) than chow-fed animals perfused in the absence of added insulin (52.1 versus 36.5 mumol/g). Furthermore, the ability of insulin to suppress glucose outflow was less in livers from fructose-fed rats at perfusate insulin level of 165 microunits/ml (13.2 versus 41.4% as well as at insulin concentration greater than 900 microunits/ml, (32.5% versus 62.2%). These findings suggest that the insulin resistance resulting from chronic fructose feeding is due to the diminished ability of insulin to suppress hepatic glucose output, and not to a decrease in insulin-stimulated glucose uptake by muscle.

    View details for Web of Science ID A1982NR25500013

    View details for PubMedID 7043185

  • ROLE OF GLUCAGON AS A CONTRIBUTOR TO GLUCOSE-INTOLERANCE IN ACUTE AND CHRONIC UREMIA METABOLISM-CLINICAL AND EXPERIMENTAL Mondon, C. E., Marcus, R., Reaven, G. M. 1982; 31 (4): 374-379

    Abstract

    It has been suggested that increased sensitivity to glucagon may contribute to glucose intolerance in uremia. In order to evaluate this possibility systematically, we have assessed the effect of glucagon on hepatic glucose outflow, formation of cAMP, and activation of adenylate cyclase by livers obtained from acutely and chronically uremic rats and their respective sham operated controls. Glucagon infused at rates of 6 ng/min/kg rat resulted in minimal and equivalent increases in hepatic glucose outflow and cAMP accumulation when livers from acutely uremic and control rats were perfused for 30 min. However, at glucagon infusion rates of 18 ng/min/kg, glucose efflux from perfused livers of acutely uremic rats was significantly reduced (p less than 0.001) compared to perfused livers of control rats (4.64 +/- .9 vs 12.7 +/- 2.4 mumol/g liver) and cAMP accumulation was also significantly lower (p less than 0.01) (1352 +/- 222 vs 3100 +/- 348 pmol/g liver). Basal adenylate cyclase activity of hepatic membranes obtained from uremic and control rats was similar, and was stimulated by glucagon concentrations ranging from 10(-8) to 10(-6) at equivalent rates in both groups. In livers from chronically uremic rats, glucagon infused at rates of 6 ng/kg/min significantly increased hepatic glucose outflow (32.5 +/- 6.9 mumol/g liver). However this was not greater than that of control animals (37.6 +/- 9.2). Furthermore, cAMP accumulation was significantly lower (p less than .02) in chronically uremic rats than in controls, and activation of adenylate cyclase by glucagon was similar in both groups. These findings indicate that glucagon does not increase glucose efflux, cAMP accumulation or enhance activation of adenylate cyclase by isolated perfused livers from either acutely or chronically uremic rats. Thus, glucose intolerance in uremic rats does not appear to be due to increase hepatic glucose output resulting from increased sensitivity to glucagon.

    View details for Web of Science ID A1982NL01600010

    View details for PubMedID 7078421

  • EFFECT OF AGE ON PROINSULIN AND INSULIN SECRETORY PATTERNS IN ISOLATED RAT ISLETS DIABETES Gold, G., Reaven, G. M., REAVEN, E. P. 1981; 30 (1): 77-82

    View details for Web of Science ID A1981LD92700013

    View details for PubMedID 7014305

  • ASSESSMENT OF INSULIN RESISTANCE WITH THE INSULIN SUPPRESSION TEST AND THE EUGLYCEMIC CLAMP DIABETES GREENFIELD, M. S., DOBERNE, L., Kraemer, F., TOBEY, T., Reaven, G. 1981; 30 (5): 387-392

    Abstract

    Insulin resistance was quantified with two different methods in 30 subjects with varying degrees of glucose tolerance. One method, the insulin suppression test, is performed by continuously infusing epinephrine, propranolol, insulin, and glucose. Epinephrine and propranolol suppress endogenous insulin release, and steady-state plasma levels of exogenous insulin and glucose are reached in all individuals. Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance. The other method, the euglycemic clamp technique, produces a steady-state level of exogenous hyperinsulinemia by means of a primed and continuous insulin infusion. Glucose is also infused at a rate sufficient to prevent an insulin-induced fall in glucose concentration, and the amount of glucose required to maintain the basal plasma glucose level provides the estimates of insulin resistance. The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of assessing insulin resistance indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance. These results serve to further emphasize the importance of insulin resistance in the pathogenesis of hyperglycemia in type II diabetes.

    View details for Web of Science ID A1981LP16100005

    View details for PubMedID 7014307

  • EFFECT OF VARIATIONS IN ISLET SIZE AND SHAPE ON GLUCOSE-STIMULATED INSULIN-SECRETION HORMONE AND METABOLIC RESEARCH REAVEN, E. P., Gold, G., Walker, W., Reaven, G. M. 1981; 13 (12): 673-674

    Abstract

    The present study considers the effects of differences islet size and shape on in vitro glucose-stimulated insulin secretion. Islets were obtained from young rats and rapidly sorted into different size categories before incubation with 16.7 mM glucose. Subsequently, the diameters of each islet were measured and estimates of surface area and volume, assuming various spheroidal or ellipsoidal shapes, were obtained for each islet. These various figures were correlated with the amount of insulin secreted from the same islets and a regression curve was generated for each different islet shape. The results indicate that insulin secretion rates increased directly as a function of islet size (volume or surface area), regardless of islet shape (r = 0.78, p less than .01); thus, islet size is of major importance in predicting insulin secretion and studies utilizing isolated islets should be normalized for this factor. Measurements of islet diameter provide an easy solution to this problem.

    View details for Web of Science ID A1981MV77400006

    View details for PubMedID 7033094

  • RELATIONSHIP BETWEEN INSULIN RESISTANCE, INSULIN-SECRETION, VERY LOW-DENSITY LIPOPROTEIN KINETICS, AND PLASMA TRIGLYCERIDE LEVELS IN NORMOTRIGLYCERIDEMIC MAN METABOLISM-CLINICAL AND EXPERIMENTAL TOBEY, T. A., Greenfield, M., Kraemer, F., Reaven, G. M. 1981; 30 (2): 165-171

    Abstract

    We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations less than 175 mg/dl. The results demonstrate the following degree of correlation: insulin resistance (Formula: see text) insulin response to food (Formula: see text) VLDL-TG secretion rate (Formula: see text) plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.

    View details for Web of Science ID A1981LE34800011

    View details for PubMedID 7007804

  • PREVENTION OF AGE-RELATED HYPERTRIGLYCERIDEMIA BY CALORIC RESTRICTION AND EXERCISE TRAINING IN THE RAT METABOLISM-CLINICAL AND EXPERIMENTAL Reaven, G. M., REAVEN, E. P. 1981; 30 (10): 982-986

    Abstract

    Plasma triglyceride concentrations were determined in three experimental groups of rats as they grew from 1 1/2-12 mo of age. One group was kept sedentary and allowed food ad lib (control), the second group was allowed to eat and exercise in a running wheel ad lib, and the third calorically-restricted in order to maintain weight equal to that of the exercising rats. The exercise-trained and calorically-restricted rats gained less weight than did the control rats, and the age-related rise in plasma triglyceride concentration in control rats was totally abolished in the other two groups. In addition, exercise training and caloric restriction inhibited the increase in plasma insulin concentrations noted to occur with age in the control rats. These data indicate that there are two effective ways to prevent the development of hypertriglyceridemia that occurs with age in otherwise normal rats.

    View details for Web of Science ID A1981MJ20100007

    View details for PubMedID 7278651

  • AGE-RELATED-CHANGES IN VERY LOW-DENSITY LIPOPROTEIN METABOLISM IN NORMAL RATS METABOLISM-CLINICAL AND EXPERIMENTAL TOBEY, T. A., Mondon, C. E., Reaven, G. M. 1981; 30 (6): 583-587

    Abstract

    Plasma triglyceride (TG) concentrations rise with age, and we have carried out studies of very low density lipoprotein (VLDL) kinetics in the rat in an effort to define the cause of this phenomenon. Efficiency of VLDL-TG secretion by perfused rat liver decreases at rats age from 1 1/2-12 mo. However, this is compensated for by an increase in liver weight, and VLDL-TG secretion per perfused liver does not change with age. In contrast, total VLDL-TG secretion by the interact rat increases significantly as rats grow from 1 1/2-12 mo of age, and this increase is proportionate to the age-related increase in liver weight. The ability of the older rat to maintain VLDL-TG secretion proportionate to liver weight is most likely due to the concomitant rise in plasma free fatty acid concentration that occurs with age. However, the efficiency with which VLDL-TG is removed from plasma is not maintained as rats age. Consequently, the age-related rise in plasma TG concentration is due to an increase in VLDL-TG secretion proportionate to secretory mass, accompanied by a relative decline in efficiency of VLDL-TG removal from plasma.

    View details for Web of Science ID A1981LS13200010

    View details for PubMedID 7231194

  • ABILITY OF EXERCISE TO INHIBIT CARBOHYDRATE-INDUCED HYPERTRIGLYCERIDEMIA IN RATS METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., CHEN, Y. D., Mondon, C. E., Reaven, G. M. 1981; 30 (5): 476-480

    Abstract

    The ability of spontaneous running to prevent carbohydrate-induced hypertriglyceridemia was studied in young, nonobese rats. Exercise-trained and sedentary rats were fed a diet consisting of (as percent total calories) 12% fat, 22% protein, and 66% carbohydrate. The source of the carbohydrate was varied, and experiments were carried out with sucrose and glucose as the sole dietary carbohydrate. Plasma triglyceride (TG) levels rose in response to both forms of dietary carbohydrate in both sedentary and exercise-trained rats, but the magnitude of the elevation was greatly attenuated in the exercise-trained group. Plasma insulin concentrations were also significantly lower in exercise-trained rats. Measurements of hepatic very low density lipoprotein (VLDL)-TG secretion rate and adipose tissue lipoprotein lipase (LPL) activity were made in an effort to determine how exercise-training prevented the development of carbohydrate-induced hypertriglyceridemia. The results of these studies indicated that perfused livers of exercise-trained rats secreted significantly less VLDL-TG, whereas adipose tissue LPL activity of the two groups was similar. On the basis of these results, it is postulated that the ability of exercise-training to inhibit carbohydrate-induced hypertriglyceridemia is due to an increase in insulin sensitivity resulting from chronic exercise. As a result, the postprandial insulin responses to high carbohydrate diets would be relatively reduced in exercise-trained rats, leading to decreased hepatic VLD-TG secretion, and lower plasma triglyceride concentrations.

    View details for Web of Science ID A1981LN73400011

    View details for PubMedID 7015069

  • INHIBITION OF CARBOHYDRATE-INDUCED HYPERTRIGLYCERIDEMIA BY A DISACCHARIDASE INHIBITOR METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Reaven, G. M. 1981; 30 (4): 417-420

    Abstract

    The ability of an inhibitor of intestinal alpha-glucosiadase activity to prevent sucrose-induced hypertriglyceridemia was studied in nonobese rats. The results indicated that plasma triglyceride levels were approximately twice as high in untreated rats, and the reduction in plasma triglyceride levels of drug-treated rats was associated with lowered very low density lipoprotein-triglyceride secretion rates and plasma insulin levels. Since these changes could be produced with an amount of glucosidase inhibitor which did not prevent normal rate of weight gain, the possibility arises that this approach may be useful in the treatment of various hypertriglyceridemic states in man. Finally, the observation that the fall in plasma TG concentration was associated with a fall in plasma insulin concentration provides further evidence for the existence of a causal relationship between the two variables.

    View details for Web of Science ID A1981LJ56900018

    View details for PubMedID 7010078

  • EVIDENCE THAT MICROTUBULES PLAY A PERMISSIVE ROLE IN HEPATOCYTE VERY LOW-DENSITY LIPOPROTEIN SECRETION JOURNAL OF CELL BIOLOGY REAVEN, E. P., Reaven, G. M. 1980; 84 (1): 28-39

    Abstract

    To determine whether a minimum number of assembled microtubules is required for very low density lipoprotein (VLDL) triglyceride TG) secretion in hepatocytes, antimicrotubule drugs of different concentrations were given to rats. Hepatic VLDL-TG release was subsequently measured by a liver perfusion system, and hepatocyte ultrastructural changes were analyzed by quantitative ultrastructural methods. The results demonstrate a tight coupling between the reduction in hepatocyte microtubule content and the reduction in hepatic VLDL-TG secretion which is related to the dose of colchicine or vinblastine administered. The various estimates imply that a minimum number of microtubules is necessary for hepatic VLDL secretion to proceed normally and that hepatic VLDL secretion rates reach their nadir (10--30% of control) when microtubules comprise less than 0.005% of the cytoplasm (or less than 10% of control values) when microtubules comprise less than 0.005% of the cytoplasm (or less than 10% of control values). At this point, hepatocyte Golgi complexes are also greatly altered; Golgi complexes with recognizable dictyosomal membranes are reduced to 15% of control values and the region is filled with large numbers of electron-dense bodies which appear to be lysosomes in the process of digesting VLDL. There is a predilection for the remaining Golgi complexes to be associated with a few segments of microtubules, even when no microtubules can be measured in random samplings of hepatocytes. Clusters of vacuoles containing VLDL are also present throughout the cytoplasm; the limiting membranes of 25% of these vacuoles are studded with ribosomes. These findings demonstrate that the administration of antimicrotubule agents results in decreases in hepatic VLDL-TG secretion which are associated with loss of microtubules and alteration of existing Golgi complexes.

    View details for Web of Science ID A1980HY78700003

    View details for PubMedID 7350169

  • EFFECT OF AGE ON PLASMA TRIGLYCERIDE CONCENTRATIONS IN MAN METABOLISM-CLINICAL AND EXPERIMENTAL GREENFIELD, M. S., Kraemer, F., TOBEY, T., Reaven, G. 1980; 29 (11): 1095-1099

    Abstract

    Plasma triglyceride (TG) concentrations increase with advancing age. To determine if this phenomenon is due to age per se or to age-related changes in other metabolic variables, determination of fasting plasma TG, glucose, insulin, and free fatty acid (FFA) concentrations, as well as body mass index (BMI), were made on 167 normal subjects from 18 to 77 yr of age. Significant simple correlation coefficients (r) were found between TG concentrations and age (0.47), BMI (0.39) and fasting plasma glucose (0.40), insulin (0.24), and FFA (0.20) concentrations. Multiple regression analysis was used to determine the total amount of variability in TG concentration that could be accounted for by the combination of the examined metabolic parameters. A highly significant (p < 0.0001) total correlation of 0.57 was obtained, indicating that these variables could account for approximately one-third of the total variances. Partial correlation analysis (fixing four of the five variables) yielded a correlation coefficient of 0.35 (p < 0.001) between age and fasting TG concentration. Hence, age per se, or an age-dependent phenomenon, appears to be an independent factor with a role in determining plasma TG concentrations.

    View details for Web of Science ID A1980KR16400014

    View details for PubMedID 7001176

  • EFFECT OF SOURCE OF DIETARY CARBOHYDRATE ON PLASMA-GLUCOSE AND INSULIN RESPONSES TO TEST MEALS IN NORMAL SUBJECTS AMERICAN JOURNAL OF CLINICAL NUTRITION Coulston, A., Greenfield, M., Kraemer, F., TOBEY, T., Reaven, G. 1980; 33 (6): 1279-1282

    Abstract

    Plasma glucose and insulin responses were measured in 22 subjects after two meal tolerance tests that varied only in the food source of carbohydrate. Each meal contained 45% carbohydrate, 15% protein, and 40% fat and provided 40% of calculated daily caloric requirement. The meals elicited a similar glucose response; however, the insulin response was significantly lower when rice and corn supplied the carbohydrate as compared to potato and gelatin. The total insulin response, calculated as area under the response curve, was 60% (P less than 0.001) greater in the meal with potato and gelatin versus the rice and corn meal.

    View details for Web of Science ID A1980JW45400015

    View details for PubMedID 6992561

  • SITE OF ENHANCED INSULIN SENSITIVITY IN EXERCISE-TRAINED RATS AT REST AMERICAN JOURNAL OF PHYSIOLOGY Mondon, C. E., DOLKAS, C. B., Reaven, G. M. 1980; 239 (3): E169-E177

    Abstract

    Spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin and lower plasma insulin levels after oral glucose than sedentary control rats. To assess insulin sensitivity of specific organs, glucose uptake by perfused hindlimb muscle and liver from resting exercise-trained rats was compared with perfused organs from control rats. Glucose uptake, assessed by metabolic clearance formulas, was 17% faster in hindlimbs from exercise-trained rats when perfused without added insulin and 43% faster at perfusate insulin levels of 40 microU/ml. After an overnight fast, glucose clearance in exercise-trained hindlimbs increased over controls by 57% in the basal state and by 97% at low perfusate levels. In contrast, glucose clearance by livers from both fed and fasted exercise-trained rats was less than one-half that of livers from control rats. These results suggest that skeletal muscle, and not liver, is the organ primarily responsible for the increased sensitivity to insulin-induced glucose uptake with exercise training and that this response is enhanced after overnight fasting.

    View details for Web of Science ID A1980KJ26000011

    View details for PubMedID 7001913

  • EFFECT OF AGE ON LEUCINE-INDUCED INSULIN-SECRETION BY THE BETA-CELL JOURNALS OF GERONTOLOGY Reaven, E., Gold, G., Reaven, G. 1980; 35 (3): 324-328

    Abstract

    We have previously shown that aging is associated with a marked decrease in glucose-stimulated insulin release by the beta-cell. To determine whether this age-related defect occurs with other insulin secretagogues, we have investigated leucine-stimulated insulin release. Islets of Langerhans were isolated from 2- and 12-month-old rats, and incubated with 5-20 mM 5-20 mM leucine or with 16.7 mM glucose. Islets from 12-month-old rats showed a decline in rate of leucine-induced secretion as compared to islets of 2-month-old donors (i.e., mean (+/- SEM) insulin secretion at 20 mM leucine was 0.79 (+/- 0.06) and 1.17 (+/- 0.09) microU/min/islet), respectively for 12- and 2-month-old rats. beta-cell number is increased in islets from 12-month-old donors, and when this increase is taken into account, the average beta-cell from 12-month-old donors secretes only one-half the rate of beta-cells from 2-month-old donors. These findings are comparable to those seen after glucose-stimulation, and emphasize the potential global nature of the age-related defect in beta-cell function.

    View details for Web of Science ID A1980JR32200001

    View details for PubMedID 6997361

  • EFFECTS OF AGE ON VARIOUS ASPECTS OF GLUCOSE AND INSULIN METABOLISM MOLECULAR AND CELLULAR BIOCHEMISTRY Reaven, G. M., REAVEN, E. P. 1980; 31 (1): 37-47

    Abstract

    Age is known to be associated with the development of glucose intolerance. In this review an effort has been made to differentiate between the effects of age per se on glucose tolerance, as distinguished from those of such age-related variables as obesity, diet, development of frank diabetes, etc. At the same time, an attempt was made to evaluate the evidence implicating abnormalities of insulin secretion and/or insulin action in the development of glucose intolerance with age. It is concluded that the questions being asked are far from simple, and that available data do not provide unequivocal answers.

    View details for Web of Science ID A1980KB44300003

    View details for PubMedID 6993916

  • EFFECT OF AGE ON GLUCOSE-OXIDATION BY ISOLATED RAT ISLETS DIABETOLOGIA Reaven, G. M., Reaven, P. D. 1980; 18 (1): 69-71

    Abstract

    Islets were isolated from pancreases of 2-month and 12-month-old rats, and the oxidation of 14C-glucose to 14CO2 determined at various medium D-glucose concentration. Islets from 12-month-old rats oxidized significantly less glucose than those from 2-month-old rats at glucose concentrations of 150, 300, and 450 mg/dl, and this was true when islets were selected by hand or by Ficoll density gradient separation. The effect of age on glucose oxidation was seen when islets were incubated with [U-14C], [1-14C], or [6-14C] glucose. The results raise the possibility that previously reported age-related defects in glucose-stimulated insulin secretion may be secondary to the effect of age on islet glucose catabolism.

    View details for Web of Science ID A1980JC82800013

    View details for PubMedID 6988268

  • EFFECT OF FRUCTOSE FEEDING ON INSULIN-SECRETION AND INSULIN ACTION IN THE RAT METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Sander, S., Scott, S., Reaven, G. M. 1980; 29 (10): 970-973

    Abstract

    Insulin secretion and insulin action were studied in rats fed either a diet containing (as percent of calories) 66% fructose, 22% protein, and 12% fat, or standard rat chow (60% vegetable starch, 29% protein, 11% fat) for 7 days. Plasma glucose concentration following either an oral glucose or fructose load (180 mg/100 g body weight) were slightly higher in the fructose-fed rats, and this was associated with a much greater elevation of plasma insulin concentrations. The ability of insulin to stimulate disposal of glucose load was determined during the continuous infusion of epinephrine, propranolol, glucose, and insulin. Under these condtions the steady state plasma insulin levels were the same in the two groups of rats, whereas the steady state plasma glucose levels were almost twice as high in the fructose fed rats. Thus, fructose feeding for 7 days resulted in an increase in the insulin response to an oral carbohydrate challenge, as well as to a loss of normal insulin sensitivity.

    View details for Web of Science ID A1980KM49500011

    View details for PubMedID 6999292

  • EVIDENCE FOR MULTIPLE CAUSALITY IN THE DEVELOPMENT OF DIABETIC HYPERTRIGLYCERIDEMIA DIABETOLOGIA Weiland, D., Mondon, C. E., Reaven, G. M. 1980; 18 (4): 335-340

    Abstract

    The relationship between varying degrees of insulin deficiency and hypertriglyceridaemia in rats have been examined. Rats were studied 7--10 days after injection with streptozotocin, and plasma glucose concentrations used to classify rats as having either moderate (200--350 mg/dl) or severe diabetes (< 350 mg/dl). A 2- to 3-fold rise in plasma triglyceride (TG) concentration developed in six week old insulin deficient rats associated with elevated plasma non esterified fatty acid (NEFA) concentrations and decreased very low density lipoprotein secretion. Perfused liver from six week old rats with either moderate or severe diabetes were incapable of increasing hepatic TG secretion when perfusate NEFA concentrations were raised from 0.4 to 1.8 mmol/l. In one year old, spontaneously obese rats, an equivalent degree of hypertriglyceridaemia could be produced with a lesser degree of insulin deficiency, and in this instance very low density lipoprotein secretion was increased over control values. Hepatic TG secretion by perfused livers from these rats with moderate diabetes approximately doubled when perfusate NEFA condentration was raised from 0.40 to 0.85 mmol/l. These results emphasize the complex causality of diabetic hypertriglyeridaemia in situations characterised by comparable degrees of fasting hyperglycaemia.

    View details for Web of Science ID A1980JN68900014

    View details for PubMedID 6998805

  • EFFECT OF AGE ON GLUCOSE-STIMULATED INSULIN RELEASE BY THE BETA-CELL OF THE RAT JOURNAL OF CLINICAL INVESTIGATION REAVEN, E. P., Gold, G., Reaven, G. M. 1979; 64 (2): 591-599

    Abstract

    To assess the effect of age on beta-cell insulin release, collagenase-isolated islets of Langerhans were obtained from rats aged 2--18 mo and incubated with increasing concentrations of glucose. Similar islets were analyzed for insulin content or subjected to morphometric measurements to identify both the number of beta-cells and the volume of beta-granules per islet. In parallel studies, the islet content of intact pancreata was also determined. The results showed that beta-cell number increased from 2,300 t0 5,000 cells as rats aged from 2 to 18 mo and islet insulin content doubled. However, glucose-stimulated insulin release decreased progressively with age, and this was especially striking when considered in terms of the increase in number of beta-cells/islet; e.g., mean (+/- SEM) insulin secretion (nanounits per minute per beta-cell) of islets incubated with 450 mg/dl of glucose was 1.3 (+/- 0.02), 1.0 (+/- 0.1), 0.4 (+/- 0.05), and 0.3 (+/- 0.01), respectively for 2-, 6-, 12-, and 18-mo-old rats. Thus, insulin secretion per beta-cell was decreased, despite increased stores of insulin per cell. These findings demonstrate that the aging process leads to a profound defect in glucose-stimulated insulin release from the beta-cell. Whether this is a global secretory defect, or solely a failure of the beta-cell to respond to glucose, remains to be defined.

    View details for Web of Science ID A1979HE44400030

    View details for PubMedID 379046

  • CHARACTERIZATION OF A MODEL OF DIETARY-INDUCED HYPERTRIGLYCERIDEMIA IN YOUNG, NON-OBESE RATS JOURNAL OF LIPID RESEARCH Reaven, G. M., RISSER, T. R., CHEN, Y. D., REAVEN, E. P. 1979; 20 (3): 371-378

    Abstract

    Healthy, nonobese, young rats developed hypertriglyceridemia (mean triglyceride levels of 250 mg/dl) following consumption of a sucrose-lard diet. The hypertriglyceridemia was apparent three days after start of the diet and persisted throughout the 4-week experimental period. Body weight, liver weight, and serum glucose levels were similar in animals eating either the sucrose-lard diet or standard rat chow. On the other hand, serum free fatty acid levels were slightly increased and serum insulin levels were substantially increased in animals eating the sucrose-lard diet. Determination of very low density lipoprotein turnover revealed that total triglyceride secretion in rats eating the sucrose-lard diet was significantly (P < 0.01) increased over that of rats eating standard chow. Direct measurement of hepatic and intestinal very low density lipoprotein secretion indicated that the observed rise in total triglyceride secretion was secondary to increased secretion of very low density lipoproteins by the liver. Finally, lipoprotein lipase activity of adipose tissue from rats eating the sucrose-lard diet was equal to, or greater than (depending upon sampling time), the activity of the enzyme from adipose tissue of rats eating the control diet. These data indicate that young, nonobese, rats develop hypertriglyceridemia when they ingest a sucrose-lard diet, and that the rise in plasma triglyceride levels results from an increase in hepatic very low density lipoprotein secretion. The dietary-induced hypertriglyceridemia is associated with elevated serum insulin levels, and, as such, may provide a useful animal model to use in studies aimed at defining the pathogenesis of endogenous hypertriglyceridemia in man.-Reaven, G. M., T. R. Risser, Y-D. I. Chen, and E. P. Reaven. Characterization of a model of dietary-induced hypertriglyceridemia in young, nonobese rats.

    View details for Web of Science ID A1979GP24200008

    View details for PubMedID 221604

  • NUTRITIONAL MANAGEMENT OF DIABETES MEDICAL CLINICS OF NORTH AMERICA Reaven, G. M., Coulston, A. M., Marcus, R. A. 1979; 63 (5): 927-943

    View details for Web of Science ID A1979JD11500003

    View details for PubMedID 388113

  • PROLONGATION OF INSULIN REMOVAL BY PERFUSED LIVER FROM SPONTANEOUSLY OBESE RATS DIABETOLOGIA Weiland, D., Mondon, C. E., Reaven, G. M. 1979; 16 (3): 173-177

    View details for Web of Science ID A1979GQ94000005

    View details for PubMedID 428687

  • INTESTINAL VERY LOW-DENSITY LIPOPROTEIN SECRETION IN INSULIN-DEFICIENT RATS DIABETES RISSER, T. R., Reaven, G. M., REAVEN, E. P. 1978; 27 (9): 902-908

    View details for Web of Science ID A1978FQ57000004

    View details for PubMedID 211062

  • INTESTINAL CONTRIBUTION TO SECRETION OF VERY LOW-DENSITY LIPOPROTEINS INTO PLASMA AMERICAN JOURNAL OF PHYSIOLOGY RISSER, T. R., Reaven, G. M., REAVEN, E. P. 1978; 234 (3): E277-E281

    Abstract

    To resolve the question of the magnitude of the intestine's contribution to circulating very low density lipoproteins (VLDL), measurements of intestinal, hepatic, and total VLDL--triglyceride were made on the same animals or on animals studied under comparable conditions. Animals were examined in the fasted state and during infusion of a fat-free meal. Intestinal VLDL secretion was determined through timed collections of lymph from the mesenteric lymph duct; hepatic and total VLDL secretion rates were estimated by the accumulation of plasma VLDL after injections of Triton WR 1339. Results indicate that the intestine contributes only a minor portion (11%) of the amount of triglyceride entering into the plasma compartment in the fasted state. Although intestinal triglyceride production is increased by 50% (p less than 0.01) in fed rats, the overall contribution of the intestine is not significantly altered in fed rats and represents only 14--17% of total body VLDL secretion. Thus, although intestinal VLDL secretion can be modified experimentally, its total impact on endogenous triglyceride production in normotriglyceridemic rats is small.

    View details for Web of Science ID A1978ES25600021

    View details for PubMedID 204197

  • INSULIN RESPONSIVENESS OF ISOLATED PERFUSED LIVERS FROM RATS WITH STREPTOZOTOCIN INDUCED DIABETES HORMONE AND METABOLIC RESEARCH WARTH, D. C., Mondon, C. E., Reaven, G. M. 1978; 10 (2): 110-114

    Abstract

    The ability of insulin to inhibit efflux of potassium (K) and amino acid nitrogen (AAN) from perfused livers of normal and insulin deficient rats was studied. Two groups of rats with different degrees of insulin deficiency were produced by injecting varying amounts of streptozotocin. One group, classified as being moderately diabetic (MD), had fasting plasma glucose levels between 235--425 mg%, while the other group, whose plasma glucose levels greater than 425 mg%, were considered to have severe diabetes (SD). Two other groups of rats were food restricted in order to attain body weights comparable to the two groups of diabetic rats, and livers from these animals were used for control perfusions. The results indicated that the ability of insulin to suppress efflux of K and AAN from perfused livers of rats with MD was comparable to that seen in control perfusions. On the other hand, insulin could not suppress the efflux of either K or AAN from perfused livers of rats with SD. These results indicate that normal hepatic responsiveness to insulin can be lost secondary to the production of insulin deficiency.

    View details for Web of Science ID A1978EW28000006

    View details for PubMedID 148426

  • SITE OF INSULIN RESISTANCE IN ACUTE UREMIA DIABETES Mondon, C. E., DOLKAS, C. B., Reaven, G. M. 1978; 27 (5): 571-576

    Abstract

    In order to define the mechanism of glucose intolerance in acutely uremic rats, various studies were carried out 24 hours after bilateral nephrectomy. Glucose removal following intravenous glucose was significantly (p is less than 0.001) decreased in uremic rats compared with sham-operated rats (k = 2.1 +/- 0.03 per cent vs. 5.1 +/- 0.2 per cent). This deterioration in glucose tolerance was associated with higher insulin levels in uremic rats from one to 40 minutes after glucose administration, suggesting that insulin resistance accounted for the decrease in glucose removal by uremic rats. To identify the site of the insulin resistance, we compared the ability of insulin to enhance net glucose uptake by isolated perfused liver and muscle (hindlimb) preparations obtained from uremic and sham-operated rats. Insulin suppressed glucose outflow from perfused livers of uremic rats at least as well as it did from livers of sham-operated rats, and suppression occurred at both maximal ( greater than 600 micromicron./ml.) and threshold (75 micromicron./ml.) perfusate insulin levels. In contrast, there was a significant decrease in the ability of insulin (mean perfusate level = 225 micromicron./ml.) to enhance glucose uptake of perfused hindlimbs of uremic as compared with sham-operated rats. These results suggest that the insulin resistance of acute uremia may be due primarily to decreased insulin-mediated uptake of glucose by skeletal muscle without any decrease in sensitivity of the liver to insulin.

    View details for Web of Science ID A1978EZ38500008

    View details for PubMedID 648747

  • EFFECT OF ACUTE UREMIA ON INSULIN REMOVAL BY ISOLATED PERFUSED RAT-LIVER AND MUSCLE METABOLISM-CLINICAL AND EXPERIMENTAL Mondon, C. E., DOLKAS, C. B., Reaven, G. M. 1978; 27 (2): 133-142

    View details for Web of Science ID A1978EL77800002

    View details for PubMedID 622045

  • DISSOCIATION BETWEEN RATE OF HEPATIC LIPOPROTEIN SECRETION AND HEPATOCYTE MICROTUBULE CONTENT JOURNAL OF CELL BIOLOGY REAVEN, E. P., Reaven, G. M. 1978; 77 (3): 735-742

    Abstract

    The fact that colchicines inhibits hepatic secretion of very low density lipoprotein (VLDL) particles has been interpreted to mean that microtubules are involved in hepatic VLDL secretion. To further define this relationship, we have attempted to see if changes in hepatic VLDL secretion are associated with changes in hepatocyte microtubule or tubulin content. Accordingly, hepatic secretion of VLDL was increased in rats, and the hepatocyte content of both microtubules (using quantitative morphometric methods) and tubulin (using a time-decay colchicine binding assay) was determined. In acute experiments, VLDL secretion was increased by perfusion of isolated rat livers for 2 h with varying concentrations of free fatty acids (FFA). Results indicate that hepatic VLDL triglyceride (TG) secretion at perfusate FFA levels of 0.7 muEq/ml is threefold greater (P < 0.01) than when livers are perfused without added FFA. However, no differences are observed in the content of microtubules in these livers: specifically, microtubules occupy 0.029 percent of hepatocyte cytoplasm in livers perfused without FFA and 0.030 percent of cytoplasm in livers perfused with FFA. In chronic experiments, rats were fed for 1 wk with either standard rat chow or a hyperlipidemic (sucrose/lard) diet. With the experimental diet, plasma triglyceride levels increase threefold over controls, and liver VLDL-TG production, as determined by [(3)H]glycerol turnover studies, is 55 percent greater (P < 0.01) than controls. However, microtubules occupy 0.027 percent of the cytoplasm of hepatocyte cytoplasm whether rats are on standard or hyperlipidemic diets. Furthermore, the tubulin content of isolated hepatocytes does change, and represents 1 percent of hepatocyte soluble protein, irrespective of diet. These results suggest that increases in hepatic VLDL secretion can occur without any demonstrable change in hepatocyte assembled microtubule or tubulin content, and raise questions as to the role played by microtubules in hepatic VLDL secretion.

    View details for Web of Science ID A1978FA89800012

    View details for PubMedID 210192

  • DEVELOPMENT OF FASTING HYPERGLYCEMIA IN UREMIC RATS METABOLISM-CLINICAL AND EXPERIMENTAL Reaven, G. M., Reaven, P. D. 1977; 26 (11): 1251-1256

    Abstract

    Rats which had been fasted for the previous 24 hr were subjected to either sham surgery, bilateral nephrectomy, or bilateral ureterotomy. The fast was continued for another 24 hr before the animals were decapitated and blood was obtained for determination of serum glucose, insulin, and urea nitrogen levels. A moderate but statistically significant (p less than 0.02) fall in serum glucose levels occurred in rats made uremic by bilateral nephrectomy. In contrast, rats made equally uremic by bilateral ureterotomy developed a significant (p less than 0.001) elevation of both serum glucose and insulin levels. The combination of hyperglycemia and hyperinsulinemia suggested that insulin resistance had developed in these rats, and this was confirmed by demonstrating that the hypoglycemic effect of exogenously administered insulin was attenuated in rats following bilateral ureterotomy as compared to sham-operated rats. Unilateral ureterotomy did not lead to the same metabolic response, and the difference in serum glucose levels between sham-operated and bilaterally ureterotomized rats disappeared when a 5% glucose solution was substituted for tap water as the rat's drinking water. It is suggested that the coexistence of fasting and metabolic acidosis led to increased renal gluconeogenesis in rats subjected to bilateral ureterotomy, and the combination of increased renal glucose production and insulin resistance was responsible for the development of fasting hyperglycemia.

    View details for Web of Science ID A1977DZ83100010

    View details for PubMedID 909400

  • EFFECTS OF CHRONIC UREMIA AND DEXAMETHASONE ON TRIGLYCERIDE KINETICS IN RAT METABOLISM-CLINICAL AND EXPERIMENTAL GREGG, R. C., Diamond, A., Mondon, C. E., Reaven, G. M. 1977; 26 (8): 875-882

    View details for Web of Science ID A1977DQ09200006

    View details for PubMedID 195180

  • HYPERCALCEMIA IN ACUTE UREMIA AND FOLLOWING CITRIC-ACID ADMINISTRATION - DIFFERENTIAL EFFECT ON PARATHYROID-GLAND MICROTUBULE CONTENT METABOLISM-CLINICAL AND EXPERIMENTAL Reaven, G. M., Reaven, P. D., REAVEN, E. P. 1976; 25 (2): 203-209

    Abstract

    Hypercalcemia, which occurs 4 hr after bilateral nephrectomy in normal rats, is not seen 4 hr after either bilateral ureterotomy or sham surgery. These results indicate that it is loss of renal mass per se, not the uremic syndrome, which is responsible for the hypercalcemia. Citric acid levels also increase 4 hr after nephrectomy, and a degree of hypercalcemia and hypercitricemia comparable to that which follows nephrectomy can be produced by administration of citric acid to normal rats. In an attempt to evaluate the role of the parathyroid gland in the development of hypercalcemia in these two situations, the microtubule content of parathyroid gland chief cells was determined by ultrastructural sterologic techniques 4 hr after either bilateral nephrectomy or citric acid administration. The results of these measurements indicate that parathyroid gland chief cell microtubule content increases after citric acid administration but not following bilateral nephrectomy. The significance of these results is not clear. However, since a previous study has suggested a correlation between increased microtubule content and increased secretory status in the chief cell, one may speculate that increased microtubule content resulting from citric acid administration may also be associated with increased parathyroid hormone secretion. By this formulation, citric acid-induced hypercalcemia would be secondary to increased parathyroid hormone secretion, but the transient hypercalcemia that occurs after nephrectomy would take place in the absence of an increase in parathyroid hormone secretion. In this latter instance, it is possible that loss of the kidney, a major site of parathyroid hormone removal from plasma, leads to an increase in circulating parathyroid hormone level, and hypercalcemia, in the absence of an increase in hormone secretion rate.

    View details for Web of Science ID A1976BF05400010

    View details for PubMedID 1250158

  • QUANTITATIVE ULTRASTRUCTURAL STUDY OF MICROTUBULE CONTENT AND SECRETORY GRANULE ACCUMULATION IN PARATHYROID-GLANDS OF PHOSPHATE-TREATED AND COLCHICINE-TREATED RATS JOURNAL OF CLINICAL INVESTIGATION REAVEN, E. P., Reaven, G. M. 1975; 56 (1): 49-55

    Abstract

    Microtubule involvement in secretory events of the parathyroid gland was investigated in rats treated with colchicine and/or phosphorus, agents which have been shown to modify parathyroid secretion. Quantitative ultrastructural techniques were used in an effort to assess the cytoplasmic microtubule and secretory granule content of chief cells 3 h after treatment, when hypocalcemia was well established. After cochicine administration, the chief cells appeared to have lost all assembled microtubules and accumulated greater than normal amounts of cytoplasmic secretory granules. On the other hand, phosphorus treatment was associated with increased microtubule content although the cytoplasmic content of secretory granules remained unchanged. When colchicine and phosphorus were given concomitantly, microtubules were again absent, but the secretory granule content of the cells was markedly increased. These data provide direct evidence that colchicine disrupts assembled microtubules in chief cells of rat parathyroids; the consequence of this effect appears to be a blockage of hormone release which is reflected in the accumulation of secretory granules in the cell. The fact that microtubules also show a significant increase in content when hormone release from chief cells is presumed to increase, suggests that microtubules may participate in the physiological control of parathyroid hormone secretion.

    View details for Web of Science ID A1975AG92300007

    View details for PubMedID 1141440

  • INSULIN SENSITIVITY OF ISOLATED PERFUSED RAT-LIVER DIABETES Mondon, C. E., DOLKAS, C. B., Olefsky, J. M., Reaven, G. M. 1975; 24 (2): 225-229

    Abstract

    The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6, 9, 16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 muU/ml., respectively. Since the portal vein insulin concentration in the intact rat averaged 48 muU/ml. after a twenty-six-hour fast and 125 muU/ml. two hours after removal of food, the studies were conducted at insulin levels within the physiological range. The effect of each insulin concentration on the net accumulation of K+, AMINO ACID NITROGEN, UREA NITROGEN AND GLUCOSE IN The perfusing medium was assessed against the net accumulation of perfusate constituents during perfusion of control livers and livers perfused with perfusate insulin levels greater than 500 muU/ml. The results indicate that essentially maximal suppression of amino acid nitrogen outflow and retention of K+ OCCURRED AT INSULIN CONCENTRAtions of 72 muU/ml., with lesser effects being noted at 41 muU/ml. Inhibition of ureogenesis was demonstrated at insulin levels above 120 muU/ml. However, significant effects of insulin on suppressing net glucose outflow was not observed until insulin levels had reached 500 muU/ml. due presumably to the absence of a sustained rate of glycogenolysis by control livers. The observation that perfused livers from normal rats are extremely sensitive to several metabolic effects of insulin at physiological concentrations suggests that this experimental approach can provide useful information as to the role of the liver in the pathogenesis of various insulin resistant states.

    View details for Web of Science ID A1975V822200007

    View details for PubMedID 1123110

  • REMOVAL OF INSULIN BY PERFUSED RAT-LIVER - EFFECT OF CONCENTRATION METABOLISM-CLINICAL AND EXPERIMENTAL Mondon, C. E., Olefsky, J. M., DOLKAS, C. B., Reaven, G. M. 1975; 24 (2): 153-160

    Abstract

    The kinetics of insulin removal by isolated rat liver were investigated by measuring the rate of disappearance of insulin from the perfusate during recycling perfusion and by comparing the extraction of insulin over a wide range of constant arterial hormone levels during nonrecycling perfusion. In the recycling studies, insulin was removed from the perfusing medium at a uniform rate between 5 and 45 min. The reaction velocity constant, or hepatic clearance, during this period of uniform disappearance averaged 1.8 ml/min and represented 34% of the volume flow through the liver. In the nonrecycling flow-through studies at constant arterial insulin concentration, an initial period of accelerated hepatic uptake of insulin was seen. This period lasted for 3 to 7 min, was seen at every level of arterial insulin concentration, and was followed by a period of constant hepatic insulin removal. The hepatic removal rate during the period of constant uptake increased in a linear fashion until arterial insulin concentration reached 500 muU/ml and attained a maximal value at concentrations over 800 muU/ml. These findings indicate that the time course of hepatic insulin uptake by the perfused rat liver consists of two phases-an initial rapid phase, possibly associated with insulin binding, followed by a sustained rate of insulin removal, which probably represents insulin utilization and degradation. The rate of hepatic insulin removal was found to be proportional to arterial insulin concentration overa range of 20 to 500 muU/ML. Above this concentration, hepatic removal processes became saturated, reaching a maximal value of 183 muU of insulin per gram of liver per minute.

    View details for Web of Science ID A1975V536500005

    View details for PubMedID 1113679

  • Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic DIABETIC MEDICINE Kim, S. H., Silvers, A., Viren, J., Reaven, G. M. 2016; 33 (7): 961-967

    Abstract

    There is general acceptance that the physiological relationship between insulin sensitivity and insulin secretion is hyperbolic. This conclusion has evolved from studies in which one test assessed both variables, and changes in plasma insulin concentration were used as a surrogate measure for insulin secretion rate. The aim of this study was to see if a hyperbolic relationship would also emerge when separate and direct measures were used to quantify both insulin sensitivity and insulin secretion rate.Steady-state plasma glucose (SSPG) was determined in 146 individuals without diabetes using the insulin suppression test, with 1/SSPG used to quantify insulin sensitivity. The graded-glucose infusion test was used to quantify insulin secretion rate. Plasma glucose and insulin concentrations obtained during an oral glucose tolerance test (OGTT) were used to calculate surrogate estimates of insulin action and insulin secretion rate. A hyperbolic relationship was assumed if the β coefficient was near -1 using the following model: log (insulin secretion measure) = constant + β × log (insulin sensitivity measure).OGTT calculations of insulin sensitivity (Matsuda) and plasma insulin response [ratio of insulin/glucose area-under-the-curve (AUC) or insulin total AUC] provided the expected hyperbolic relationship [β = -0.95, 95% CI (-1.09, -0.82); -1.06 (-1.14, -0.98)]. Direct measurements of insulin sensitivity and insulin secretion rate did not yield the same curvilinear relationship [β = -1.97 (-3.19, -1.36)].These findings demonstrate that the physiological relationship between insulin sensitivity and insulin secretion rate is not necessarily hyperbolic, but will vary with the method(s) by which it is determined.

    View details for DOI 10.1111/dme.13055

    View details for Web of Science ID 000379930900014

    View details for PubMedID 26670479

  • Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study. Sleep medicine Liu, A., Kim, S. H., Ariel, D., Abbasi, F., Lamendola, C., Cardell, J., Xu, S., Patel, S., Tomasso, V., Mojaddidi, H., Grove, K., Tsao, P. S., Kushida, C. A., Reaven, G. M. 2016; 22: 57-60

    Abstract

    High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures.Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test).A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed.Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.

    View details for DOI 10.1016/j.sleep.2016.06.005

    View details for PubMedID 27544837

  • Metabolic markers associated with insulin resistance predict type 2 diabetes in Koreans with normal blood pressure or prehypertension CARDIOVASCULAR DIABETOLOGY Sung, K., Park, H., Kim, M., Reaven, G. 2016; 15
  • Cardiometabolic Risk in South Asian Inhabitants of California: Hypertriglyceridemic Waist vs Hypertriglyceridemic Body Mass Index. Ethnicity & disease Abbasi, F., Mathur, A., Reaven, G. M., Molina, C. R. 2016; 26 (2): 191-196

    Abstract

    Hypertriglyceridemic waist (HTG-waist), an increased waist circumference (WC) with an elevated triglyceride (TG) concentration, can identify increased cardiometabolic risk in apparently healthy individuals. Since WC and BMI are highly correlated, we examined whether an HTG-BMI would be as effective as an HTG-waist in identifying cardiometabolic risk in apparently healthy South Asians.In this cross-sectional study, we classified South Asian women (n=1156) and men (n=1842) without diabetes mellitus as having an HTG-waist (TG ≥150 mg/dL and a WC ≥80 cm in women or ≥ 90 cm in men) and an HTG-BMI (TG ≥150 mg/dL and a BMI ≥23 kg/m²).We measured cardiometabolic risk factors, including blood pressure and fasting lipid profile, glucose, insulin, fibrinogen, and high-sensitivity C-reactive protein.An HTG-waist was present in 670 individuals, of whom 648 (97%) had an HTG-BMI. The cardiometabolic profile was significantly more adverse in those in whom an HTG-waist was present vs absent; and the same was true when individuals with an HTG-BMI were compared with those without.Essentially every individual with an HTG-waist also had an HTG-BMI. An HTG-BMI identified cardiometabolic risk as effectively as an HTG-waist in a population composed entirely of South Asians.

    View details for DOI 10.18865/ed.26.2.191

    View details for PubMedID 27103769

  • Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. journal of clinical investigation Knowles, J. W., Xie, W., Zhang, Z., Chennamsetty, I., Assimes, T. L., Paananen, J., Hansson, O., Pankow, J., Goodarzi, M. O., Carcamo-Orive, I., Morris, A. P., Chen, Y. I., Mäkinen, V., Ganna, A., Mahajan, A., Guo, X., Abbasi, F., Greenawalt, D. M., Lum, P., Molony, C., Lind, L., Lindgren, C., Raffel, L. J., Tsao, P. S., Schadt, E. E., Rotter, J. I., Sinaiko, A., Reaven, G., Yang, X., Hsiung, C. A., Groop, L., Cordell, H. J., Laakso, M., Hao, K., Ingelsson, E., Frayling, T. M., Weedon, M. N., Walker, M., Quertermous, T. 2016; 126 (1): 403-?

    View details for DOI 10.1172/JCI85921

    View details for PubMedID 26727231

  • Metabolic markers associated with insulin resistance predict type 2 diabetes in Koreans with normal blood pressure or prehypertension. Cardiovascular diabetology Sung, K., Park, H., Kim, M., Reaven, G. 2016; 15 (1): 47-?

    Abstract

    Questions remain as to the association between essential hypertension and increased incidence of type 2 diabetes (T2DM). The premise of this analysis is that insulin resistance/compensatory hyperinsulinemia is a major predictor of T2DM, and the greater the prevalence of insulin resistance within any population, normotensive or hypertensive, the more likely T2DM will develop. The hypothesis to be tested is that surrogate estimates of insulin resistance will predict incident T2DM to a significant degree in persons with normal blood pressure or prehypertension.Analysis of data from a population-based survey of 10, 038 inhabitants of rural and urban areas of Korea, ≥40 years-old, initiated in 2001, with measures of demographic and metabolic characteristics at baseline and 8-years later. Participants were classified as having normal blood pressure or prehypertension, and three simple manifestations of insulin resistance related to the pathophysiology of T2DM used to predict incident T2DM: (1) glycemia (plasma glucose concentration 2-hour after 75 g oral glucose challenge = 2-hour PG); (2) hyperinsulinemia (plasma insulin concentration 2-hour after 75 g oral glucose challenge = 2-hour PI); and (3) dyslipidemia (ratio of fasting plasma triglyceride/high/density lipoprotein cholesterol concentration = TG/HDL-C ratio).Fully adjusted hazard ratios (HR, 95 % CI) for incident T2DM were highest (P < 0.001) in the quartile of individuals with the highest 2-hour PG concentrations, ranging from 5.84 (3.37-10.1) in women with prehypertension to 12.2 (7.12-21.00) in men with normal blood pressure. T2DM also developed to a significantly greater degree in subjects within the highest quartile of TG/HDL-C ratios, with HRs varying from 2.91 (1.63-2.58) in women with prehypertension (P < 0.001) to 1.77 (1.12-2.81, P < 0.05) in men with prehypertension. The least predictive index of insulin resistance was the 2-hour PI concentration. Subjects with normal blood pressure in the highest quartile of 2-hour PI concentrations were significantly associated with incident T2DM, with HRs of 1.5 (1.02-2.20, P = 0.25) and 2.02 (1.35-3.02, P < 0.001), in men and women, respectively. Finally, incidence of T2DM in the highest quartile was somewhat greater in patients with prehypertension, irrespective of predictor.Metabolic variables associated with insulin resistance (glycemia, insulinemia, and dyslipidemia) predict the development of T2DM in patients with either normal blood pressure or prehypertension.

    View details for DOI 10.1186/s12933-016-0368-7

    View details for PubMedID 27001495

  • Hyperinsulinemia in Individuals with Obesity: Role of Insulin Clearance OBESITY Kim, M. K., Reaven, G. M., Chen, Y. I., Kim, E., Kim, S. H. 2015; 23 (12): 2430-2434

    View details for DOI 10.1002/oby.21256

    View details for Web of Science ID 000367189300023

  • Salsalate-induced changes in lipid, Lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals JOURNAL OF CLINICAL LIPIDOLOGY Ariel, D., Kim, S. H., Liu, A., Abbasi, F., Lamendola, C. A., Grove, K., Tomasso, V., Reaven, G. M. 2015; 9 (5): 658-663
  • Salsalate-induced changes in lipid, lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals. Journal of clinical lipidology Ariel, D., Kim, S. H., Liu, A., Abbasi, F., Lamendola, C. A., Grove, K., Tomasso, V., Reaven, G. M. 2015; 9 (5): 658-663

    Abstract

    Although salsalate administration consistently lowers plasma triglyceride concentrations in patients with type II diabetes, prediabetes, and/or insulin resistance, changes in low-density lipoprotein cholesterol (LDL-C) concentrations have been inconsistent; varying from no change to a significant increase. To evaluate the clinical relevance of this discordance in more detail, we directly measured LDL-C and obtained a comprehensive assessment of changes in lipid, lipoprotein, and apoprotein concentrations associated with salsalate use in insulin-resistant individuals, overweight or obese, but without diabetes, using vertical auto profile method.A single-blind, randomized, placebo-controlled study was performed in volunteers who were overweight or obese, without diabetes, and insulin resistant on the basis of their steady-state plasma glucose concentration during an insulin suppression test. Participants were randomized 2:1 to receive salsalate 3.5 g/d (n = 27) or placebo (n = 14) for 4 weeks. Comprehensive lipid, lipoprotein, and apoprotein analysis by vertical auto profile was obtained after an overnight fast, before and after study intervention.There was no change in directly measured LDL-C concentration in salsalate-treated individuals. However, salsalate administration was associated with various changes considered to decrease atherogenicity; including decreases in triglyceride and total very low-density lipoprotein cholesterol (VLDL-C) concentrations, a shift from small denser LDL lipoproteins toward larger, more buoyant LDL particles, decreases in VLDL1+2-C and LDL4-C, and nonsignificant decreases in non-high-density lipoprotein cholesterol and apolipoprotein B. No significant changes occurred in the placebo-treated group.Atherogenicity of the lipid, lipoprotein, and apoprotein profile of insulin-resistant individuals who were overweight or obese improved significantly in association with salsalate treatment. The clinical importance of this finding awaits further study.

    View details for DOI 10.1016/j.jacl.2015.06.009

    View details for PubMedID 26350812

  • Circulating microRNA-320a and microRNA-486 predict thiazolidinedione response: Moving towards precision health for diabetes prevention. Metabolism: clinical and experimental Flowers, E., Aouizerat, B. E., Abbasi, F., Lamendola, C., Grove, K. M., Fukuoka, Y., Reaven, G. M. 2015; 64 (9): 1051-1059

    Abstract

    The aims of this study were to compare microRNA (miR) expression between individuals with and without insulin resistance and to determine whether miRs predict response to thiazolidinedione treatment.In a sample of 93 healthy adults, insulin resistance was defined as steady state plasma glucose (SSPG)≥180mg/dL and insulin sensitive as <120mg/dL. Response to thiazolidinedione therapy was defined as ≥10% decrease in SSPG. We selected a panel of microRNAs based on prior evidence for a role in insulin or glucose metabolism. Fold change and Wilcoxon rank sum tests were calculated for the 25 miRs measured.At baseline, 81% (n=75) of participants were insulin resistant. Five miRs were differentially expressed between the insulin resistant and sensitive groups: miR-193b (1.45 fold change (FC)), miR-22-3p (1.15 FC), miR-320a (1.36 FC), miR-375 (0.59 FC), and miR-486 (1.21 FC) (all p<0.05). In the subset who were insulin resistant at baseline and received thiazolidinediones (n=47), 77% (n=36) showed improved insulin sensitivity. Six miRs were differentially expressed between responders compared to non-responders: miR-20b-5p (1.20 FC), miR-21-5p, (0.92 FC), miR-214-3p (1.13 FC), miR-22-3p (1.14 FC), miR-320a (0.98 FC), and miR-486-5p (1.25 FC) (all p<0.05).This study is the first to report miRs associated with response to a pharmacologic intervention for insulin resistance. MiR-320a and miR-486-5p identified responders to thiazolidinedione therapy among the insulin resistant group.

    View details for DOI 10.1016/j.metabol.2015.05.013

    View details for PubMedID 26031505

  • Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance SLEEP Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-?

    View details for DOI 10.5665/sleep.4678

    View details for Web of Science ID 000353876600017

  • Relationship between insulin resistance and amino acids in women and men. Physiological reports Seibert, R., Abbasi, F., Hantash, F. M., Caulfield, M. P., Reaven, G., Kim, S. H. 2015; 3 (5)

    Abstract

    Insulin resistance has been associated with higher plasma amino acid (AA) concentrations, but majority of studies have used indirect measures of insulin resistance. Our main objective was to define the relationship between plasma AA concentrations and a direct measure of insulin resistance in women and men. This was a cross-sectional study of 182 nondiabetic individuals (118 women and 64 men) who had measurement of 24 AAs and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. Fourteen out of 24 AA concentrations were significantly (P < 0.05) higher in men than women; only glycine was lower in men. Majority of these AAs were positively associated with SSPG; only glycine concentration was negatively associated. Glutamic acid, isoleucine, leucine, and tyrosine concentrations had the strongest correlation with SSPG (r ≥ 0.4, P < 0.001). The degree of association was similar in women and men, independent of obesity, and similar to traditional markers of insulin resistance (e.g., glucose, triglyceride, high-density lipoprotein cholesterol). Compared with women, men tended to have a more unfavorable AA profile with higher concentration of AAs associated with insulin resistance and less glycine. However, the strength of association between a direct measurement of insulin resistance and AA concentrations were similar between sexes and equivalent to several traditional markers of insulin resistance.

    View details for DOI 10.14814/phy2.12392

    View details for PubMedID 25952934

  • Modulation of coronary heart disease risk by insulin resistance in subjects with normal glucose tolerance or prediabetes ACTA DIABETOLOGICA Ariel, D., Reaven, G. 2014; 51 (6): 1033-1039
  • Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study DIABETES CARE Kim, S. H., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Ochoa, H., Reaven, G. 2014; 37 (7): 1944-1950

    View details for DOI 10.2337/dc13-2977

    View details for Web of Science ID 000338020400030

  • Evaluation of fasting plasma insulin concentration as an estimate of insulin action in nondiabetic individuals: comparison with the homeostasis model assessment of insulin resistance (HOMA-IR) ACTA DIABETOLOGICA Abbasi, F., Okeke, Q., Reaven, G. M. 2014; 51 (2): 193-197

    Abstract

    Insulin-mediated glucose disposal varies severalfold in apparently healthy individuals, and approximately one-third of the most insulin resistant of these individuals is at increased risk to develop various adverse clinical syndromes. Since direct measurements of insulin sensitivity are not practical in a clinical setting, several surrogate estimates of insulin action have been proposed, including fasting plasma insulin (FPI) concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) calculated by a formula employing fasting plasma glucose (FPG) and FPI concentrations. The objective of this study was to compare FPI as an estimate of insulin-mediated glucose disposal with values generated by HOMA-IR in 758 apparently healthy nondiabetic individuals. Measurements were made of FPG, FPI, triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) concentrations, and insulin-mediated glucose uptake was quantified by determining steady-state plasma glucose (SSPG) concentration during the insulin suppression test. FPI and HOMA-IR were highly correlated (r = 0.98, P < 0.001). The SSPG concentration also correlated to a similar degree (P < 0.001) with FPI (r = 0.60) and HOMA-IR (r = 0.64). Furthermore, the relationship between FPI and TG (r = 0.35) and HDL-C (r = -0.40) was comparable to that between HOMA-IR and TG (r = 0.39) and HDL-C (r = -0.41). In conclusion, FPI and HOMA-IR are highly correlated in nondiabetic individuals, with each estimate accounting for ~40 % of the variability (variance) in a direct measure of insulin-mediated glucose disposal. Calculation of HOMA-IR does not provide a better surrogate estimate of insulin action, or of its associated dyslipidemia, than measurement of FPI.

    View details for DOI 10.1007/s00592-013-0461-2

    View details for Web of Science ID 000334054200003

    View details for PubMedID 23420066

  • Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study DIABETOLOGIA Kim, S. H., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Reaven, G. 2014; 57 (3): 455-462

    Abstract

    Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.

    View details for DOI 10.1007/s00125-013-3134-3

    View details for Web of Science ID 000331558400003

    View details for PubMedID 24326527

  • Adiposity and Cardiovascular Risk Clustering in South Asians METABOLIC SYNDROME AND RELATED DISORDERS Flowers, E., Molina, C., Mathur, A., Reaven, G. M. 2013; 11 (6): 434-440

    Abstract

    South Asians have increased risk for type-2 diabetes and cardiovascular disease, but the relationship between metabolic health and weight has not been described. This study establishes the prevalence of metabolic abnormalities in normal weight, overweight, and obese South Asians.Participants were categorized by body mass index and waist circumference. Subjects with two or more cardiometabolic risk factors (blood pressure, glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and C-reactive protein) were defined as metabolically abnormal.Forty-one percent of the sample (n=1015) was metabolically abnormal, and 12% of those were normal weight. Of metabolically healthy individuals, 58% were overweight or obese. At a normal level of adiposity, women were more likely to be metabolically unhealthy, whereas men were more likely to be unhealthy with increasing adiposity.Similar to other ethnic groups, a significant number of normal weight South Asians can be metabolically unhealthy.

    View details for DOI 10.1089/met.2013.0081

    View details for Web of Science ID 000326986300009

    View details for PubMedID 24004335

  • Reply to DN Polesel et al. American journal of clinical nutrition Liu, A., Reaven, G. M., Abbasi, F. 2013; 98 (6): 1593-?

    View details for DOI 10.3945/ajcn.113.072876

    View details for PubMedID 24259357

  • Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome? NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES Liu, A., Reaven, G. M. 2013; 23 (11): 1122-1127

    Abstract

    BACKGROUND AND AIMS: The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. METHODS AND RESULTS: Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥4.14 and ≥4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. CONCLUSION: While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.

    View details for DOI 10.1016/j.numecd.2012.12.001

    View details for Web of Science ID 000326986800013

    View details for PubMedID 23352957

  • Sex Differences in Insulin Resistance and Cardiovascular Disease Risk JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Kim, S. H., Reaven, G. 2013; 98 (11): E1716-E1721

    Abstract

    The possibility that differences in insulin sensitivity explain why women, especially younger women, have a lower cardiovascular disease (CVD) risk than men remains an unsettled issue.The objective of this study was to evaluate whether sex disparities in CVD risk are associated with differences in insulin resistance.This was a cross-sectional study of women (n = 468) and men (n = 354) who had the measurement of CVD risk factors and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. The population was also divided by median age (51 y) to evaluate the effect of age on sex differences. MAIN OUTCOME MEASURES/RESULTS: In general, the SSPG concentration was similar between sexes. At higher BMI (≥30 kg/m(2)), women had significantly lower SSPG concentration than men (sex × BMI interaction, P = .001). However, sex differences in CVD risk factors were not due to differences in SSPG but accentuated by a higher degree of insulin resistance in younger (age < 51 y) but not older (≥ 51 y) individuals. In younger individuals, women had significantly (P ≤ .007) lower diastolic blood pressure and fasting glucose and triglyceride concentration compared with men in SSPG tertile 3 (most insulin resistant) but not in tertile 1 (least insulin resistant). Older women had lower diastolic blood pressure compared with men, regardless of SSPG. High-density lipoprotein cholesterol remained higher in women, regardless of age or SSPG.The female advantage is not due to a difference in insulin action but results from an attenuation of the relationship between insulin resistance and CVD risk, especially in younger individuals.

    View details for DOI 10.1210/jc.2013-1166

    View details for Web of Science ID 000327180700003

    View details for PubMedID 24064694

  • Habitual shortened sleep and insulin resistance: An independent relationship in obese individuals METABOLISM-CLINICAL AND EXPERIMENTAL Liu, A., Kushida, C. A., Reaven, G. M. 2013; 62 (11): 1553-1556

    Abstract

    Short sleep duration has been reported to be associated with obesity, type 2 diabetes, and pre-diabetes. Since excess weight, glucose abnormalities, and insulin resistance tend to cluster, the individual role insulin resistance may have in habitual shortened sleep is unclear. The study purpose was to assess whether habitual sleep curtailment is independently related to insulin resistance in obese individuals.Non-diabetic, overweight/obese individuals from the community were stratified as insulin-resistant (n=35) or insulin-sensitive (n=21) based on steady-state plasma glucose concentrations (SSPG) during the insulin suppression test. Seventy-five gram oral glucose tolerance tests were performed. Participants were asked, "On average, how many hours of sleep do you get per night?" Shortened sleep duration was defined as less than 7h of sleep per night.SSPG concentrations differed 2.5-fold (P<0.001) between insulin-resistant and insulin-sensitive individuals. Impaired fasting glucose and glucose intolerance were prevalent in both groups (>40%); however, body mass index, waist circumference, mean fasting or 2-h post-glucola glucose concentrations were not significantly different. Insulin-resistant individuals reported (mean±SD) fewer hours of sleep than did insulin-sensitive individuals (6.53±1.1 vs 7.24±0.9h, P<0.05). Shortened sleep duration was more prevalent among insulin-resistant as compared with insulin-sensitive individuals (60% vs 24%, P<0.05).Non-diabetic, insulin-resistant individuals averaged fewer hours of sleep and were more likely to report shortened sleep duration as compared with similarly obese insulin-sensitive individuals. There appears to be an independent association between habitual shortened sleep and insulin resistance among obese, dysglycemic adults without diabetes.

    View details for DOI 10.1016/j.metabol.2013.06.003

    View details for Web of Science ID 000330924500005

    View details for PubMedID 23849514

  • Plasma triglyceride/HDL-cholesterol ratio, insulin resistance, and cardiometabolic risk in young adults JOURNAL OF LIPID RESEARCH Murguia-Romero, M., Rafael Jimenez-Flores, J., Sigrist-Flores, S. C., Espinoza-Camacho, M. A., Jimenez-Morales, M., Pina, E., Rene Mendez-Cruz, A., Villalobos-Molina, R., Reaven, G. M. 2013; 54 (10): 2795-2799

    Abstract

    Studies in mature adults suggest that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) provides a simple way to identify apparently healthy individuals who are insulin resistant (IR) and at increased cardiometabolic risk. This study extends these observations by examining the clinical utility of the TG/HDL-C ratio and the metabolic syndrome (MetS) in 2,244 healthy college students (17-24 years old) of Mexican Mestizo ancestry. The TG/HDL-C ratio separating the 25% with the highest value was used to identify IR and increased cardiometabolic risk. Cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively, and approximately one third were identified as being IR. The MetS identified fewer individuals as being IR, but their risk profile was accentuated. In conclusion, both a higher TG/HDL-C ratio and a diagnosis of the MetS identify young IR individuals with an increased cardiometabolic risk profile. The TG/HDL-C ratio identified a somewhat greater number of "high risk" subjects, whereas the MetS found a group whose risk profile was somewhat magnified. These findings suggest that the TG/HDL-C ratio may serve as a simple and clinically useful approach to identify apparently healthy, young individuals who are IR and at increased cardiometabolic risk.

    View details for DOI 10.1194/jlr.M040584

    View details for Web of Science ID 000330534000022

    View details for PubMedID 23863983

  • Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes DIABETES CARE Kim, S. H., Abbasi, F., Lamendola, C., Liu, A., Ariel, D., Schaaf, P., Grove, K., Tomasso, V., Ochoa, H., Liu, Y. V., Chen, Y. I., Reaven, G. 2013; 36 (10): 3276-3282

    Abstract

    OBJECTIVEThe aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.RESEARCH DESIGN AND METHODSWe randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.RESULTSEleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P = 0.001).CONCLUSIONSThe addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.

    View details for DOI 10.2337/dc13-0354

    View details for Web of Science ID 000324749500073

  • Beyond fasting plasma glucose: The association between coronary heart disease risk and postprandial glucose, postprandial insulin and insulin resistance in healthy, nondiabetic adults METABOLISM-CLINICAL AND EXPERIMENTAL Bhat, S. L., Abbasi, F. A., Blasey, C., Reaven, G. M., Kim, S. H. 2013; 62 (9): 1223-1226

    Abstract

    Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals.Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile.For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p<0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals.In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.

    View details for DOI 10.1016/j.metabol.2013.04.012

    View details for Web of Science ID 000324151800004

  • Cardiometabolic risk factors and obesity: does it matter whether BMI or waist circumference is the index of obesity? AMERICAN JOURNAL OF CLINICAL NUTRITION Abbasi, F., Blasey, C., Reaven, G. M. 2013; 98 (3): 637-640

    Abstract

    It has been suggested that the cardiometabolic risk associated with excess adiposity is particularly related to central obesity.The objective was to compare the associations between cardiometabolic risk of apparently healthy individuals and measures of central obesity [waist circumference (WC)] and overall obesity [body mass index (BMI)].In this cross-sectional, observational study, 492 subjects (306 women and 303 non-Hispanic whites) were classified by BMI (in kg/m(2)) as normal weight (BMI <25) or overweight/obese (BMI = 25.0-34.9) and as having an abnormal WC (≥80 cm in women and ≥94 cm in men) or a normal WC (<80 cm in women and <94 cm in men). Measurements were also made of the cardiometabolic risk factors: age, systolic blood pressure (SBP), and fasting plasma glucose (FPG), triglyceride, and high-density lipoprotein (HDL)-cholesterol concentrations. Associations among cardiometabolic risk factors and BMI and WC were evaluated with Pearson correlations.There was a considerable overlap in the normal and abnormal categories of BMI and WC, and ∼81% of the subjects had both an abnormal BMI and WC. In women, BMI and WC correlated with SBP (r = 0.30 and 0.19, respectively), FPG (r = 0.25 and 0.22, respectively), triglycerides (r = 0.17 and 0.20, respectively), and HDL cholesterol (r = -0.23 and -0.20, respectively) (P < 0.01 for all). In men, BMI and WC also correlated with SBP (r = 0.22 and 0.22, respectively), FPG (r = 0.22 and 0.25, respectively), triglycerides (r = 0.21 and 0.18, respectively), and HDL cholesterol (r = -0.20 and -0.13, respectively) [P < 0.05 for all, except for the association of WC with HDL cholesterol (P = 0.08)].Most individuals with an abnormal BMI also have an abnormal WC. Both indexes of excess adiposity are positively associated with SBP, FPG, and triglycerides and inversely associated with HDL cholesterol.

    View details for DOI 10.3945/ajcn.112.047506

    View details for Web of Science ID 000323532700003

    View details for PubMedID 23885045

  • Measurement of insulin-mediated glucose uptake: Direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp METABOLISM-CLINICAL AND EXPERIMENTAL Knowles, J. W., Assimes, T. L., Tsao, P. S., Natali, A., Mari, A., Quertermous, T., Reaven, G. M., Abbasi, F. 2013; 62 (4): 548-553

    Abstract

    Two direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals.A total of 15 nondiabetic subjects (9 women and 6 men) underwent both an EC and a modified version of the IST within a median interval of 5days. We performed standard correlation metrics of the two measures and developed transformation regression equations for the two measures.The mean±SD age of the subjects was 57±7years and body mass index, 27.7±3.9kg/m(2). The median (interquartile range) SSPG concentration was 6.7 (5.1, 9.8) mmol/L and M value, 49.6 (28.9, 64.2) μmol/min/kg-LBM. There was a highly significant correlation between SSPG and M (r=-0.87, P <0.001). The relationship was best fit by regression models with exponential/logarithmic functions (R(2)=0.85). Bland-Altman plots demonstrated an excellent agreement between these measures of insulin action.The SSPG and M are highly related measures of insulin sensitivity and the results provide the means to directly compare the two measurements.

    View details for DOI 10.1016/j.metabol.2012.10.002

    View details for Web of Science ID 000317530800010

  • Risk for obstructive sleep apnea in obese, nondiabetic adults varies with insulin resistance status SLEEP AND BREATHING Liu, A., Kushida, C. A., Reaven, G. M. 2013; 17 (1): 333-338

    Abstract

    Obstructive sleep apnea (OSA) is an increasingly common sleep disorder, especially among obese adults. Early identification of adults at risk for OSA would be of substantial benefit; however, the magnitude of the obesity epidemic requires that screening be performed judiciously. The study's aim was to utilize questionnaires that assess OSA risk and symptoms to test the hypothesis that the most insulin-resistant subset of obese individuals is at highest risk for OSA.Nondiabetic, overweight to obese volunteers underwent direct quantification of insulin sensitivity by measuring steady-state plasma glucose concentrations during the insulin suppression test. Insulin-sensitive and insulin-resistant individuals were administered the Berlin and STOP questionnaires to determine OSA risk status, and Epworth Sleepiness Scale (ESS) to evaluate daytime sleepiness. Fasting insulin and lipid/lipoprotein measurements were performed.Insulin-mediated glucose disposal differed threefold (p < 0.001) between equally obese, insulin-resistant (n = 22) and insulin-sensitive (n = 14) individuals, associated with higher fasting insulin and triglyceride and lower high-density lipoprotein cholesterol (HDL-C) concentrations in insulin-resistant individuals. Fourteen (64 %) insulin-resistant as compared with 2 (14 %) insulin-sensitive individuals were found to be at high risk for OSA by both questionnaires (p < 0.01). Whereas half of insulin-resistant individuals met the ESS criteria for excessive daytime sleepiness, only one insulin-sensitive individual did (p = 0.011).High risk for OSA and excessive daytime sleepiness is prevalent among the insulin-resistant subgroup of obese individuals. Surrogate estimates of insulin resistance based on fasting insulin, triglycerides, and/or HDL-C can be used to help identify those obese adults who would benefit most from OSA screening and referral for polysomnography.

    View details for DOI 10.1007/s11325-012-0696-0

    View details for Web of Science ID 000315167200052

    View details for PubMedID 22481243

  • What do we learn from measurements of HOMA-IR? Diabetologia Reaven, G. M. 2013

    View details for PubMedID 23722624

  • Body mass index and waist circumference associate to a comparable degree with insulin resistance and related metabolic abnormalities in South Asian women and men DIABETES & VASCULAR DISEASE RESEARCH Abbasi, F., Malhotra, D., Mathur, A., Reaven, G. M., Molina, C. R. 2012; 9 (4): 296-300

    Abstract

    The aim of this study was to test the hypothesis that body mass index (BMI) and waist circumference (WC) associate to a comparable degree with insulin resistance and cardiometabolic risk factors in South Asians.We measured blood pressure and fasting glucose, insulin, triglyceride, high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and fibrinogen and calculated the homeostasis model assessment of insulin resistance (HOMA-IR) in a community-based sample of 923 nondiabetic South Asians.BMI and WC were highly correlated in both genders (r = 0.82 and 0.87). The relationship between BMI and values of blood pressure, glucose, insulin, HOMA-IR, triglyceride, HDL-C, hs-CRP, and fibrinogen was comparable to that between WC and these variables. Fasting insulin and HOMA-IR correlated most strongly with BMI (r = 0.49 to 0.56) and WC (r = 0.52 to 0.59).These results show that BMI and WC associate to a comparable degree with estimates of insulin resistance and related metabolic abnormalities in South Asians.

    View details for DOI 10.1177/1479164111433578

    View details for Web of Science ID 000309799300007

    View details for PubMedID 22278736

  • Insulin Resistance and Coronary Heart Disease in Nondiabetic Individuals ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Reaven, G. 2012; 32 (8): 1754-1759

    Abstract

    The goal of this review was to summarize evidence supporting the view that insulin resistance/compensatory hyperinsulinemia play an important role in the pathogenesis of coronary heart disease (CHD) in nondiabetic individuals. Results of case-control and epidemiological studies in nondiabetic individuals will be reviewed to examine the link between insulin resistance/compensatory hyperinsulinemia, associated abnormalities, and CHD. The primary focus of the review will be on the central role that dyslipidemia plays in the link between insulin resistance/compensatory hyperinsulinemia and CHD. Additional issues to be addressed include the following: (1) the relationship among obesity, insulin resistance, and CHD; (2) a listing of other abnormalities that contribute to risk of CHD in insulin-resistant individuals; and (3) discussion of the importance of differential tissue insulin sensitivity in the development of abnormalities that increase CHD risk in insulin-resistant, nondiabetic individuals. The information will reflect the author's decision as to what issues are believed to be of particular relevance or less well appreciated concerning the complex relationship between insulin resistance and CHD. Resistance to insulin-mediated glucose disposal and hyperinsulinemia is a common finding in apparently healthy individuals and is associated with a number of abnormalities that greatly increase risk of CHD.

    View details for DOI 10.1161/ATVBAHA.111.241885

    View details for Web of Science ID 000306558100010

    View details for PubMedID 22815340

  • Relations between obesity, insulin resistance, and 25-hydroxyvitamin D AMERICAN JOURNAL OF CLINICAL NUTRITION Lamendola, C. A., Ariel, D., Feldman, D., Reaven, G. M. 2012; 95 (5): 1055-1059

    Abstract

    Although low circulating 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and obesity, the relations between these 3 variables have not been completely resolved.The objective was to compare circulating 25(OH)D concentrations in apparently healthy individuals who were matched for degree of obesity or insulin sensitivity.This was a case-control study in which 78 apparently healthy individuals were classified as being normal weight (NW) or obese (OB) on the basis of their BMI and as being insulin sensitive (IS) or insulin resistant (IR) on the basis of their steady state plasma glucose (SSPG) concentration during the insulin suppression test.Groups did not differ in terms of age, sex distribution, race, or mean (± SD) plasma 25(OH)D concentration. Values for 25(OH)D were 32 ± 10, 30 ± 10, and 28 ± 8 ng/mL in NW-IS, OB-IS, and OB-IR groups, respectively. These concentrations were essentially identical when comparing IR with IS subjects matched for BMI or when comparing OB with NW subjects matched for SSPG. Concentrations of 25(OH)D ? 30 ng/mL were somewhat more common in OB subjects than in NW subjects (54% compared with 35%), but SSPG concentrations were not different within either the IR or IS groups when subgroups with 25(OH)D concentrations ? 30 or > 30 ng/mL were compared.In 78 individuals, 47% of whom were vitamin D deficient or insufficient (? 30 ng/mL), 25(OH)D concentrations did not vary with differences in insulin sensitivity (SSPG concentration) when matched for BMI (OB-IR compared with OB-IS). Similarly, when matched for SSPG concentrations, plasma 25(OH)D concentrations were not different in NW or OB individuals (NW-IS compared with OB-IS).

    View details for DOI 10.3945/ajcn.111.032060

    View details for Web of Science ID 000303140700010

    View details for PubMedID 22440850

  • A LARGE-SCALE MULTI ETHNIC STUDY OF A DIRECT MEASURE OF INSULIN SENSITIVITY DEMONSTRATES THAT SOUTH ASIANS ARE THE MOST INSULIN RESISTANT ETHNIC GROUP IN THE US Divakaruni, M. S., Abbasi, F., Desai, M., Lamendola, C., Palaniappan, L., Reaven, G., Assimes, T. ELSEVIER SCIENCE INC. 2012: E1792-E1792
  • Comparison of two methods using plasma triglyceride concentration as a surrogate estimate of insulin action in nondiabetic subjects: triglycerides x glucose versus triglyceride/high-density lipoprotein cholesterol METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Reaven, G. M. 2011; 60 (12): 1673-1676

    Abstract

    The objective was to compare relationships between insulin-mediated glucose uptake and surrogate estimates of insulin action, particularly those using fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations. Insulin-mediated glucose uptake was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in 455 nondiabetic subjects. Fasting TG, HDL-C, glucose, and insulin concentrations were measured; and calculations were made of the following: (1) plasma concentration ratio of TG/HDL-C, (2) TG × fasting glucose (TyG index), (3) homeostasis model assessment of insulin resistance, and (4) insulin area under the curve (insulin-AUC) during a glucose tolerance test. Insulin-AUC correlated most closely with SSPG (r ? 0.75, P < .001), with lesser but comparable correlations between SSPG and TG/HDL-C ratio, TyG index, homeostasis model assessment of insulin resistance, and fasting TG and insulin (r ? 0.60, P < .001). Calculations of TG/HDL-C ratio and TyG index correlated with SSPG concentration to a similar degree, and the relationships were comparable to estimates using fasting insulin. The strongest relationship was between SSPG and insulin-AUC.

    View details for DOI 10.1016/j.metabol.2011.04.006

    View details for Web of Science ID 000297528400005

    View details for PubMedID 21632070

  • Plasma glucose and insulin responses to mixed meals: Impaired fasting glucose re-visited DIABETES & VASCULAR DISEASE RESEARCH BHAT, S. L., Abbasi, F., Blasey, C., Reaven, G. M., Kim, S. H. 2011; 8 (4): 271-275

    Abstract

    In individuals with varying glucose tolerance, glucose and insulin comparisons are usually made based on response to oral glucose challenge. However, an oral glucose tolerance test may not reflect daylong glucose and insulin excursions in response to meals. To better understand individuals with impaired fasting glucose (IFG), we compared insulin action as well as plasma glucose and insulin responses to mixed meals in individuals with normal fasting glucose (NFG; n = 141) and IFG (n = 148) concentrations.Insulin action was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Plasma glucose and insulin concentrations were measured before and hourly after two mixed meals.SSPG concentrations were significantly higher in the IFG group (11.8 ± 3.6 vs. 9.1 ± 3.8 mmol/l). Mean hourly daylong glucose (6.4 ± 0.07 vs. 5.5 ± 0.04 mmol/l) and insulin (390 ± 20 vs. 279 ± 15 pmol/l) concentrations were also higher in those with IFG (p < 0.001). Daylong incremental meal-stimulated glucose response, however, was comparable (p = 0.77) in the two groups, whereas the incremental insulin response was 44% higher in the IFG group.Although individuals are currently defined as having IFG based on fasting plasma glucose concentration, our data show that these individuals with IFG also are insulin resistant and have higher daylong insulin concentrations.

    View details for DOI 10.1177/1479164111421036

    View details for Web of Science ID 000296976700004

    View details for PubMedID 21933842

  • Insulin Resistance: the Link Between Obesity and Cardiovascular Disease MEDICAL CLINICS OF NORTH AMERICA Reaven, G. M. 2011; 95 (5): 875-?

    Abstract

    There seems to be general agreement that the prevalence of obesity is increasing in the United States and that we are in the midst of an obesity epidemic. The disease-related implications of this epidemic have received an enormous amount of publicity in the popular media, but public awareness of the untoward effects of excess weight has not led to an effective approach to dealing with the dilemma. The gravity of the problem is accentuated in light of the report that only approximately 50% of physicians polled provided weight loss counseling. Given the importance of excess adiposity as increasing the risk of CVD, 2DM, and hypertension and the combination of an increase in the prevalence of overweight/obesity and a health care system unprepared to deal with this situation, it is essential that considerable thought be given as to how to best address this dilemma. In this context, it must be emphasized that CVD, 2DM, and hypertension are characterized by resistance to insulin-mediated glucose disposal and that insulin resistance and the compensatory hyperinsulinemia associated with insulin resistance have been shown to be independent predictors of all three clinical syndromes. It has also been apparent for many years that overweight/obese individuals tend to be insulin resistant and become more insulin sensitive with weight loss.25 In light of these observations, it seems reasonable to suggest that insulin resistance is the link between overweight/obesity and the adverse clinical syndromes related to excess adiposity. The evidence summarized in this review shows that the more overweight an individual, the more likely he or she is insulin resistant and at increased risk to develop all the abnormalities associated with this defect in insulin action. Not all overweight/obese individuals are insulin resistant, however, any more than all insulin resistant individuals are overweight/obese. More important, there is compelling evidence that CVD risk factors are present to a significantly greater degree in the subset of overweight/obese individuals that is also insulin resistant. Not surprisingly,we have also demonstrated that an improvement in CVD risk factors with weight loss occurs to a significantly greater degree in those overweight/obese individuals who are also insulin resistant at baseline. In view of the ineffectiveness of current clinical approaches to weight loss, it seems necessary to recognize that not all overweight/obese individuals are at equal risk to develop CVD and that it is clinically useful to identify those at highest risk. The simplest way to achieve this task seems to be focusing on the CVD risk factors that are highly associated with insulin resistance/hyperinsulinemia. If this is done, then intense efforts at weight control can be brought to bear on those who not only need it the most but also have the most to gain by losing weight.

    View details for DOI 10.1016/j.mcna.2011.06.002

    View details for Web of Science ID 000294830300003

    View details for PubMedID 21855697

  • Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES Liu, A., Abbasi, F., Reaven, G. M. 2011; 21 (8): 553-560

    Abstract

    The prevalence of insulin resistance and cardiovascular disease (CVD) increases with degree of obesity. Whether measurements of generalized and abdominal obesity differ in the ability to predict changes associated with increased CVD risk is widely debated. We compared the prevalence of metabolic abnormalities in 275 women and 204 men stratified by categories of body mass index (BMI) and waist circumference (WC), and assessed the ability of these adiposity indices in combination with metabolic risk variables to predict insulin resistance.Healthy, non-diabetic volunteers underwent measurements of BMI, WC, blood pressure, fasting plasma glucose (FPG), lipoprotein concentrations, and direct quantification of insulin-mediated glucose uptake. Insulin resistance was defined as the top tertile of steady-state plasma glucose (SSPG) concentrations. BMI and WC were highly correlated (P < 0.001) in both women and men. Abnormal SSPG and triglyceride concentrations were associated with increasing adiposity by either index in both genders. Among women, abnormal FPG and high density lipoprotein cholesterol (HDL-C) concentrations were associated with increasing BMI and WC. In men, abnormal HDL-C was associated with increasing BMI only. Elevated systolic blood pressure (SBP) was associated with increasing BMI in both genders. The odds of insulin resistance were greatest in women with elevated FPG and triglycerides (4.5-fold). In men, the best predictors were BMI and SBP, and WC and HDL-C (3-fold).BMI is at least comparable to WC in stratifying individuals for prevalence of metabolic abnormalities associated with increased CVD risk and predicting insulin resistance.

    View details for DOI 10.1016/j.numecd.2009.12.009

    View details for Web of Science ID 000293596800003

    View details for PubMedID 20304617

  • Estimates of Insulin Secretory Function in Apparently Healthy Volunteers Vary as a Function of How the Relevant Variables Are Quantified CLINICAL CHEMISTRY Johns, B. R., Abbasi, F., Reaven, G. M. 2011; 57 (4): 627-632

    Abstract

    Several surrogate estimates have been used to define relationships between insulin action and pancreatic ?-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic ?-cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL).We determined 2 indices of insulin secretion [homeostasis model assessment of ?-cell function (HOMA-?) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia.Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-?) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used).Conclusions about ?-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic ?-cell function has been obtained.

    View details for DOI 10.1373/clinchem.2010.152744

    View details for Web of Science ID 000288854000017

    View details for PubMedID 21296973

  • Relationships Among Insulin Resistance, Type 2 Diabetes, Essential Hypertension, and Cardiovascular Disease: Similarities and Differences JOURNAL OF CLINICAL HYPERTENSION Reaven, G. M. 2011; 13 (4): 238-243

    Abstract

    Insulin resistance plays a major role in the pathogenesis and clinical course of patients with type 2 diabetes (2DM) and essential hypertension. However, the syndromes differ in prevalence of insulin resistance, and associated insulin secretory response. Essentially all patients with type 2 diabetes are insulin resistant, whereas only approximately 50% of those with essential hypertension are insulin resistant. Furthermore, 2DM develops when the pancreatic ?-cell can no longer maintain the degree of compensatory hyperinsulinemia needed to prevent hyperglycemia. In contrast, the compensatory hyperinsulinemia that prevents most insulin resistant individuals from developing 2DM acts on normally insulin sensitive tissues in a manner that predisposes to the development of essential hypertension. This review will discuss these similarities and differences in some detail, as well as exploring the relationship among insulin resistance and related metabolic abnormalities in the pathogenesis of cardiovascular disease in patients with 2DM and essential hypertension.

    View details for DOI 10.1111/j.1751-7176.2011.00439.x

    View details for Web of Science ID 000289168900003

    View details for PubMedID 21466618

  • Insulin resistance: from bit player to centre stage CANADIAN MEDICAL ASSOCIATION JOURNAL Reaven, G. M. 2011; 183 (5): 536-537

    View details for DOI 10.1503/cmaj.101430

    View details for Web of Science ID 000288953900020

    View details for PubMedID 21220445

  • The metabolic syndrome: time to get off the merry-go-round? JOURNAL OF INTERNAL MEDICINE Reaven, G. M. 2011; 269 (2): 127-136

    Abstract

    The diagnostic category of the metabolic syndrome (MetS) has received considerable attention over the last decade, and prestigious organizations continue to strive for its incorporation into medical practice. This review has three goals: (i) summarize the history of the several attempts to define a diagnostic category designated as the MetS; (ii) question the aetiological role of abdominal obesity in the development of the other components of the MetS; and (iii) evaluate a diagnosis of the MetS as an effective way to identify apparently healthy individuals at increased risk to develop cardiovascular disease (CVD) or type 2 diabetes (2DM). The most important conclusion is that the MetS seems to be less effective in this population than the Framingham Risk Score in predicting CVD, and no better, if not worse, than fasting plasma glucose concentrations in predicting 2DM.

    View details for DOI 10.1111/j.1365-2796.2010.02325.x

    View details for Web of Science ID 000286110100001

    View details for PubMedID 21129047

  • What is the effect of rosiglitazone treatment on insulin secretory function in insulin-resistant individuals? It depends on how you measure It METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Lamendola, C., Reaven, G. M. 2011; 60 (1): 57-62

    Abstract

    The goal of this study was to compare methods used to quantify the effect of rosiglitazone (RSG) on insulin secretory function, particularly estimates based on changes in fasting plasma glucose and insulin concentration vs daylong insulin responses to meals. To do this, we compared these measures of insulin secretion before and 3 months after RSG treatment in insulin-resistant individuals, subdivided into nondiabetic subjects (n = 29) and patients with type 2 diabetes mellitus (2DM) (n = 22). Insulin resistance was quantified by determining the steady-state plasma glucose concentration during the insulin suppression test and insulin secretory function by homeostasis model assessment of ?-cell function (HOMA-?) and the total integrated daylong plasma insulin responses to mixed meals (insulin area under the curve). Baseline fasting and daylong plasma glucose concentrations were higher (P < .001) in patients with 2DM, associated with lower HOMA-? values (P < .001). However, neither fasting nor daylong insulin concentrations after mixed meals differed in the 2 groups. Insulin sensitivity improved (P < .001) after RSG administration, with decreases of 31% ± 23% and 21% ± 14% in steady-state plasma glucose concentration in nondiabetic and diabetic subjects, respectively. Although fasting and daylong plasma glucose and insulin concentrations fell (P < .001) in both groups of RSG-treated individuals, HOMA-? decreased in nondiabetic subjects and did not change in those with 2DM. In conclusion, RSG administration improved insulin sensitivity in both groups, associated with lower fasting and daylong glucose concentrations. Fasting and daylong insulin concentrations were also lower in both groups of RSG-treated subjects, but the values of HOMA-? indicated either a decrease (nondiabetics) or no change (diabetics) in insulin secretory function. These results suggest that measurements of HOMA-? may not provide a complete view of insulin secretory function, either when comparing diabetic with nondiabetic individuals or when assessing the response to RSG treatment in insulin-resistant individuals.

    View details for DOI 10.1016/j.metabol.2010.02.015

    View details for Web of Science ID 000285441300006

    View details for PubMedID 20356610

  • Insulin resistance and cardiovascular disease risk factors in subjects with prehypertension DIABETES & VASCULAR DISEASE RESEARCH Knobler, H., Abbasi, F., Lamendola, C., Reaven, G. M. 2011; 8 (1): 43-46

    Abstract

    Prehypertension is considered to be associated with increased cardiovascular disease (CVD), and some data suggest that insulin resistance is common in this group. The goal of this study was to quantify insulin action by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in apparently healthy individuals with prehypertension (n=126) and to elucidate the relationship between insulin action and CVD risk.We found a marked heterogeneity in insulin sensitivity in the prehypertension group, and when we divided the population into insulin-sensitive, insulin-resistant and intermediate groups, there were significant (p<0.01) increases in plasma glucose and triglyceride concentrations and decreases in high-density lipoprotein cholesterol concentrations with progressive degrees of insulin resistance. These data show that at least one-third of patients with prehypertension are insulin resistant, display the accompanying metabolic abnormalities, and merit enhanced surveillance and intensive efforts at therapeutic intervention to prevent CVD.

    View details for DOI 10.1177/1479164110396919

    View details for Web of Science ID 000287469500006

    View details for PubMedID 21262870

  • Relationship between insulin resistance and C-reactive protein in a patient population treated with second generation antipsychotic medications INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Kim, S. H., Reaven, G., Lindley, S. 2011; 26 (1): 43-47

    Abstract

    C-reactive protein (CRP) is an inflammatory marker associated with obesity, insulin resistance, and cardiovascular disease. A recent study found CRP levels to be higher in individuals treated with certain antipsychotic medications such as olanzapine; however, it is not clear whether this is associated directly with drug intake or indirectly with drug-associated weight gain and insulin resistance. The objective of this study was to explore the potential predictors of CRP including insulin resistance, components of the metabolic syndrome, psychiatric diagnosis, and antipsychotic medication in patients treated with antipsychotics. Sixty-four outpatients without diabetes being treated with a single second generation antipsychotic medication had direct measurements of insulin resistance at the end of a 180-min infusion of glucose, insulin, and octreotide (insulin suppression test) as well as components of the metabolic syndrome. Insulin resistance was the strongest predictor of CRP (r=0.52, P<0.001). When adjusted for insulin resistance, there was no significant relationship between CRP and any of the components of the metabolic syndrome criteria, specific drug treatment or psychiatric diagnoses. In conclusion, insulin resistance is strongly associated with CRP levels and likely contributes to earlier associations between CRP and certain antipsychotic treatments.

    View details for DOI 10.1097/YIC.0b013e3283400cd3

    View details for Web of Science ID 000285083700005

    View details for PubMedID 20861740

  • Apelin Decreases Lipolysis via G(q), G(i), and AMPK-Dependent Mechanisms ENDOCRINOLOGY Yue, P., Jin, H., Xu, S., Aillaud, M., Deng, A. C., Azuma, J., Kundu, R. K., Reaven, G. M., Quertermous, T., Tsao, P. S. 2011; 152 (1): 59-68

    Abstract

    The release of free fatty acids (FFAs) from adipocytes (i.e. lipolysis) is increased in obesity and is a contributory factor to the development of insulin resistance. A recently identified adipokine, apelin, is up-regulated in states of obesity. Although apelin is secreted by adipocytes, its functions in them remain largely unknown. To determine whether apelin affects lipolysis, FFA, glycerol, and leptin levels, as well as abdominal adiposity, were measured at baseline and after reintroduction of exogenous apelin in apelin-null mice. To examine apelin's effects in vitro, isoproterenol-induced FFA/glycerol release, and hormone-sensitive lipase (HSL) and acetyl CoA carboxylase phosphorylation were investigated in 3T3-L1 cells and isolated wild-type adipocytes. Serum FFA, glycerol, and leptin concentrations, as well as abdominal adiposity, were significantly increased in apelin-null vs. wild-type mice; these changes were ameliorated in response to exogenous apelin. Apelin also reduced isoproterenol-induced FFA release in adipocytes isolated from wild-type but not APJ-null mice. In 3T3-L1 cells and isolated adipocytes, apelin attenuated isoproterenol-induced FFA/glycerol release. Apelin's inhibition was reversed by pertussis toxin, the G(q) inhibitor glycoprotein antagonist 2A, and the AMP-activated protein kinase inhibitors compound C and dorsomorphin. Apelin increased HSL phosphorylation at Ser-565 and also abrogated isoproterenol-induced HSL phosphorylation at Ser-563. Notably, apelin increased acetyl CoA carboxylase phosphorylation, suggesting AMPK activation. In conclusion, apelin negatively regulates lipolysis. Its actions may be mediated by pathways involving G(q), G(i), and AMP-activated protein kinase.

    View details for DOI 10.1210/en.2010-0576

    View details for Web of Science ID 000285573000008

    View details for PubMedID 21047945

  • Apelin Inhibits Lipolysis in a Gq-, Gi-, and AMPK-Dependent Manner Yue, P., Jin, H., Aillaud, M., Deng, A., Azuma, J., Kundu, R., Reaven, G., Quertermous, T., Tsao, P. LIPPINCOTT WILLIAMS & WILKINS. 2010
  • Differential adipogenic and inflammatory properties of small adipocytes in Zucker Obese and Lean rats DIABETES & VASCULAR DISEASE RESEARCH Liu, A., Sonmez, A., Yee, G., Bazuine, M., Arroyo, M., Sherman, A., McLaughlin, T., Reaven, G., Cushman, S., Tsao, P. 2010; 7 (4): 311-318

    Abstract

    We recently reported that a preponderance of small adipose cells, decreased expression of cell differentiation markers, and enhanced inflammatory activity in human subcutaneous whole adipose tissue were associated with insulin resistance. To test the hypothesis that small adipocytes exhibited these differential properties, we characterised small adipocytes from epididymal adipose tissue of Zucker Obese (ZO) and Lean (ZL) rats. Rat epididymal fat pads were removed and adipocytes isolated by collagenase digestion. Small adipocytes were separated by sequential filtration through nylon meshes. Adipocytes were fixed in osmium tetroxide for cell size distribution analysis via Beckman Coulter Multisizer. Quantitative real-time PCR for cell differentiation and inflammatory genes was performed. Small adipocytes represented a markedly greater percentage of the total adipocyte population in ZO than ZL rats (58±4% vs. 12±3%, p<0.001). In ZO rats, small as compared with total adipocytes had 4-fold decreased adiponectin, and 4-fold increased visfatin and IL-6 levels. Comparison of small adipocytes in ZO versus ZL rats revealed 3-fold decreased adiponectin and PPAR? levels, and 2.5-fold increased IL-6. In conclusion, ZO rat adipose tissue harbours a large proportion of small adipocytes that manifest impaired cell differentiation and pro-inflammatory activity, two mechanisms by which small adipocytes may contribute to insulin resistance.

    View details for DOI 10.1177/1479164110386126

    View details for Web of Science ID 000285080700008

    View details for PubMedID 20961992

  • Glucose-Stimulated Insulin Secretion in Gastric Bypass Patients with Hypoglycemic Syndrome: No Evidence for Inappropriate Pancreatic beta-cell Function OBESITY SURGERY Kim, S. H., Abbasi, F., Lamendola, C., Reaven, G. M., McLaughlin, T. 2010; 20 (8): 1110-1116

    Abstract

    Roux-en-Y gastric bypass surgery (RYGB) has been associated with a hypoglycemic syndrome characterized by postprandial hypoglycemia and hyperinsulinemia. The syndrome is believed to occur due to insulin hypersecretion from either pancreatic beta-cell hyperplasia or hyperfunction.Eight RYGB patients with hypoglycemic syndrome had insulin secretion rates determined during a 240-min graded intravenous glucose infusion. They were compared to 34 nondiabetic, nonsurgical individuals who were divided based on their insulin sensitivity status as measured by the insulin suppression test: insulin-sensitive (n = 8), insulin intermediate (n = 7), and insulin-resistant (n = 19).RYGB patients had insulin concentrations and HOMA-IR similar to the insulin-sensitive reference group. In addition, integrated insulin secretion rates were comparable to the insulin-sensitive group and significantly lower than the insulin intermediate (p

    View details for DOI 10.1007/s11695-010-0183-2

    View details for Web of Science ID 000280746100304

    View details for PubMedID 20665189

  • PPAR-gamma agonists, insulin resistance and dyslipidemia: not a simple relationship CLINICAL LIPIDOLOGY Johns, B. R., Reaven, G. M. 2010; 5 (4): 509-525

    View details for DOI 10.2217/CLP.10.36

    View details for Web of Science ID 000281332200014

  • Comparison of Surrogate and Direct Measurement of Insulin Resistance in Chronic Hepatitis C Virus Infection: Impact of Obesity and Ethnicity HEPATOLOGY Lam, K. D., Bacchetti, P., Abbasi, F., Ayala, C. E., Loeb, S. M., Shah, V., Wen, M. J., Reaven, G. M., Maher, J. J., Khalili, M. 2010; 52 (1): 38-46

    Abstract

    Studies using surrogate estimates show high prevalence of insulin resistance in hepatitis C infection. This study prospectively evaluated the correlation between surrogate and directly measured estimates of insulin resistance and the impact of obesity and ethnicity on this relationship. Eighty-six nondiabetic, noncirrhotic patients with hepatitis C virus (age = 48 +/- 7 years, 74% male, 44% white, 22% African American, 26% Latino, 70% genotype 1) were categorized into normal-weight (body mass index [BMI] < 25, n = 30), overweight (BMI = 25-29.9, n = 38), and obese (BMI > or = 30, n = 18). Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during a 240-minute insulin suppression test. Surrogate estimates included: fasting glucose and insulin, glucose/insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), insulin (I-AUC) and glucose (G-AUC) area under the curve during oral glucose tolerance test, and the Belfiore and Stumvoll indexes. All surrogate estimates correlated with SSPG, but the magnitude of correlation varied (r = 0.30-0.64). The correlation coefficients were highest in the obese. I-AUC had the highest correlation among all ethnic and weight groups (r = 0.57-0.77). HOMA-IR accounted for only 15% of variability in SSPG in the normal weight group. The common HOMA-IR cutoff of < or =3 to define insulin resistance had high misclassification rates especially in the overweight group independent of ethnicity. HOMA-IR > 4 had the lowest misclassification rate (75% sensitivity, 88% specificity). Repeat HOMA-IR measurements had higher within-person variation in the obese (standard deviation = 0.77 higher than normal-weight, 95% confidence interval = 0.25-1.30, P = 0.005).Because of limitations of surrogate estimates, caution should be used in interpreting data evaluating insulin resistance especially in nonobese, nondiabetic patients with HCV.

    View details for DOI 10.1002/hep.23670

    View details for Web of Science ID 000279409200007

    View details for PubMedID 20578127

  • Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents JOURNAL OF PSYCHIATRIC RESEARCH Kim, S. H., Nikolics, L., Abbasi, F., Lamendola, C., Link, J., Reaven, G. M., Lindley, S. 2010; 44 (8): 493-498

    Abstract

    Second generation antipsychotics (SGAs) can increase weight gain and weight-induced insulin resistance. Recent studies have suggested weight-independent effects of certain SGAs on insulin resistance; however the magnitude of these effects and the relationship between BMI and insulin resistance in patients on SGAs are not established. To evaluate, the relationship between body mass index (BMI) and insulin resistance in 54 patients being stably treated with olanzapine (n=19), risperidone (n=16), or aripiprazole (n=19) was compared with data from a large reference population (n=201) not on SGAs. Insulin resistance was directly quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. The relationship between BMI and SSPG was similar between the SGA (r=0.58) and the reference population (r=0.50). When SSPG was standardized based on expected values for the reference population, patients on olanzapine had a higher degree of insulin resistance (mean z-score+/-SD, 0.68+/-0.9) than expected for level of BMI compared with those on aripiprazole (-0.25+/-1) and risperidone (-0.3+/-0.9), F(2,51)=6.28 (p=0.004). Thus, olanzapine group was 0.76 SD above the reference population or in the 78 percentile for insulin resistance. SSPG was correlated with fasting plasma insulin concentration (0.78 (0.64-0.87), p<0.001) but not fasting glucose concentration (0.15 (-0.13-0.40), p=0.29). In conclusion, BMI contributes a quarter to a third of the variance in insulin resistance in the SGA population similar to the reference population. Olanzapine also appears to have an independent effect on insulin resistance that is above and beyond obesity.

    View details for DOI 10.1016/j.jpsychires.2009.11.007

    View details for Web of Science ID 000278653500002

    View details for PubMedID 19962157

  • Pioglitazone Increases the Proportion of Small Cells in Human Abdominal Subcutaneous Adipose Tissue OBESITY McLaughlin, T. M., Liu, T., Yee, G., Abbasi, F., Lamendola, C., Reaven, G. M., Tsao, P., Cushman, S. W., Sherman, A. 2010; 18 (5): 926-931

    Abstract

    Rodent and in vitro studies suggest that thiazolidinediones promote adipogenesis but there are few studies in humans to corroborate these findings. The purpose of this study was to determine whether pioglitazone stimulates adipogenesis in vivo and whether this process relates to improved insulin sensitivity. To test this hypothesis, 12 overweight/obese nondiabetic, insulin-resistant individuals underwent biopsy of abdominal subcutaneous adipose tissue at baseline and after 12 weeks of pioglitazone treatment. Cell size distribution was determined via the Multisizer technique. Insulin sensitivity was quantified at baseline and postpioglitazone by the modified insulin suppression test. Regional fat depots were quantified by computed tomography (CT). Insulin resistance (steady-state plasma insulin and glucose (SSPG)) decreased following pioglitazone (P < 0.001). There was an increase in the ratio of small-to-large cells (1.16 +/- 0.44 vs. 1.52 +/- 0.66, P = 0.03), as well as a 25% increase in the absolute number of small cells (P = 0.03). The distribution of large cell diameters widened (P = 0.009), but diameter did not increase in the case of small cells. The increase in proportion of small cells was associated with the degree to which insulin resistance improved (r = -0.72, P = 0.012). Visceral abdominal fat decreased (P = 0.04), and subcutaneous abdominal (P = 0.03) and femoral fat (P = 0.004) increased significantly. Changes in fat volume were not associated with SSPG change. These findings demonstrate a clear effect of pioglitazone on human subcutaneous adipose cells, suggestive of adipogenesis in abdominal subcutaneous adipose tissue, as well as redistribution of fat from visceral to subcutaneous depots, highlighting a potential mechanism of action for thiazolidinediones. These findings support the hypothesis that defects in subcutaneous fat storage may underlie obesity-associated insulin resistance.

    View details for DOI 10.1038/oby.2009.380

    View details for Web of Science ID 000277234800013

    View details for PubMedID 19910937

  • Utility of Homeostasis Model Assessment of beta-Cell Function in Predicting Diabetes in 12,924 Healthy Koreans Response DIABETES CARE Kim, S. H., Sung, K., Reaven, G. M. 2010; 33 (5): E72-E72

    View details for DOI 10.2337/dc10-0283

    View details for Web of Science ID 000208521200008

  • Using Pre-existing Microarray Datasets to Increase Experimental Power: Application to Insulin Resistance PLOS COMPUTATIONAL BIOLOGY Daigle, B. J., Deng, A., McLaughlin, T., Cushman, S. W., Cam, M. C., Reaven, G., Tsao, P. S., Altman, R. B. 2010; 6 (3)

    Abstract

    Although they have become a widely used experimental technique for identifying differentially expressed (DE) genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources; thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT), a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes' expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58%) of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a freely available software package that is immediately applicable to any human microarray study.

    View details for DOI 10.1371/journal.pcbi.1000718

    View details for Web of Science ID 000278125200026

    View details for PubMedID 20361040

  • Inflammation in subcutaneous adipose tissue: relationship to adipose cell size DIABETOLOGIA McLaughlin, T., Deng, A., Yee, G., Lamendola, C., Reaven, G., Tsao, P. S., Cushman, S. W., Sherman, A. 2010; 53 (2): 369-377

    Abstract

    Inflammation is associated with increased body mass and purportedly with increased size of adipose cells. We sought to determine whether increased size of adipose cells is associated with localised inflammation in weight-stable, moderately obese humans.We recruited 49 healthy, moderately obese individuals for quantification of insulin resistance (modified insulin suppression test) and subcutaneous abdominal adipose tissue biopsy. Cell size distribution was analysed with a multisizer device and inflammatory gene expression with real-time PCR. Correlations between inflammatory gene expression and cell size variables, with adjustment for sex and insulin resistance, were calculated.Adipose cells were bimodally distributed, with 47% in a 'large' cell population and the remainder in a 'small' cell population. The median diameter of the large adipose cells was not associated with expression of inflammatory genes. Rather, the fraction of small adipose cells was consistently associated with inflammatory gene expression, independently of sex, insulin resistance and BMI. This association was more pronounced in insulin-resistant than insulin-sensitive individuals. Insulin resistance also independently predicted expression of inflammatory genes.This study demonstrates that among moderately obese, weight-stable individuals an increased proportion of small adipose cells is associated with inflammation in subcutaneous adipose tissue, whereas size of mature adipose cells is not. The observed association between small adipose cells and inflammation may reflect impaired adipogenesis and/or terminal differentiation. However, it is unclear whether this is a cause or consequence of inflammation. This question and whether small vs large adipose cells contribute differently to inflammation in adipose tissue are topics for future research. Trial registration: ClinicalTrials.gov NCT00285844.

    View details for DOI 10.1007/s00125-009-1496-3

    View details for Web of Science ID 000273084400019

    View details for PubMedID 19816674

  • The increase in plasma PAI-1 associated with insulin resistance may be mediated by the presence of hepatic steatosis ATHEROSCLEROSIS Ardigo, D., Franzini, L., Valtuena, S., Numeroso, F., Piatti, P. M., Monti, L., Reaven, G. M., Zavaroni, I. 2010; 208 (1): 240-245

    Abstract

    Recent evidence suggests that plasminogen-activator inhibitor-1 (PAI-1) is abundantly produced by the fatty liver, but it is unclear whether hepatic steatosis (HS) can mediate the increase in plasma PAI-1 induced by insulin resistance/compensatory hyperinsulinemia (IR/CH).To address this issue, we cross-sectionally evaluated IR/CH as area under the curve of plasma insulin (AUC-PI) concentrations during OGTT, metabolic profile, and ultrasound degree of HS in 235 healthy volunteers (132M, age: 60+/-7 years) with normal transaminase concentrations. Circulating PAI-1 was increased in subjects with classical features of IR/CH (overweight, high fasting and post-OGTT insulin and glucose, high triglycerides (TG), and low HDL-cholesterol), and significantly correlated to prevalence and degree of HS, but not to alcohol intake. In a multivariate model, AUC-PI, TG and degree of HS were independent predictors of plasma PAI-1 (R(2)=0.32). However, AUC-PI was significantly correlated to PAI-1 only in subjects with HS, suggesting an interaction between AUC-PI and HS. In addition, in the presence of HS and IR/CH, PAI-1 concentrations were increased to a similar extent both in heavy and moderate drinkers, suggesting that metabolic and alcoholic steatosis have a similar effect on the relationship between IR/CH and PAI-1.These results support the hypothesis that HS has a major impact on the relationship between IR/CH and plasma PAI-1 concentrations, and this effect seems to be unaffected by the etiology of the HS.

    View details for DOI 10.1016/j.atherosclerosis.2009.06.026

    View details for Web of Science ID 000273567300040

    View details for PubMedID 19656511

  • Apelin is necessary for the maintenance of insulin sensitivity AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Yue, P., Jin, H., Aillaud, M., Deng, A. C., Azuma, J., Asagami, T., Kundu, R. K., Reaven, G. M., Quertermous, T., Tsao, P. S. 2010; 298 (1): E59-E67

    Abstract

    The recently discovered peptide apelin is known to be involved in the maintenance of insulin sensitivity. However, questions persist regarding its precise role in the chronic setting. Fasting glucose, insulin, and adiponectin levels were determined on mice with generalized deficiency of apelin (APKO). Additionally, insulin (ITT) and glucose tolerance tests (GTT) were performed. To assess the impact of exogenously delivered apelin on insulin sensitivity, osmotic pumps containing pyroglutamated apelin-13 or saline were implanted in APKO mice for 4 wk. Following the infusion, ITT/GTTs were repeated and the animals euthanized. Soleus muscles were harvested and homogenized in lysis buffer, and insulin-induced Akt phosphorylation was determined by Western blotting. Apelin-13 infusion and ITTs/GTTs were also performed in obese diabetic db/db mice. To probe the underlying mechanism for apelin's effects, apelin-13 was also delivered to cultured C2C12 myotubes. 2-[3H]deoxyglucose uptake and Akt phosphorylation were assessed in the presence of various inhibitors. APKO mice had diminished insulin sensitivity, were hyperinsulinemic, and had decreased adiponectin levels. Soleus lysates had decreased insulin-induced Akt phosphorylation. Administration of apelin to APKO and db/db mice resulted in improved insulin sensitivity. In C2C12 myotubes, apelin increased glucose uptake and Akt phosphorylation. These events were fully abrogated by pertussis toxin, compound C, and siRNA knockdown of AMPKalpha1 but only partially diminished by LY-294002 and not at all by L-NAME. We conclude that apelin is necessary for the maintenance of insulin sensitivity in vivo. Apelin's effects on glucose uptake and Akt phosphorylation are in part mediated by a G(i) and AMPK-dependent pathway.

    View details for DOI 10.1152/ajpendo.00385.2009

    View details for Web of Science ID 000272793700007

    View details for PubMedID 19861585

  • Apelin is Necessary for the Maintenance of Insulin Sensitivity Yue, P., Jin, H., Aillaud-Manzanera, M., Deng, A. C., Azuma, J., Kundu, R. K., Reaven, G. M., Quertermous, T., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1114-S1115
  • Differential Intra-abdominal Adipose Tissue Profiling in Obese, Insulin-resistant Women OBESITY SURGERY Liu, A., McLaughlin, T., Liu, T., Sherman, A., Yee, G., Abbasi, F., Lamendola, C., Morton, J., Cushman, S. W., Reaven, G. M., Tsao, P. S. 2009; 19 (11): 1564-1573

    Abstract

    We recently identified differences in abdominal subcutaneous adipose tissue (SAT) from insulin-resistant (IR) as compared to obesity-matched insulin sensitive individuals, including accumulation of small adipose cells, decreased expression of cell differentiation markers, and increased inflammatory activity. This study was initiated to see if these changes in SAT of IR individuals were present in omental visceral adipose tissue (VAT); in this instance, individuals were chosen to be IR but varied in degree of adiposity. We compared cell size distribution and genetic markers in SAT and VAT of IR individuals undergoing bariatric surgery.Eleven obese/morbidly obese women were IR by the insulin suppression test. Adipose tissue surgical samples were fixed in osmium tetroxide for cell size analysis via Beckman Coulter Multisizer. Quantitative real-time polymerase chain reaction for genes related to adipocyte differentiation and inflammation was performed.While proportion of small cells and expression of adipocyte differentiation genes did not differ between depots, inflammatory genes were upregulated in VAT. Diameter of SAT large cells correlated highly with increasing proportion of small cells in both SAT and VAT (r = 0.85, p = 0.001; r = 0.72, p = 0.01, respectively). No associations were observed between VAT large cells and cell size variables in either depot. The effect of body mass index (BMI) on any variables in both depots was negligible.The major differential property of VAT of IR women is increased inflammatory activity, independent of BMI. The association of SAT adipocyte hypertrophy with hyperplasia in both depots suggests a primary role SAT may have in regulating regional fat storage.

    View details for DOI 10.1007/s11695-009-9949-9

    View details for Web of Science ID 000271282900016

    View details for PubMedID 19711137

  • Plasma Glucose and Insulin Regulation Is Abnormal Following Gastric Bypass Surgery with or Without Neuroglycopenia OBESITY SURGERY Kim, S. H., Liu, T. C., Abbasi, F., Lamendola, C., Morton, J. M., Reaven, G. M., McLaughlin, T. L. 2009; 19 (11): 1550-1556

    Abstract

    Enhanced insulin sensitivity is commonly seen following Roux-en-Y gastric bypass surgery (RYGB) whereas symptomatic hypoglycemia post-RYGB seems to occur infrequently. It is unclear how different plasma glucose and insulin responses are in patients with symptomatic hypoglycemia (SX-RYGB) versus those who remain asymptomatic (ASX-RYGB), nor when compared with non-surgical controls with varying degrees of insulin sensitivity.Plasma glucose and insulin concentrations were determined following a 75-g oral glucose challenge in five groups: symptomatic and asymptomatic patients following RYGB (n = 9 each) and overweight/obese controls, divided into three subgroups (n = 30 each) on the basis of degree of insulin sensitivity measured by the insulin suppression test.SX-RYGB group had higher 30-min glucose after oral glucose compared with the ASX-RYGB group (p = 0.04). The two groups did not differ in peak glucose and insulin concentrations, nadir glucose concentration, or insulin-to-glucose ratio 30 min after oral glucose. These values were significantly different from the three control groups, and peak insulin concentrations post-RYGB were increased at every degree of insulin sensitivity as compared with the control groups.Plasma glucose and insulin responses to oral glucose in patients with symptomatic hypoglycemia post-RYGB are minimally different when compared to individuals who remain asymptomatic, and both groups demonstrate hyperinsulinemia out of proportion to their degree of insulin sensitivity.

    View details for DOI 10.1007/s11695-009-9893-8

    View details for Web of Science ID 000271282900014

    View details for PubMedID 19557485

  • Insulin secretory function in Type 2 diabetes: Does it matter how you measure it? JOURNAL OF DIABETES Reaven, G. M. 2009; 1 (3): 142-150

    Abstract

    The following estimates of insulin secretory function have been used widely to evaluate the role of pancreatic β-cells in the pathogenesis and treatment of patients with type 2 diabetes (2DM): (i) Homeostatic Model Assessment (HOMA)-β, a calculation based on fasting plasma glucose and insulin concentrations; (ii) post-glucose acute insulin response (AIRg), the increment in insulin concentration measured in the 5 min after intravenous glucose; and (iii) ΔI/ΔG, the ratio of the increment in plasma insulin concentration (I)/increment in plasma glucose concentration (G) 30 min after the oral administration of 75 g glucose. Experiments based on these approaches have led to a widely held point of view that that the natural history of 2DM is characterized by a progressive increase in the magnitude of hyperglycemia, secondary to an inexorable decline in pancreatic β-cell function: the greater the increase in plasma glucose concentration, the greater the impairment of the ability of the pancreas to secrete insulin. In the present review, theoretical questions are raised as to the physiological validity of these estimates of insulin secretory function and experimental data are presented demonstrating that hourly measurements of plasma insulin and glucose concentrations in response to mixed meals throughout an 8-h day lead to a very different point of view. Studies are also reviewed that question the 'inexorability' of the changes in insulin secretory function that have been reported. It is concluded that it may be time to challenge current conventional wisdom as to the role of the β-cell in the natural history of 2DM.

    View details for DOI 10.1111/j.1753-0407.2009.00016.x

    View details for Web of Science ID 000208415100010

  • Pioglitazone decreases postprandial accumulation of remnant lipoproteins in insulin-resistant smokers DIABETES OBESITY & METABOLISM Abbasi, F., Lamendola, C., Leary, E. T., Reaven, G. M. 2009; 11 (8): 779-785

    Abstract

    Fasting hypertriglyceridaemia has been reported to occur commonly in cigarette smokers and is thought to increase cardiovascular disease (CVD) risk in these individuals. More recently, it has been suggested that an increase in non-fasting triglycerides, rather than fasting hypertriglyceridaemia, is an independent CVD risk factor.In this study, we divided 24 smokers into insulin-resistant (IR) and insulin-sensitive (IS) groups by determining their steady-state plasma glucose concentrations during the insulin suppression test and compared fasting and daylong postprandial accumulation of total triglycerides and remnant lipoprotein (RLP) concentrations, before and after 3 months of pioglitazone (PIO) administration.The two groups were similar in age, body mass index, race and gender distribution, but differed dramatically in insulin sensitivity. Baseline fasting and postprandial triglyceride, RLP cholesterol and RLP triglyceride concentrations were significantly higher in the IR smokers (p=0.01 to <0.01). Insulin resistance [corrected] and both fasting and postprandial triglyceride and RLP triglyceride levels decreased significantly (p=0.05 to 0.01) [corrected] in PIO-treated IR smokers, without any significant increase in weight instead of insulin sensitivity and both fasting and postprandial triglyceride and RLP triglyceride levels decreased significantly (p = 0.05 to, 0.01) in PIO-treated IR smokers, without any significant increase in weight. [corrected]The postprandial accumulation of RLP particles is increased in the IR subset of smokers and is likely to contribute to the increased CVD risk in these individuals. Furthermore, PIO administration provides a possible therapeutic approach to decreasing postprandial lipaemia and CVD risk in IR smokers who are unwilling or unable to stop smoking.

    View details for DOI 10.1111/j.1463-1326.2009.01041.x

    View details for Web of Science ID 000267426100005

    View details for PubMedID 19476476

  • In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment JOURNAL OF PSYCHIATRIC RESEARCH Reaven, G. M., Lieberman, J. A., Sethuraman, G., Kraemer, H., Davis, J. M., Blasey, C., Tsuang, M. T., Schatzberg, A. F. 2009; 43 (11): 997-1002

    Abstract

    Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients.

    View details for DOI 10.1016/j.jpsychires.2009.01.010

    View details for Web of Science ID 000268287100006

    View details for PubMedID 19268968

  • HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not? DIABETES & VASCULAR DISEASE RESEARCH Reaven, G. M. 2009; 6 (2): 133-138

    View details for DOI 10.1177/1479164109336038

    View details for Web of Science ID 000268991000010

    View details for PubMedID 20368203

  • Is diagnosing metabolic syndrome a uniquely simple way to predict incident type 2 diabetes mellitus? CANADIAN MEDICAL ASSOCIATION JOURNAL Reaven, G. M. 2009; 180 (6): 601-602

    View details for DOI 10.1503/cmaj.090092

    View details for Web of Science ID 000263984300003

    View details for PubMedID 19289800

  • Comparison of the antilipolytic effects of an A(1) adenosine receptor partial agonist in normal and diabetic rats DIABETES OBESITY & METABOLISM Dhalla, A. K., Santikul, M., Chisholm, J. W., Belardinelli, L., Reaven, G. M. 2009; 11 (2): 95-101

    Abstract

    Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT-3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary-induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT-3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats.ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC(50) values for forskolin-stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 +/- 60 microM) compared with SD rats (332 +/- 38 microM). EC(50) values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol-stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 +/- 23 microM) compared with SD rats (343 +/- 27 microM). Insulin inhibited lipolysis in adipocytes from SD rats with an IC(50) value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC(50) values for CVT-3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT-3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT-3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT-3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A(1) receptors relative to beta-actin expression in adipocytes from SD (0.98 +/- 0.2) and ZDF rats (0.99 +/- 0.3).The antilipolytic effects of CVT-3619 appear to be independent of insulin resistance and animal model.

    View details for DOI 10.1111/j.1463-1326.2008.00902.x

    View details for Web of Science ID 000262105800003

    View details for PubMedID 18494808

  • Insulin resistance in pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Zamanian, R. T., Hansmann, G., Snook, S., Lilienfeld, D., Rappaport, K. M., Reaven, G. M., RABINOVITCH, M., Doyle, R. L. 2009; 33 (2): 318-324

    Abstract

    Although obesity, dyslipidemia and insulin resistance (IR) are well known risk factors for systemic cardiovascular disease, their impact on pulmonary arterial hypertension (PAH) is unknown. The present authors' previous studies indicate that IR may be a risk factor for PAH. The current study has investigated the prevalence of IR in PAH and explored its relationship with disease severity. Clinical data and fasting blood samples were evaluated in 81 nondiabetic PAH females. In total, 967 National Health and Nutrition Examination Surveys (NHANES) females served as controls. The fasting triglyceride to high-density lipoprotein cholesterol ratio was used as a surrogate of insulin sensitivity. While body mass index was similar in NHANES versus PAH females (28.6 versus 28.7 kg.m(-2)), PAH females were more likely to have IR (45.7 versus 21.5%) and less likely to be insulin sensitive (IS; 43.2 versus 57.8%). PAH females mostly (82.7%) had New York Heart Association (NYHA) class II and III symptoms. Aetiology, NYHA class, 6-min walk-distance and haemodynamics did not differ between IR and IS PAH groups. However, the presence of IR and a higher NYHA class was associated with poorer 6-months event-free survival (58 versus 79%). Insulin resistance appears to be more common in pulmonary arterial hypertension females than in the general population, and may be a novel risk factor or disease modifier that might impact on survival.

    View details for DOI 10.1183/09031936.00000508

    View details for Web of Science ID 000263709300014

    View details for PubMedID 19047320

  • Prevalence of Insulin Resistance and Related Risk Factors for Cardiovascular Disease in Patients With Essential Hypertension AMERICAN JOURNAL OF HYPERTENSION Lima, N. K., Abbasi, F., Lamendola, C., Reaven, G. M. 2009; 22 (1): 106-111

    Abstract

    There is evidence that the subgroup of patients with essential hypertension who are also insulin resistant is at increased risk of cardiovascular disease (CVD). We are unaware of the frequency of insulin resistance in patients with essential hypertension as well as the CVD risk in this subgroup of patients. This analysis was aimed at providing the prevalence of insulin resistance and associated CVD risk factors in treated and untreated patients with essential hypertension.The study population consisted of 126 patients with hypertension: 56 untreated and 70 in a stable treatment program. Body mass index (BMI), blood pressure, plasma glucose and insulin responses to an oral glucose challenge, lipid and lipoprotein concentrations, and steady-state plasma glucose (SSPG) concentration during the insulin suppression test were measured. Insulin resistance was defined operationally as a SSPG concentration >180 mg/dl.Demographic characteristics and metabolic CVD risk factors were comparable in both groups, with 30-50% of both treated and untreated patients having abnormalities of all risk factors measured. Approximately 50% of patients met the criteria for insulin resistance in both groups, and the prevalence of abnormal CVD risk factors in this group was increased two to threefold as compared to the other half of the subjects.Approximately 50% of patients with essential hypertension, both treated and untreated, appear to be insulin resistant, and CVD risk factors are greatly accentuated in this subset of patients.

    View details for DOI 10.1038/ajh.2008.263

    View details for Web of Science ID 000261939700021

    View details for PubMedID 18772854

  • A1 adenosine receptor: role in diabetes and obesity. Handbook of experimental pharmacology Dhalla, A. K., Chisholm, J. W., Reaven, G. M., Belardinelli, L. 2009: 271-295

    Abstract

    Adenosine mediates its diverse effects via four subtypes (A(1), A(2A), A(2B) and A(3)) of G-protein-coupled receptors. The A(1) adenosine receptor (A(1)AR) subtype is the most extensively studied and is well characterized in various organ systems. The A(1)ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A(1)ARs. Activation of the A(1)ARs in adipocytes reduces adenylate cyclase and cAMP content and causes inhibition of lipolysis. The role of A(1)ARs in lipolysis has been well characterized by using several selective A(1)AR agonists as well as A(1)AR knockout mice. However, the contribution of A(1)ARs to the regulation of lipolysis in pathological conditions like insulin resistance, diabetes and dyslipidemia, where free fatty acids (FFA) play an important role, has not been well characterized. Pharmacological agents that reduce the release of FFA from adipose tissue and thus the availability of circulating FFA have the potential to be useful for insulin resistance and hyperlipidemia. Toward this goal, several selective and efficacious agonists of the A(1)ARs are now available, and some have entered early-phase clinical trials; however, none have received regulatory approval yet. Here we review the existing knowledge on the role of A(1)ARs in insulin resistance, diabetes and obesity, and the progress made in the development of A(1)AR agonists as antilipolytic agents, including the challenges associated with this approach.

    View details for DOI 10.1007/978-3-540-89615-9_9

    View details for PubMedID 19639285

  • Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women DIABETOLOGIA McLaughlin, T., Deng, A., Gonzales, O., AILLAUD, M., Yee, G., Lamendola, C., Abbasi, F., Connolly, A. J., Sherman, A., Cushman, S. W., Reaven, G., Tsao, P. S. 2008; 51 (12): 2303-2308

    Abstract

    We have previously described differences in adipose cell size distribution and expression of genes related to adipocyte differentiation in subcutaneous abdominal fat obtained from insulin-sensitive (IS) and -resistant (IR) persons, matched for degree of moderate obesity. To determine whether other biological properties also differ between IR and IS obese individuals, we quantified markers of inflammatory activity in adipose tissue from overweight IR and IS individuals.Subcutaneous abdominal tissue was obtained from moderately obese women, divided into IR (n = 14) and IS (n = 19) subgroups by determining their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Inflammatory activity was assessed by comparing expression of nine relevant genes and by immunohistochemical quantification of CD45- and CD68-containing cells.SSPG concentrations were approximately threefold higher in IR than in IS individuals. Expression levels of CD68, EMR1, IL8, IL6 and MCP/CCL2 mRNAs were modestly but significantly increased (p < 0.05) in IR compared with IS participants. Results of immunohistochemical staining were consistent with gene expression data, demonstrating modest differences between IR and IS individuals. Crown-like structures, in which macrophages surround single adipocytes, were rarely seen in tissue from either subgroup.A modest increase in inflammatory activity was seen in subcutaneous adipose tissue from IR compared with equally obese IS individuals. Together with previous evidence of impaired adipose cell differentiation in IR vs equally obese individuals, it appears that at least two biological processes in subcutaneous adipose tissue characterize the insulin-resistant state independent of obesity per se.

    View details for DOI 10.1007/s00125-008-1148-z

    View details for Web of Science ID 000260686000019

    View details for PubMedID 18825363

  • Persistence of improvement in insulin sensitivity following a dietary weight loss programme DIABETES OBESITY & METABOLISM McLaughlin, T., Schweitzer, P., Carter, S., Yen, C., Lamendola, C., Abbasi, F., Reaven, G. 2008; 10 (12): 1186-1194

    Abstract

    Short-term dietary weight loss can improve insulin resistance but long-term studies are lacking. We sought to quantify the degree to which maintenance of weight loss after a short-term dietary intervention was associated with persistent metabolic benefits.Fifty-seven insulin-resistant obese subjects had insulin-mediated glucose disposal quantified through the steady-state plasma glucose (SSPG) test, and associated metabolic risk markers quantified at baseline, after a 16-week dietary weight loss intervention, and in 25 subjects, at follow-up of 28.8 +/- 13 months. Changes in metabolic variables over time were analysed and correlation with weight loss ascertained. Those with greatest vs. least long-term SSPG response (responders vs. non-responders) were compared. Multivariate analysis was performed for predictors of persistent SSPG response.At follow-up, the 25 subjects who returned for metabolic testing had, on average, maintained their weight loss. Insulin-mediated glucose disposal remained significantly improved vs. baseline, as did plasma triglyceride and HDL cholesterol (HDL-C) concentrations, and improvement correlated with total amount of weight lost. Comparison of SSPG responders to non-responders showed no difference in amount of weight lost and SSPG change during the 16-week dietary intervention; however, SSPG non-responders regained 2.6% of weight lost, whereas responders lost an additional 1.5% at follow-up (p < 0.05 vs. non-responders). Non-responders had baseline characteristics consistent with more severe insulin resistance, including higher fasting plasma glucose (p = 0.03). Long-term SSPG change was independently predicted by both total weight loss (p = 0.005) and baseline fasting plasma glucose (p = 0.007).Improvement in insulin sensitivity is maintained for 2-3 years following dietary weight loss if weight is not regained. Triglyceride and HDL-C concentrations also remain improved over time, consistent with improvement in insulin sensitivity. Fasting glucose and weight regain predict less long-term response in insulin sensitivity. These results highlight the potential long-term benefits of weight loss and importance of preventing weight regain among high-risk individuals.

    View details for DOI 10.1111/j.1463-1326.2008.00877.x

    View details for Web of Science ID 000260528300005

    View details for PubMedID 18476986

  • Differential effects of insulin sensitivity on androgens in obese women with polycystic ovary syndrome or normal ovulation METABOLISM-CLINICAL AND EXPERIMENTAL Asagami, T., Holmes, T. H., Reaven, G. 2008; 57 (10): 1355-1360

    Abstract

    The differential effects of insulin sensitivity and adiposity on androgen concentrations in women with polycystic ovary syndrome (PCOS) are unclear. To address this issue, we divided 43 overweight women into 4 groups based on both their clinical classification (PCOS or normal) and whether they were insulin resistant (IR) or insulin sensitive (IS) by their steady-state plasma glucose concentrations. Total testosterone concentrations were significantly increased as a function of both clinical classification (PCOS vs normal, P < .0001) and steady-state plasma glucose concentration (IR vs IS, P = .002). Mean testosterone concentrations were higher in PCOS-IR compared with PCOS-IS, normal-IR, or normal-IS women (P < .005). In addition, there was a statistically significant interaction (P = .03) between clinical classification (PCOS vs normal) and insulin sensitivity (IR vs IS) for testosterone concentrations. In contrast, androstenedione concentrations were higher in women with PCOS (P = .001), irrespective of whether they were IR or IS (P = .31); and no interaction between clinical classification and insulin sensitivity was discerned (P = .34). These results indicate that both PCOS and insulin resistance independently contributed to increased total testosterone concentrations within a group of overweight/obese women. These findings are consistent with the hypothesis that the ovaries of women with PCOS are hypersensitive to the ability of insulin to increase testosterone production and that the more insulin resistant the patient, the higher the testosterone concentration. In contrast, androstenedione concentrations seem to be independent of differences in insulin resistance. Our findings emphasize the need to increase understanding of the factors that modulate ovarian androgen secretion.

    View details for DOI 10.1016/j.metabol.2008.05.002

    View details for Web of Science ID 000260240500007

    View details for PubMedID 18803938

  • Pioglitazone administration decreases cardiovascular disease risk factors in insulin-resistant smokers METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Farin, H. M., Lemendola, C., McGraw, L., McLaughlin, T., Reaven, G. M. 2008; 57 (8): 1108-1114

    Abstract

    Insulin sensitivity varies in cigarette smokers, and there is evidence that cardiovascular disease (CVD) risk is greatest in those smokers who are also insulin resistant. To extend these observations, we sought to (1) compare CVD risk factors in smokers who do not plan to stop smoking, divided into insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and (2) evaluate the ability of drug-induced changes in insulin sensitivity to decrease CVD risk. Thirty-six cigarette smokers were divided into IR (n = 19) and IS (n = 17) subgroups by determining their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test (the higher the SSPG, the more insulin resistant the individual). In addition, baseline measurements were made of fasting lipid and lipoprotein concentrations; inflammatory markers; and daylong glucose, insulin, and free fatty acid responses to test meals. All subjects were treated with pioglitazone for 12 weeks, after which all baseline measurements were repeated. Baseline triglyceride and high-density lipoprotein cholesterol concentrations were significantly different in IR as compared with IS smokers (P < .05) both before and after adjustment for differences in sex and body mass index. After pioglitazone treatment, SSPG concentration significantly fell in the IR smokers (P < .001), associated with a significant improvement in the atherogenic lipoprotein profile seen at baseline (P < or = .03) and a decrease in soluble intercellular adhesion molecule 1 and C-reactive protein concentrations (P = .01 and .02, respectively), whereas the IS smokers only had a significant increase in high-density lipoprotein cholesterol (P = .004) and a decrease in soluble intercellular adhesion molecule 1 (P = .02) and CRP (P = .07) levels. In conclusion, cigarette smokers have profound differences in CVD risk factors related to their degree of insulin sensitivity. It is suggested that, in addition to smoking cessation efforts, attention should be given to identifying the subgroup of smokers most at risk for CVD, but unwilling or unable to stop smoking, and to initiating appropriate therapeutic interventions to decrease CVD in this high-risk group.

    View details for DOI 10.1016/j.metabol.2008.03.016

    View details for Web of Science ID 000258196300014

    View details for PubMedID 18640389

  • The therapeutic efficacy of rosiglitazone is enhanced in sulphonylurea-treated patients with type 2 diabetes DIABETES OBESITY & METABOLISM Itakura, H., Abbasi, F., Lamendola, C., Basina, M., Reaven, G. 2008; 10 (8): 685-687
  • Insulin resistance and hyperinsulinemia - You can't have one without the other DIABETES CARE Kim, S. H., Reaven, G. M. 2008; 31 (7): 1433-1438

    Abstract

    Recently, it has been suggested that insulin resistance and hyperinsulinemia can exist in isolation and have differential impacts on cardiovascular disease (CVD). To evaluate this suggestion, we assessed the degree of discordance between insulin sensitivity and insulin response in a healthy, nondiabetic population.Insulin sensitivity was quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 individuals. The integrated insulin response was calculated after a 75-g oral glucose challenge. We analyzed the correlation between insulin resistance and insulin response in addition to quantifying the proportion in quartiles of insulin response by quartiles of insulin sensitivity. Then we compared CVD risk factors between individuals within the same insulin sensitivity quartile but within different insulin response quartiles to evaluate the differential clinical impact of insulin resistance and hyperinsulinemia.Insulin resistance and insulin response were highly correlated (r = 0.76, P < 0.001). A majority (95%) of the most insulin-resistant individuals (top SSPG quartile) were either in the highest insulin response quartile (71%) or second highest (24%). Similarly, 92% of the most insulin-sensitive individuals (lowest SSPG quartile) were in the lowest two insulin response quartiles. There were minimal differences in CVD risk factors between individuals with different insulin responses but within the same insulin sensitivity quartile.Although not perfectly related, insulin resistance and hyperinsulinemia rarely exist in isolation in a nondiabetic population. It is difficult to discern an independent impact of hyperinsulinemia on CVD risk factors associated with insulin resistance.

    View details for DOI 10.2337/dc08-0045

    View details for Web of Science ID 000257421000032

    View details for PubMedID 18594063

  • Comparison of waist circumference versus body mass index in diagnosing metabolic syndrome and identifying apparently healthy subjects at increased risk of cardiovascular disease AMERICAN JOURNAL OF CARDIOLOGY Ryan, M. C., Farin, H. M., Abbasi, F., Reaven, G. M. 2008; 102 (1): 40-46

    Abstract

    The goal of this study was to compare the impact of differences in waist circumference (WC) defined according to the International Diabetes Federation (IDF) and the Adult Treatment Panel III (ATP III) and body mass index (BMI) on cardiovascular disease risk factors in 402 apparently healthy volunteers of European ancestry. Consequently, measurements were made of the WC, BMI, blood pressure, glucose, and lipid components of metabolic syndrome (MS) and insulin-mediated glucose uptake. Subjects were divided according to WC (IDF and ATP III criteria) and by normal weight, overweight, or obesity using BMI, and comparisons were made of the effect of these different indexes of adiposity on cardiovascular disease risk factors. The results indicated that WC and BMI significantly correlated (p <0.001) and were associated with differences in insulin-mediated glucose uptake to a similar degree in men (r = 0.57 and r = 0.59) and women (r = 0.53 and r = 0.52). Prevalences of MS were essentially identical irrespective of the measure of WC used (ATP III vs IDF), as were metabolic characteristics of those classified using IDF or ATP III criteria. Cardiovascular disease risk factor status did not vary substantially when subjects were divided on the basis of WC or BMI. In conclusion, prevalences of MS or cardiovascular disease risk factors did not vary as a function of differences in IDF and ATP III criteria for WC. BMI identified individuals at increased cardiovascular disease risk as effectively as determination of WC.

    View details for DOI 10.1016/j.amjcard.2008.02.096

    View details for Web of Science ID 000257300100007

    View details for PubMedID 18572033

  • Comparison of three treatment approaches to decreasing cardiovascular disease risk in nondiabetic insulin-resistant dyslipidemic subjects AMERICAN JOURNAL OF CARDIOLOGY Abbasi, F., Chen, Y. I., Farin, H. M., Lamendola, C., Reaven, G. M. 2008; 102 (1): 64-69

    Abstract

    The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese insulin-resistant nondiabetic subjects. Insulin sensitivity, fasting lipids and lipoproteins, and postprandial plasma glucose, insulin, free fatty acid, and triglycerides were measured before and after 3 months of treatment with FEN, RSG, or CRD. Weight decreased in the CRD group, but did not change significantly after treatment with either drug. Insulin sensitivity improved significantly in the CRD- and RSG-treated groups, but to a greater extent in those administered RSG, without a significant difference comparing FEN treatment with the CRD. Total cholesterol was significantly lower after FEN and CRD treatment. Fasting plasma triglycerides decreased significantly in the FEN- and CRD-treated groups, but postprandial concentrations decreased in only FEN-treated subjects. Significant decreases in postprandial glucose and insulin were seen in only the RSG- and CRD-treated groups. FEN administration improved dyslipidemia in these subjects without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients without improvement in dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated patients, and improvement in lipid metabolism not as great as with FEN. In conclusion, there did not appear to be 1 therapeutic intervention that effectively treated all metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.

    View details for DOI 10.1016/j.amjcard.2008.02.097

    View details for Web of Science ID 000257300100011

    View details for PubMedID 18572037

  • Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Galluccio, E., Piatti, P., Citterio, L., Lucotti, P. C., Setola, E., Cassina, L., Oldani, M., Zavaroni, I., Bosi, E., Colombo, A., Alfieri, O., Casari, G., Reaven, G. M., Monti, L. D. 2008; 294 (5): E978-E986

    Abstract

    Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.

    View details for DOI 10.1152/ajpendo.00003.2008

    View details for Web of Science ID 000255501600021

    View details for PubMedID 18349107

  • Ethnic differences in the relationship between adiponectin and insulin sensitivity in south Asian and Caucasian women DIABETES CARE Martin, M., Palaniappan, L. P., Kwan, A. C., Reaven, G. M., Reaven, P. D. 2008; 31 (4): 798-801

    Abstract

    To assess whether lower adiponectin concentrations in South Asian Indians may be responsible for their greater degree of insulin resistance.Insulin-mediated glucose uptake and plasma total and high molecular weight (HMW) adiponectin concentrations were quantified in 52 women of South Asian (SA) and Caucasian (CAU) ancestry and compared.Mean +/- SD total (2,965 +/- 1,278 vs. 4,235 +/- 160 ng/ml) and HMW (1,001 +/- 352 vs. 1,591 +/- 854 ng/ml) adiponectin were lower in SAs than CAUs (P < 0.005). Insulin-resistant CAUs (CAU-IR) had lower total (2,665 +/- 1,040 vs. 5,133 +/- 1,086 ng/ml) and HMW (987 +/- 479 vs. 1,935 +/- 838 ng/ml) adiponectin than insulin-sensitive CAUs (CAU-IS) (P < 0.01), but there were no significant differences between insulin-resistant (SA-IR) and insulin-sensitive (SA-IS) SAs. HMW adiponectin did not differ between SA-IR and CAU-IR, but SA-IS had significantly lower adiponectin concentrations than CAU-IS.Insulin resistance status is not associated with significantly lower levels of adiponectin in these SA women, in contrast to the CAU women.

    View details for DOI 10.2337/dc07-1781

    View details for Web of Science ID 000254591900033

    View details for PubMedID 18202246

  • Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity? CARDIOVASCULAR DIABETOLOGY Li, C., Ford, E. S., Meng, Y., Mokdad, A. H., Reaven, G. M. 2008; 7

    Abstract

    The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported to be as closely correlated with insulin resistance as is the fasting serum insulin concentration (FSI), and therefore it is seen as a clinically useful way to identify the concomitant presence of insulin resistance and dyslipidemia. However, conflicting findings exist for the association of the TG/HDL-C ratio with FSI by race/ethnicity.The associations of FSI concentration, serum triglyceride concentrations, and HDL-C were analyzed using log-binomial regression analyses and receiver operating characteristic (ROC) curve analysis among nondiabetic adults (n = 2652, aged > or = 20 years, 51.2% men) in the United States.After adjustment for potential confounding effects, the prevalence ratio of hyperinsulinemia was 2.16 (95% confidence interval [CI], 1.74 to 2.08) when using a single cutoff point of 3.5, and 2.23 (95% CI, 1.83 to 2.72) when using race/ethnicity-specific cutoff points of 3.0 for non-Hispanic whites and Mexican Americans and 2.0 for non-Hispanic blacks for the TG/HDL-C ratio. The area under the ROC curve of the TG/HDL-C ratio for predicting hyperinsulinemia was 0.77 (95% CI, 0.74 to 0.79), 0.75 (95% CI, 0.69 to 0.77), and 0.74 (95% CI, 0.69 to 0.76) for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively.There was a significant association between the TG/HDL-C ratio and FSI among three major racial/ethnic groups in the United States. Our results add further support to the notion that the TG/HDL-C ratio may be a clinically simple and useful indicator for hyperinsulinemia among nondiabetic adults regardless of race/ethnicity.

    View details for DOI 10.1186/1475-2840-7-4

    View details for Web of Science ID 000255912800001

    View details for PubMedID 18307789

  • Isolated Impaired Fasting Glucose and Peripheral Insulin Sensitivity Not a simple relationship DIABETES CARE Kim, S. H., Reaven, G. M. 2008; 31 (2): 347-352

    Abstract

    In a recent consensus statement, the American Diabetes Association (ADA) concluded that individuals with impaired fasting glucose (IFG) have "normal muscle insulin sensitivity." To subject this conclusion to further validation, we evaluated the relationship between glucose tolerance categories and peripheral insulin sensitivity in a large nondiabetic population.Insulin sensitivity was directly quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 nondiabetic individuals divided into four groups: normal glucose tolerance (NGT, n = 318), isolated IFG (n = 63), isolated impaired glucose tolerance (IGT, n = 33), and combined IFG and IGT (IFG/IGT, n = 32).Insulin sensitivity was significantly different in all three groups with pre-diabetes (IFG, IGT, IFG/IGT) as compared with NGT (P < 0.05). Using tertiles of SSPG concentration in the NGT group as operational definitions of insulin resistance (highest tertile) and insulin sensitivity (lowest tertile), there was considerable heterogeneity within the pre-diabetic groups. Thus, 57% of IFG individuals were insulin resistant, and 13% were insulin sensitive. The IFG/IGT group was most homogeneous, with 94% classified as insulin resistant and only 3% as insulin sensitive.Peripheral insulin sensitivity varies considerably in nondiabetic individuals, with IFG individuals showing the most heterogeneity within the pre-diabetes group. We believe that this heterogeneity in insulin sensitivity, and the relatively few patients in whom insulin sensitivity has been measured directly in the past, explain the discrepancy between our findings and those of the recent ADA consensus statement.

    View details for DOI 10.2337/dc07-1574

    View details for Web of Science ID 000266563300033

    View details for PubMedID 18000184

  • Metabolic syndrome: do clinical criteria identify similar individuals among overweight premenopausal women? METABOLISM-CLINICAL AND EXPERIMENTAL Alhassan, S., Kiazand, A., Balise, R. R., King, A. C., Reaven, G. M., Gardner, C. D. 2008; 57 (1): 49-56

    Abstract

    The purpose of this analysis was to determine to what extent the clinical criteria for metabolic syndrome (MetSyn) proposed by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Adult Treatment Panel III (ATP III), and the International Diabetes Foundation (IDF); triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio >/=3.0; and enlarged waist circumference (>/=88 cm) and elevated TG (>/=129 mg/dL) (EWET) identified similar or different overweight women and, secondarily, to examine the effect of 7% weight reduction on MetSyn status. Metabolic syndrome was determined among 256 premenopausal women (age = 41 +/- 6 years, body mass index [BMI] = 32 +/- 4 kg/m(2)) participating in a dietary weight loss clinical trial based on the clinical criteria proposed by WHO, EGIR, ATP III, and IDF. The prevalence of TG/HDL-C ratio >/=3.0 and EWET was determined and compared with MetSyn status. Based on the clinical criteria, 16.1% (EGIR), 20.7% (WHO), 31.0% (ATP III), and 31.8% (IDF) of participants met the criteria for MetSyn; 30.3% and 31.8% had TG/HDL-C >/=3.0 and EWET, respectively. Between 77% and 99% of participants were similarly classified across the clinical criteria. The highest and lowest agreements were between ATP III and IDF (kappa = 0.98; 95% confidence interval, 0.96-1.0) and WHO and IDF (kappa = 0.39; 95% confidence interval, 0.26-0.51), respectively. The TG/HDL-C ratio >/=3.0 and EWET moderately agreed with all 4 clinical criteria for MetSyn (kappa range, 0.36-0.59). Among those diagnosed with MetSyn at baseline, 64.0% to 75.0% of the participants who lost >/=7% and 25.8% to 55.6% of participants who lost <7% of their baseline body weight in 6 months no longer met the various clinical criteria for MetSyn, TG/HDL-C >/=3.0, or EWET. Our findings indicate that MetSyn varies substantially between clinical criteria, which raise questions about the clinical utility of these criteria. Regardless of MetSyn clinical criteria, >/=7% reduction in body weight has a beneficial impact on variables used to define MetSyn.

    View details for DOI 10.1016/j.metabol.2007.08.006

    View details for Web of Science ID 000251929400006

    View details for PubMedID 18078858

  • Clinical experience with a relatively low carbohydrate, calorie-restricted diet improves insulin sensitivity and associated metabolic abnormalities in overweight, insulin resistant South Asian Indian women ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION Backes, A. C., Abbasi, F., Lamendola, C., McLaughlin, T. L., Reaven, G., Palaniappan, L. P. 2008; 17 (4): 669-671

    Abstract

    South Asian Indians are at increased risk for cardiovascular disease associated with insulin resistance and a dyslipidemia characterized by high triglyceride and low high-density lipoprotein cholesterol concentrations. The purpose of this study is to determine the effects of a calorie-restricted, relatively low carbohydrate diet on weight loss, insulin sensitivity, and associated cardiovascular disease risk factors in overweight, insulin resistant, but apparently healthy, South Asian Indian women. Twenty-three, overweight, insulin resistant, apparently healthy, South Asian Indian women were advised on a calorie-restricted diet containing 40 percent carbohydrate for 3 months. Change in weight, insulin sensitivity (quantified by the steady state plasma glucose concentration during the insulin suppression test), and associated cardiovascular disease risk factors were measured. Weight fell from 75.5 to 70.5 kg (p<0.001), associated with significant decreases in diastolic blood pressure, plasma concentrations (mg/dL) of steady state plasma glucose (217 to 176, p<0.001), triglycerides (137 to 101, p = 0.003), and glucose (98 to 92, p = 0.005). A calorie-restricted diet, moderately lower in carbohydrate, can lead to weight loss, decreased insulin resistance, and reduction in several cardiovascular disease risk factors in overweight, insulin resistant, apparently healthy, South Asian Indian women.

    View details for Web of Science ID 000262520400020

    View details for PubMedID 19114407

  • HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Glassford, A. J., Yue, P., Sheikh, A. Y., Chun, H. J., Zarafshar, S., Chan, D. A., Reaven, G. M., Quertermous, T., Tsao, P. S. 2007; 293 (6): E1590-E1596

    Abstract

    Apelin, a novel peptide with significant cardioactive properties, is upregulated by insulin in adipocytes. However, the mechanism by which insulin promotes apelin production is unknown. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor involved in the angiogenic and metabolic responses to tissue hypoxia, has been shown to be activated by insulin in various settings. We therefore hypothesized that HIF-1 regulates insulin-mediated apelin expression in adipocytes. 3T3-L1 cells were differentiated into adipocytes in culture. For experiments, serum-starved 3T3-L1 cells were exposed to insulin and/or a 1% O(2) environment. Apelin expression was assessed using quantitative real-time PCR and ELISA. To directly assess the role of HIF-1 in apelin production, we differentiated mouse embryonic fibroblasts (MEFs) containing a targeted deletion of the HIF-1alpha gene into adipocytes and measured their response to insulin and hypoxia. Apelin expression in mature 3T3-L1 adipocytes was increased significantly by insulin and was attenuated by pharmacological inhibition of insulin signaling. Exposure of cells to either hypoxia or the chemical HIF activators cobalt chloride (CoCl(2)) and dimethyloxaloylglycine (DMOG) resulted in significant upregulation of apelin, consistent with a role for HIF in apelin induction. Moreover, hypoxia-, CoCl(2)-, DMOG-, and insulin-induced apelin expression were all attenuated in differentiated HIF-1alpha-deficient MEFs. In summary, in cultured 3T3-L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.

    View details for DOI 10.1152/ajpendo.00490.2007

    View details for Web of Science ID 000251510200014

    View details for PubMedID 17878221

  • Relationship among alcohol, body weight, and cardiovascular risk factors in 27,030 Korean men DIABETES CARE Sung, K., Kim, S. H., Reaven, G. M. 2007; 30 (10): 2690-2694

    Abstract

    Recent studies suggest a lower risk for overweight/obesity in moderate alcohol drinkers. However, the validity of this relationship and its impact on the putative benefits of alcohol consumption on cardiovascular disease (CVD) risk has not been well evaluated.We assessed the impact of BMI on the relationship between alcohol consumption and CVD risk factors (blood pressure, lipid panel, and glucose and insulin concentrations) in 27,030 healthy Korean men with no major comorbidities or medication intake seen in a large urban Korean hospital.BMI and overweight prevalence increased linearly with alcohol intake (P < 0.001). Alcohol intake was also positively associated with blood pressure and triglyceride, HDL, and fasting glucose concentrations (P < 0.001) and negatively associated with LDL and insulin concentrations (P < 0.001). With nondrinkers as the reference group, the odds ratio for having insulin in the top quartile also declined linearly when adjusted for age, BMI, smoking, and exercise, with the heaviest drinkers (>40 g/day) having an odds ratio of 0.71 (95% CI 0.62-0.82) (P < 0.001). The relationship between alcohol and CVD risk factors was similar in normal-weight and overweight individuals.Alcohol intake is associated with increasing BMI and several metabolic abnormalities, including higher fasting glucose. Paradoxically, it is also associated with lower insulin concentrations. The clinical significance of these findings needs further investigation.

    View details for DOI 10.2337/dc07-0315

    View details for Web of Science ID 000250223400056

    View details for PubMedID 17623829

  • Metabolic impact of switching antipsychotic therapy to aripiprazole after weight gain - A pilot study JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Kim, S. H., Ivanova, O., Abbasi, F. A., Lamendola, C. A., Reaven, G. M., Glick, I. D. 2007; 27 (4): 365-368

    Abstract

    Switching antipsychotic regimen to agents with low weight gain potential has been suggested in patients who gain excessive weight on their antipsychotic therapy. In an open-label pilot study, we evaluated the metabolic and psychiatric efficacy of switching to aripiprazole in 15 (9 men, 6 women) outpatients with schizophrenia who had gained at least 10 kg on their previous antipsychotic regimen. Individuals had evaluation of glucose tolerance, insulin resistance (insulin suppression test), lipid concentrations, and psychiatric status before and after switching to aripiprazole for 4 months. A third of the individuals could not psychiatrically tolerate switching to aripiprazole. In the remaining individuals, psychiatric symptoms significantly improved with decline in Clinical Global Impression Scale (by 26%, P = 0.015) and Positive and Negative Syndrome Scale (by 22%, P = 0.023). Switching to aripiprazole did not alter weight or metabolic outcomes (fasting glucose, insulin resistance, and lipid concentrations) in the patients of whom 73% were insulin resistant and 47% had impaired or diabetic glucose tolerance at baseline. In conclusion, switching to aripiprazole alone does not ameliorate the highly prevalent metabolic abnormalities in the schizophrenia population who have gained weight on other second generation antipsychotic medications.

    View details for DOI 10.1097/JCP.0b013e3180a9076c

    View details for Web of Science ID 000248062400007

    View details for PubMedID 17632220

  • Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis DIABETOLOGIA McLaugblin, T., Sherman, A., Tsao, P., Gonzalez, O., Yee, G., Lamendola, C., Reaven, G. M., Cusbman, S. W. 2007; 50 (8): 1707-1715

    Abstract

    The biological mechanism by which obesity predisposes to insulin resistance is unclear. One hypothesis is that larger adipose cells disturb metabolism via increased lipolysis. While studies have demonstrated that cell size increases in proportion to BMI, it has not been clearly shown that adipose cell size, independent of BMI, is associated with insulin resistance. The aim of this study was to test this widely held assumption by comparing adipose cell size distribution in 28 equally obese, otherwise healthy individuals who represented extreme ends of the spectrum of insulin sensitivity, as defined by the modified insulin suppression test.Subcutaneous periumbilical adipose tissue biopsy samples were fixed in osmium tetroxide and passed through the Beckman Coulter Multisizer to obtain cell size distributions. Insulin sensitivity was quantified by the modified insulin suppression test. Quantitative real-time PCR for adipose cell differentiation genes was performed for 11 subjects.All individuals exhibited a bimodal cell size distribution. Contrary to expectations, the mean diameter of the larger cells was not significantly different between the insulin-sensitive and insulin-resistant individuals. Moreover, insulin resistance was associated with a higher ratio of small to large cells (1.66 +/- 1.03 vs 0.94 +/- 0.50, p = 0.01). Similar cell size distributions were observed for isolated adipose cells. The real-time PCR results showed two- to threefold lower expression of genes encoding markers of adipose cell differentiation (peroxisome proliferator-activated receptor gamma1 [PPARgamma1], PPARgamma2, GLUT4, adiponectin, sterol receptor element binding protein 1c) in insulin-resistant compared with insulin-sensitive individuals.These results suggest that after controlling for obesity, insulin resistance is associated with an expanded population of small adipose cells and decreased expression of differentiation markers, suggesting that impairment in adipose cell differentiation may contribute to obesity-associated insulin resistance.

    View details for DOI 10.1007/s00125-007-0708-y

    View details for Web of Science ID 000248225100017

    View details for PubMedID 17549449

  • Relationships between estimates of adiposity, insulin resistance, and nonalcoholic fatty liver disease in a large group of nondiabetic Korean adults DIABETES CARE Sung, K. C., Ryan, M. C., Kim, B. S., Cho, Y. K., Kim, B. I., Reaven, G. M. 2007; 30 (8): 2113-2118

    Abstract

    Nonalcoholic fatty liver disease (NAFLD) is emerging as a major health problem in parallel with an increasing prevalence of obesity. Insulin resistance and abdominal and overall adiposity are closely associated with NAFLD; however, the interplay between them in the relationship with NAFLD is unclear, especially in nondiabetic individuals.Abdominal ultrasound, hepatitis serology, and measurements of fasting plasma insulin (FPI), lipid concentrations, overall obesity (BMI), and abdominal obesity (waist circumference) were performed in 56,249 Korean subjects.After rigorous exclusion criteria, 36,654 nondiabetic subjects (54% male) were enrolled. Subjects were divided into control (no fatty liver on ultrasound, serum alanine aminotransferase [ALT] <30 units/l [men] or <19 units/l [women]), fatty liver with normal ALT (FL-NALT), and fatty liver with a high ALT (FL-HALT) groups. After adjusting for age, BMI, and waist circumference, FPI and ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) were significantly higher in the FL-NALT than in the control group and even higher in the FL-HALT group. Odds ratios for the presence of FL-HALT with increasing quartiles of FPI and TG/HDL-C ratio were increased five- to sevenfold over those of the control group, independent of age, BMI, and waist circumference.In this large population of individuals of Korean ancestry, results indicate that while overall (BMI) and abdominal (waist circumference) overweight/obesity are associated with features of NAFLD, surrogate estimates of insulin resistance, FPI concentration, and TG/HDL-C ratio predict NAFLD independently of age, BMI, and waist circumference.

    View details for DOI 10.2337/dc07-0512

    View details for Web of Science ID 000248570200034

    View details for PubMedID 17475935

  • Lipoprotein abnormalities are associated with insulin resistance in South Asian Indian women METABOLISM-CLINICAL AND EXPERIMENTAL Palaniappan, L. P., Kwan, A. C., Abbasi, F., Lamendola, C., McLaughlin, T. L., Reaven, G. M. 2007; 56 (7): 899-904

    Abstract

    South Asian Indians are at increased risk of coronary heart disease (CHD), possibly related to dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations. The importance of differences in insulin resistance as compared to abdominal obesity in the development of this atherogenic lipoprotein profile is not clear, and the current cross-sectional study was initiated to examine this issue. Consequently, we defined the relationship between differences in insulin-mediated glucose uptake (IMGU), abdominal obesity, and various measures of lipoprotein metabolism known to increase CHD risk in 52 apparently healthy women of South Asian Indian ancestry. IMGU was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test and abdominal obesity was assessed by measurement of waist circumference (WC), and the population was divided into tertiles on the basis of their SSPG results. Results indicated that although there were significant differences in SSPG, TG, and HDL-C values, there were no differences in age, blood pressure, total cholesterol, low-density lipoprotein cholesterol, body mass index, or WC between the highest and lowest tertiles. SSPG concentrations were significantly correlated with both log TG (r = 0.44, P = .001) and HDL-C (r = -0.44, P < .001) concentration, whereas TG and HDL-C concentrations were not significantly related to WC. Furthermore, the relationships between SSPG concentration and TG and HDL-C remained significant when adjusted for age and WC. Finally, a more extensive lipoprotein analysis indicated that the most insulin resistant tertile had higher TG concentrations, lower concentrations of HDL-C and HDL-C subclasses, and smaller and denser low-density lipoprotein particles than the most insulin sensitive tertile, despite the 2 groups not being different in age, BMI, or WC. These results indicate that a highly atherogenic lipoprotein profile seen in South Asian Indian women is significantly associated with insulin resistance independent of differences in WC.

    View details for DOI 10.1016/j.metabol.2007.01.020

    View details for Web of Science ID 000247542300007

    View details for PubMedID 17570249

  • Clinical efficacy of two hypocaloric diets that vary in overweight patients with type 2 diabetes - Comparison of moderate fat versus carbohydrate reductions DIABETES CARE McLaughlin, T., Carter, S., Lamendola, C., Abbasi, F., Schaaf, P., Basina, M., Reaven, G. 2007; 30 (7): 1877-1879

    View details for DOI 10.2337/dc07-0301

    View details for Web of Science ID 000247768400036

    View details for PubMedID 17475941

  • The individual components of the metabolic syndrome: Is there a Raison d'Etre? JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Reaven, G. M. 2007; 26 (3): 191-195

    View details for Web of Science ID 000248283700001

    View details for PubMedID 17634163

  • A(1) adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Dhalla, A. K., Wong, M. Y., Voshol, P. J., Belardinelli, L., Reaven, G. M. 2007; 292 (5): E1358-E1363

    Abstract

    There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A(1) adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

    View details for DOI 10.1152/ajpendo.00573.2006

    View details for Web of Science ID 000247938900015

    View details for PubMedID 17227958

  • Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals - Effect of differences in insulin sensitivity ARCHIVES OF INTERNAL MEDICINE McLaughlin, T., Abbasi, F., Lamendola, C., Reaven, G. 2007; 167 (7): 642-648

    Abstract

    The possibility that substantial heterogeneity in metabolic abnormalities exists in moderately obese individuals has not been emphasized in studies of the effect of obesity on morbidity and mortality. We tested the hypothesis that risk factors for type 2 diabetes mellitus and cardiovascular disease vary dramatically in moderately obese individuals as a function of differences in a specific measure of insulin sensitivity.Participants included 211 apparently healthy, obese (body mass index [calculated as weight in kilograms divided by height in meters squared], 30.0-34.9) volunteers for weight loss studies. Main outcome measures included insulin-mediated glucose uptake as quantified by the insulin suppression test and metabolic variables known to increase the risk for type 2 diabetes and cardiovascular disease.Insulin sensitivity varied 6-fold. When compared with the most insulin-sensitive third, the most insulin-resistant third of the population had significantly higher (P<.001) systolic and diastolic blood pressure (139 +/- 20 vs 123 +/- 18 mm Hg, and 83 +/- 3 vs 75 +/- 10 mm Hg, respectively), higher fasting and 2-hour oral glucose load concentrations (103 +/- 11 vs 95 +/- 11 mg/dL [5.7 +/- 0.6 vs 5.3 +/- 0.6 mmol/L], and 139 +/- 30 vs 104 +/- 19 mg/dL [7.7 +/- 1.7 vs 5.8 +/- 1.1 mmol/L], respectively), higher plasma triglyceride concentrations (198 +/- 105 vs 114 +/- 51 mg/dL [2.2 +/- 1.2 vs 1.3 +/- 0.6 mmol/L]), lower plasma high-density lipoprotein cholesterol concentrations (41 +/- 9 vs 50 +/- 13 mg/dL [1.1 +/- 0.2 vs 1.3 +/- 0.3 mmol/L]), and more prevalent impaired glucose tolerance (47% vs 2%).The magnitude of risk factors for type 2 diabetes and cardiovascular disease varies markedly in moderately obese individuals as a function of differences in degree of insulin sensitivity. Because not all moderately obese individuals are at similar risk for developing type 2 diabetes and cardiovascular disease, intensive therapeutic interventions should be addressed to the insulin-resistant subset of this population.

    View details for Web of Science ID 000245628700003

    View details for PubMedID 17420421

  • ADMA is independently related to flow-mediated vasodilation in subjects at low cardiovascular risk EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ardigo, D., Stuehlinger, M., Franzini, L., Valtuena, S., Piatti, P. M., Pachinger, O., Reaven, G. M., Zavaroni, I. 2007; 37 (4): 263-269

    Abstract

    Increased plasma concentrations of asymmetric dimethylarginine (ADMA) contribute to impair endothelial function in patients with established cardiovascular disease (CVD) and/or individuals with clinical syndromes known to increase CVD. However, the impact of ADMA on endothelial function in apparently healthy individuals has not been determined.To address this issue, we measured endothelial-dependent vasodilatation in response to forearm ischaemia (flow-mediated vasodilatation, FMD) in 111 non-smoking, healthy volunteers with low CVD risk by the Framingham risk equation. Measurements were also made of multiple anthropometric, metabolic, and dynamic variables related to FMD. l-arginine and its methylated derivates (ADMA and SDMA) were quantified by high-liquid pressure chromatography.After adjustment by gender, lower values for FMD were significantly associated with increases in plasma ADMA concentrations (anova linear trend by FMD tertiles, P < 0.05) as well as in brachial artery diameter (partial r = -0.352, P = 0.001), body mass index (-0.337, P = 0.001), fasting insulin (-0.368, P < 0.001) and high-sensitivity C-reactive protein (-0.283, P = 0.007) plasma concentrations, and with decreased HDL cholesterol (0.233, P = 0.026). Multiple linear regression analysis indicated that the only statistically significant predictors of FMD were brachial artery diameter (P < 0.001), ADMA (P < 0.05) and fasting plasma insulin (P < 0.001) concentrations.In conclusion, a significant relationship between increases in plasma ADMA concentration and lower values of FMD is not limited to patients with clinical syndromes related to CVD, but can also be seen in healthy subjects at low global CVD risk.

    View details for Web of Science ID 000244978900005

    View details for PubMedID 17373961

  • Relationship between obesity and several cardiovascular disease risk factors in apparently healthy Korean individuals: comparison of body mass index and waist circumference METABOLISM-CLINICAL AND EXPERIMENTAL Sung, K. C., Ryu, S., Reaven, G. M. 2007; 56 (3): 297-303

    Abstract

    Recent versions of the criteria for diagnosing the metabolic syndrome have emphasized the superiority of abdominal obesity, as measured by waist circumference (WC), in identifying individuals at increased risk for cardiovascular disease (CVD). On the other hand, there is evidence that body mass index (BMI), an estimate of overall obesity, fulfills this function as effectively as does WC. The present analysis was performed to compare the relative use of these 2 indices of obesity to identify multiple CVD risk factors. The study population consisted of 19584 apparently healthy men and women of Korean ethnicity, and the CVD risk factors measured included fasting plasma concentrations of the following variables: glucose, insulin, total, low-density lipoprotein, and high-density lipoprotein cholesterol, triglycerides, apolipoproteins A-I and B, and high-sensitivity C-reactive protein. The univariate relationships between the 2 indices of obesity and the 9 CVD risk factors were relatively modest (the highest r value was 0.45), but they were all statistically significant, and the magnitude of the relationships between the CVD risk factors and BMI and WC were comparable. When multivariate analysis was performed, adjusting for age and either BMI or WC, each index of obesity continued to have an independent relationship, albeit reduced in magnitude, with the CVD risk factors. These findings suggest that measurements of BMI provide as much clinical insight as do determinations of WC in identifying multiple CVD risk factors in a large population of apparently healthy Korean men and women, and that the use of both indices would provide the most information.

    View details for DOI 10.1016/j.metabol.2006.09.016

    View details for Web of Science ID 000244421900001

    View details for PubMedID 17292715

  • The relationship between insulin resistance and dyslipidaemia in cigarette smokers DIABETES OBESITY & METABOLISM Farin, H. M., Abbasi, F., Kim, S. H., Lamendola, C., McLaughlin, T., Reaven, G. M. 2007; 9 (1): 65-69

    Abstract

    Considerable evidence shows that cigarette smokers tend to have the dyslipidemic pattern of high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations, a highly atherogenic lipoprotein profile also typical of the insulin-resistant state even in the absence of cigarette smoking. However, because cigarette smokers are frequently insulin resistant, it is unclear if this dyslipidaemia is secondary to smoking, per se, or simply to the fact that smokers tend to be insulin resistant. The present study was initiated to determine whether this dyslipidaemia prevalent in cigarette smokers and characteristic of insulin-resistant individuals is a function of cigarette smoking or of insulin resistance.As measured using vertical auto profile-II methodology, the lipid and lipoprotein concentrations were compared in 34 cigarette smokers divided into insulin-sensitive and insulin-resistant subgroups. The two groups were similar in age and body mass index, differing only in their insulin-mediated glucose uptake as quantified by the steady-state plasma glucose concentration determined during the insulin suppression test.While levels of TG and very low-density lipoprotein cholesterol (VLDL-C) were significantly elevated in insulin-resistant cigarette smokers, total cholesterol (C), low-density lipoprotein cholesterol (LDL-C), narrow-density (ND) LDL-C, intermediate-density lipoprotein-C (IDL-C), HDL-C and non-HDL-C were not different in the two groups. The insulin-resistant smokers also had a preponderance of small, dense LDL particles, while the reverse was true of the insulin-sensitive cigarette smokers.These data suggest that the dyslipidaemia previously attributed to smoking occurs primarily in those smokers who are also insulin resistant.

    View details for DOI 10.1111/j.1463-1326.2006.00574.x

    View details for Web of Science ID 000242781700008

    View details for PubMedID 17199720

  • The relationship between plasma adiponectin concentration and insulin resistance is altered in smokers JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Abbasi, F., Farin, H. M., Lamendola, C., McLaughlin, T., Schwartz, E. A., Reaven, G. M., Reaven, P. D. 2006; 91 (12): 5002-5007

    Abstract

    Low plasma adiponectin concentrations in smokers may contribute to the adverse consequences that occur in these individuals.The objective of the study was to define the relationship among smoking, plasma adiponectin concentrations, insulin resistance, and inflammation.This was a cross-sectional, observational study with a 2 x 2 factorial design and a prospective longitudinal arm.The study was conducted at a general clinical research center.Apparently healthy smokers (n = 30) and nonsmokers (n = 30), subdivided into insulin resistant (IR) (n = 15) and insulin sensitive (IS) (n = 15) subgroups participated in the study.Intervention included pioglitazone administration for 3 months to 12 IR smokers and eight IS smokers. MAIN OUTCOME MEASUres: Measures included fasting plasma adiponectin and C-reactive protein (CRP) concentrations and changes in adiponectin after pioglitazone treatment in IR and IS smokers.Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). The difference in mean adiponectin concentration between smokers and nonsmokers did not depend on the insulin resistance status of the subjects. No difference was detected in average CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13). CRP concentrations were unrelated to adiponectin in smokers (r = -0.05, P = 0.78) and nonsmokers (r = 0.03, P = 0.86). Finally, pioglitazone treatment increased adiponectin concentrations in both IR (P < 0.001) and IS smokers (P = 0.001).Plasma adiponectin concentrations are lower in smokers and IR subjects and are unrelated to CRP concentrations. These findings suggest that low levels of adiponectin in smokers may be independent of both insulin resistance and a generalized inflammatory response.

    View details for DOI 10.1210/jc.2006-0419

    View details for Web of Science ID 000242581300045

    View details for PubMedID 17003098

  • Trends in hyperinsulinemia among nondiabetic adults in the US DIABETES CARE Li, C., Ford, E. S., McGuire, L. C., Mokdad, A. H., Little, R. R., Reaven, G. M. 2006; 29 (11): 2396-2402

    Abstract

    Insulin resistance and compensatory hyperinsulinemia have been proposed as increasing risk for a variety of abnormalities and clinical syndromes, including type 2 diabetes and cardiovascular disease. Our aim was to assess the trends in the mean concentrations of fasting serum insulin and the prevalence of hyperinsulinemia among nondiabetic adults during the periods of 1988-1994 and 1999-2002 in the U.S.We conducted analyses of data among men and nonpregnant women without diabetes aged >/=20 years from the Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994; n = 7,926) and NHANES 1999-2002 (n = 2,993). Both surveys were designed to represent the noninstitutionalized civilian U.S. population. We calculated age-adjusted mean concentrations of fasting insulin and the prevalence of hyperinsulinemia defined using the 75th percentile of fasting insulin among nondiabetic individuals as the cutoff value.The geometric mean concentrations of fasting insulin increased by approximately 5% from 1988-1994 to 1999-2002 among nondiabetic adults aged >/=20 years in the U.S. Mexican-American men, men and women aged 20-39 years, and non-Hispanic white women had a greater relative increase in the mean concentrations of fasting insulin than their counterparts. The prevalence of hyperinsulinemia increased by 35.1% overall (38.3% among men and 32.1% among women).In parallel with the obesity epidemic, concentrations of fasting insulin and prevalence of hyperinsulinemia have increased remarkably among nondiabetic U.S. adults.

    View details for DOI 10.2337/dc06-0289

    View details for Web of Science ID 000242030200010

    View details for PubMedID 17065674

  • Comparison of body mass index versus waist circumference with the metabolic changes that increase the risk of cardiovascular disease in insulin-resistant individuals AMERICAN JOURNAL OF CARDIOLOGY Farin, H. M., Abbasi, F., Reaven, G. M. 2006; 98 (8): 1053-1056

    Abstract

    This study compared the abilities of body mass index (BMI) and waist circumference (WC) to identify resistance to insulin-mediated glucose uptake and related metabolic abnormalities in 261 apparently healthy patients. Insulin resistance and associated metabolic abnormalities occur more commonly in the overweight/obese, and these changes increase the risk of cardiovascular disease (CVD). Determining either their BMI or WC can identify patients more likely to experience the adverse effects of excess adiposity on CVD risk, and the relative clinical utility of these measurements is not clear. Therefore, insulin-mediated glucose uptake was quantified in 261 apparently healthy adults by determining the steady-state plasma glucose concentrations during the insulin suppression test; the higher the concentration, the greater the defect in insulin action. The fasting plasma glucose, triglyceride, and total, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations were also measured, and the associations between these variables and the measurements of BMI and WC were determined. The greater the degree of adiposity, the higher the steady-state plasma glucose, fasting plasma glucose, and triglyceride concentrations, irrespective of the index of adiposity used. However, increases in the total and low-density lipoprotein cholesterol and decreases in the high-density lipoprotein cholesterol concentrations were only seen in those with higher BMI values. In conclusion, because BMI performed at least as well as WC in identifying differences in insulin sensitivity and multiple CVD risk factors, either estimate can be used to identify patients at increased CVD risk.

    View details for DOI 10.1016/j.amjcard.2006.05.025

    View details for Web of Science ID 000241427400013

    View details for PubMedID 17027570

  • Effects of moderate variations in macronutrient composition on weight loss and reduction in cardiovascular disease risk in obese, insulin-resistant adults AMERICAN JOURNAL OF CLINICAL NUTRITION McLaughlin, T., Carter, S., Lamendola, C., Abbasi, F., Yee, G., Schaaf, P., Basina, M., Reaven, G. 2006; 84 (4): 813-821

    Abstract

    Obese, insulin-resistant persons are at risk of cardiovascular disease. How best to achieve both weight loss and clinical benefit in these persons is controversial, and recent reports questioned the superiority of low-fat diets.We aimed to ascertain the effects of moderate variations in the carbohydrate and fat content of calorie-restricted diets on weight loss and cardiovascular disease risk in obese, insulin-resistant persons.Fifty-seven randomly assigned, insulin-resistant, obese persons completed a 16-wk calorie-restricted diet with 15% of energy as protein and either 60% and 25% or 40% and 45% of energy as carbohydrate and fat, respectively. Baseline and postweight-loss insulin resistance; daylong glucose, insulin, and triacylglycerol concentrations; fasting lipid and lipoprotein concentrations; and markers of endothelial function were quantified.Weight loss with 60% or 40% of energy as carbohydrate (5.7 +/- 0.7 or 6.9 +/- 0.7 kg, respectively) did not differ significantly, and improvement in insulin sensitivity correlated with the amount of weight lost (r = 0.50, P < 0.001). Subjects following the diet with 40% of energy as carbohydrate had greater reductions in daylong insulin and triacylglycerol (P < 0.05) and fasting triacylglycerol (0.53 mmol/L; P = 0.04) concentrations, greater increases in HDL-cholesterol concentrations (0.12 mmol/L; P < 0.01) and LDL particle size (1.82 s; P < 0.05), and a greater decrease in plasma E-selectin (5.6 ng/L; P = 0.02) than did subjects following the diet with 60% of energy as carbohydrate.In obese, insulin-resistant persons, a calorie-restricted diet, moderately lower in carbohydrate and higher in unsaturated fat, is as efficacious as the traditional low-fat diet in producing weight loss and may be more beneficial in reducing markers for cardiovascular disease risk.

    View details for Web of Science ID 000241140700019

    View details for PubMedID 17023708

  • Comparison of the 1997 and 2003 American Diabetes Association classification of impaired fasting glucose - Impact on prevalence of impaired fasting glucose, coronary heart disease risk factors, and coronary heart disease in a community-based medical practice JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kim, S. H., Chunawala, L., Linde, R., Reaven, G. M. 2006; 48 (2): 293-297

    Abstract

    The goals of this study were to assess the effect of the 2003 American Diabetes Association definition of impaired fasting glucose (IFG) on prevalence of IFG, coronary heart disease (CHD) risk factors, and CHD compared with the 1997 IFG definition.Although IFG is viewed as increasing CHD risk, this association is unclear and has not been well studied after changing the IFG criterion, especially in a clinical practice setting.This was a cross-sectional evaluation of 8,295 members (3,763 men and 4,532 women) of a community medical center who were between the ages of 30 and 69 years, without a history of diabetes mellitus, and who had available measurements of fasting plasma glucose and lipid concentrations within the past 2 years. The prevalence of IFG, CHD risk factors, and CHD with the 1997 and 2003 IFG definition was compared.The prevalence of IFG increased from 8% to 35% with the 2003 criterion. Individuals with glucose of 100 to 109 mg/dl had lower prevalence of most CHD risk factors (hypertension, triglyceride > or =150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, meeting 2 components of the metabolic syndrome criteria, CHD risk > or =10% by Framingham score) compared with individuals with glucose 110 to 125 mg/dl. Individuals identified with the 2003 IFG definition did not have an increase in known CHD when adjusted for covariates (odds ratio 1.4 [95% confidence interval (CI) 0.7 to 2.3] vs. 3.2 [95% CI 1.8 to 5.9]).One-third of the population has IFG with the 2003 definition, yet many of these individuals do not have increased prevalence of CHD risk factors or CHD.

    View details for DOI 10.1016/j.jacc.2006.03.043

    View details for Web of Science ID 000239080000011

    View details for PubMedID 16843178

  • The metabolic syndrome: is this diagnosis necessary ? AMERICAN JOURNAL OF CLINICAL NUTRITION Reaven, G. M. 2006; 83 (6): 1237-1247

    Abstract

    Values of insulin-mediated glucose disposal vary continuously throughout a population of apparently healthy persons, and a difference of > or = 600% exists between the most insulin-sensitive and the most insulin-resistant persons. Approximately 50% of this variability can be attributed to differences in adiposity (25%) and fitness (25%), with the remaining 50% likely of genetic origin. The more insulin-resistant a person, the more likely that he or she will develop some degree of glucose intolerance, high triacylglycerol and low HDL concentrations, essential hypertension, and procoagulant and proinflammatory states, all of which increase the risk of cardiovascular disease (CVD). To identify persons at greater CVD risk because of these abnormalities, the World Health Organization, the Adult Treatment Panel III, and the International Diabetes Federation created a new diagnostic category, the metabolic syndrome. Although the components of the 3 versions of the metabolic syndrome are similar, the specific values for those components that define an abnormality are somewhat different, and the manner in which the abnormalities are used to make a positive diagnosis varies dramatically from version to version. This review will summarize the similarities in and differences between the 3 versions of the metabolic syndrome, point out that the clustering of components that make up all 3 definitions of the metabolic syndrome is not accidental and occurs only in insulin-resistant persons, develop the argument that diagnosing the metabolic syndrome in a person has neither pedagogical nor clinical utility, and suggest that the clinical emphasis should be on treating effectively any CVD risk factor that is present.

    View details for Web of Science ID 000238369900001

    View details for PubMedID 16762930

  • Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Stuhlinger, M., Lamendola, C., Abbasi, F., Bialek, J., Reaven, G. M., Tsao, P. S. 2006; 91 (5): 1896-1900

    Abstract

    Plasma asymmetric dimethylarginine (ADMA) concentrations are higher in apparently healthy, insulin-resistant (IR) individuals and decrease in response to thiazolidenedione treatment.The objective of the study was to determine whether ADMA concentrations would also fall when insulin sensitivity is enhanced with weight loss in obese individuals. DESIGN/SETTING/PATIENTS/INTERVENTION: Twenty obese women classified as IR or insulin sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration during the insulin suppression test underwent 12 wk of dietary weight loss.Plasma glucose, insulin, and ADMA were measured at baseline and after weight loss; change in insulin resistance was quantified by repeating the SSPG after the dietary intervention.Although weight loss was similar in the two groups, significant improvements in SSPG, glucose, and insulin concentrations were confined to the IR group. Baseline plasma ADMA concentrations (mean +/- sd) were higher in IR subjects (1.69 +/- 0.44 vs. 1.18 +/- 0.45 micromol/liter, P = 0.02) and decreased to 1.20 +/- 0.22 micromol/liter (P < 0.001) with weight loss. In contrast, ADMA levels did not change with a similar extent of weight loss in the IS group.Plasma ADMA levels are higher in obese, IR women than in equally obese, IS women and decrease in response to weight loss when associated with enhancement of insulin sensitivity.

    View details for DOI 10.1210/jc.2005-1441

    View details for Web of Science ID 000237330000043

    View details for PubMedID 16507636

  • Relation of plasma insulin levels to forearm flow-mediated dilatation in healthy volunteers AMERICAN JOURNAL OF CARDIOLOGY Ardigo, D., Franzini, L., Valtuena, S., Monti, L. D., Reaven, G. M., Zavaroni, I. 2006; 97 (8): 1250-1254

    Abstract

    Although several observations suggest that insulin resistance/compensatory hyperinsulinemia (IR/CH) has a direct effect on endothelial function, independently of the metabolic abnormalities associated with the defect in insulin action, this relation has not been evaluated in apparently healthy individuals. To address this issue, we measured endothelial-dependent vasodilation in response to forearm ischemia (flow-mediated dilation [FMD]) in 47 nonsmoking, healthy volunteers without known risk factors for atherosclerosis. Measurements were also made of multiple anthropometric, metabolic, and hemodynamic variables related to IR/CH. Decreases in FMD were significantly correlated (analysis of variance for linear trend) with (1) male gender (p = 0.003), (2) waist circumference (p = 0.038), (3) higher fasting plasma insulin (p = 0.015) and triglyceride concentrations (p = 0.023), and (4) lower concentrations of high-density lipoprotein cholesterol (p = 0.001). Multivariate linear regression analysis indicated that only plasma insulin (beta -0.424) was independently associated (p <0.001) with changes in FMD, and individual differences in insulin concentrations, along with gender and brachial artery diameter at baseline, accounted for approximately 39% of the variability in FMD. In conclusion, IR/CH is an independent predictor of decreases in endothelial-dependent vasodilation in apparently healthy individuals, in the absence of traditional risk factors for atherosclerosis.

    View details for DOI 10.1016/j.amjcard.2005.11.047

    View details for Web of Science ID 000237263000025

    View details for PubMedID 16616036

  • Body mass index and waist circumference both contribute to differences in insulin-mediated glucose disposal in nondiabetic adults AMERICAN JOURNAL OF CLINICAL NUTRITION Farin, H. M., Abbasi, F., Reaven, G. M. 2006; 83 (1): 47-51

    Abstract

    Overweight and obese individuals are more likely to be insulin resistant and at increased risk of adverse clinical outcomes. Questions remain as to whether waist circumference (WC) or body mass index (BMI) most effectively identifies insulin-resistant individuals.This study quantified insulin-mediated glucose uptake (IMGU) in 330 apparently healthy volunteers and compared the relation between this value and measurements of WC and BMI.IMGU was quantified via determination of the steady-state plasma glucose (SSPG) concentration during the insulin-suppression test. Differences in SSPG concentrations due to variations in WC within a given BMI category, as well as those due to differences in BMI within a given WC classification, were then compared.BMI and WC correlated with each other (r = 0.78, P < 0.001) and equally with SSPG concentrations (r = 0.58 and 0.57, respectively; P < 0.001). When stratified by BMI, abdominally obese subjects within the overweight BMI category had higher SSPG concentrations than did those with a normal WC (P < 0.05). When classified by WC, subjects in the overweight BMI category had greater SSPG concentrations than did subjects in the normal BMI category within the normal WC category (P < 0.01), as did subjects in the obese BMI category in comparison with subjects in the overweight BMI category within the obese WC category (P < 0.01).The more overweight or obese a person, the greater the degree of insulin resistance; differences in adiposity accounted for approximately one-third of the variation in IMGU, irrespective of the index used. Furthermore, there was no difference in the relation between the degree of insulin resistance and either index of adiposity.

    View details for Web of Science ID 000234779100009

    View details for PubMedID 16400048

  • Insulin resistance/compensatory hyperinsulinemia predict carotid intimal medial thickness in patients with essential hypertension NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES Zavaroni, I., Ardigo, D., Zuccarelli, A., Pacetti, E., Piatti, P. M., Monti, L., Valtuena, S., Massironi, P., Rossi, P. C., Reaven, G. M. 2006; 16 (1): 22-27

    Abstract

    Approximately 50% of subjects with essential hypertension (EH) are insulin resistant, and this defect in insulin action could contribute to increased cardiovascular disease (CVD) risk in these patients. To test this hypothesis, we attempted to see if there was a link between insulin resistance (IR) and carotid intimal medial thickness (IMT), an early index of CVD, in patients with essential hypertension.Ultrasound quantification of carotid IMT was performed in 79 hypertensive patients, and 63 patients (31 m and 32 f), defined as being free of plaque (IMT < 1.3 mm), were further subdivided into normal (<1.0 mm) and thickened (1-1.3 mm) IMT groups. Subjects in the thickened IMT group were older and had significantly (p < 0.05) higher plasma concentrations of fasting insulin, nitric oxide (NO(x)) and intercellular adhesion molecule 1 (ICAM-1). However, the two groups were not significantly different in terms of blood pressure, overall or regional obesity, fasting lipid levels, uric acid, concentrations of other cellular adhesion molecules or levels of C-reactive protein. There were significant (p < 0.05) correlations in the whole population between IMT and age, fasting insulin and NO(x), and multiple regression analysis identified fasting insulin as an independent predictor of IMT.The presence of increased IMT is significantly related to several metabolic and endothelial abnormalities associated with IR/hyperinsulinemia, and fasting insulin independently predicts the thickness of the intima-media layer. These results support the view that CVD risk is greatest in those patients with essential hypertension who are also IR/hyperinsulinemic.

    View details for DOI 10.1016/j.numecd.2004.11.003

    View details for Web of Science ID 000235530000004

    View details for PubMedID 16399488

  • Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Abbasi, F., Chang, S. A., Chu, J. W., Ciaraldi, T. P., Lamendola, C., McLaughlin, T., Reaven, G. M., Reaven, P. D. 2006; 290 (1): R139-R144

    Abstract

    It has been suggested that changes in adiponectin levels may contribute to improved insulin sensitivity in insulin-resistant individuals both after weight loss and after treatment with thiazolidinedione compounds. If this is correct, then changes in total circulating adiponectin and/or distribution of its multimeric complexes should coincide with improvements in insulin sensitivity after both interventions. To address this issue, fasting adiponectin concentrations and distribution of adiponectin complexes were measured in plasma samples in 24 insulin-resistant, nondiabetic subjects before and after 3-4 mo of treatment with either rosiglitazone or caloric restriction. The degree of insulin resistance in each group of 12 subjects was equal at baseline and improved to a similar extent ( approximately 30%) after each therapy. Whereas total adiponectin levels increased by nearly threefold and the relative amount of several higher molecular weight adiponectin complexes increased significantly in the rosiglitazone treatment group, there were no discernible changes in adiponectin levels or in the distribution between high or low molecular weight complexes in the weight loss group. These data indicate that, although changes in total adiponectin and several specific adiponectin complexes paralleled improvements in insulin resistance in thiazolidinedione-treated subjects, neither circulating adiponectin concentrations nor multimeric complexes changed in association with enhanced insulin sensitivity after moderate weight loss in 12 insulin-resistant, obese individuals.

    View details for DOI 10.1152/ajpregu.00287.2005

    View details for Web of Science ID 000233930900020

    View details for PubMedID 16352858

  • Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome HUMAN REPRODUCTION Cataldo, N. A., Abbasi, F., McLaughlin, T. L., Basina, M., Fechner, P. Y., Giudice, L. C., Reaven, G. M. 2006; 21 (1): 109-120

    Abstract

    Insulin sensitizers have favourable metabolic and ovarian effects in polycystic ovary syndrome (PCOS). This study examined rosiglitazone, a thiazolidinedione, in PCOS.In a prospective, open-label study, the effects of rosiglitazone on metabolism and ovarian function were examined in 42 non-diabetic women with PCOS classified according to the National Institute of Child Health and Human Development criteria and insulin resistance (IR) by steady-state plasma glucose (SSPG) > or =10 mmol/l on octreotide-modified insulin suppression testing. Participants were randomized to rosiglitazone 2, 4 or 8 mg daily for 12 weeks. Endpoints included ovulation and menstrual pattern; serum testosterone, sex hormone-binding globulin (SHBG), and LH; and changes in IR and glucose-insulin responses on 8 h mixed-meal profile.After rosiglitazone 8 mg daily for 12 weeks, SSPG declined and insulinaemia fell by 46%; lower doses gave lesser effects. Serum LH, total and free testosterone were unchanged; SHBG increased. With rosiglitazone, ovulation occurred in 23/42 women (55%), without significant dose dependence. Both before and during treatment, ovulators on rosiglitazone had lower circulating insulin and free testosterone and higher SHBG than non-ovulators. Testosterone declined only in a subgroup of ovulators with early vaginal bleeding after starting rosiglitazone.Rosiglitazone in insulin-resistant PCOS promoted ovulation and dose-dependently decreased IR and insulinaemia; ovulators had lower circulating insulin and testosterone.

    View details for DOI 10.1093/humrep/dei289

    View details for Web of Science ID 000233846700014

    View details for PubMedID 16155076

  • Hyperinsulinemia predicts hepatic fat content in healthy individuals with normal transaminase concentrations METABOLISM-CLINICAL AND EXPERIMENTAL Ardigo, D., Numeroso, F., Valtuena, S., Franzini, L., Piatti, P. M., Monti, L., Delsignore, R., Reaven, G. M., Zavaroni, I. 2005; 54 (12): 1566-1570

    Abstract

    Although the prevalence of insulin resistance (IR) and compensatory hyperinsulinemia (CH) is increased in patients with nonalcoholic fatty liver disease, the role of IR/CH in regulation of hepatic fat content in healthy volunteers with normal concentrations of alanine transaminase (ALT) has not been defined. To address this issue, hepatic fat content was quantified by ultrasound in 69 (30 men, 39 women) healthy individuals, without known risk factors for liver disease and with plasma ALT concentrations of less than 30 U/L. Experimental variables quantified included body mass index, waist circumference, systolic and diastolic blood pressures, and fasting plasma glucose, fasting plasma insulin (FPI), and lipid concentrations. Subjects were classified as having no (55%), mild (27%), or moderate to severe (18%) hepatic steatosis on the basis of the ultrasound results. Statistically significant (P < .05-.001) correlations (Spearman rho values) existed between liver fat content and ALT (0.26), body mass index (0.52), waist circumference (0.50), systolic blood pressure (0.28), diastolic blood pressure (0.27), fasting plasma glucose (0.47), FPI (0.56), triglycerides (0.30), and high-density lipoprotein cholesterol (-0.35). Multivariate general discriminant analysis and multiple linear regression analysis indicated that FPI was the only independent predictor (P < .001) of both liver fat content and ALT concentrations. Fasting plasma insulin (a surrogate estimate of IR/CH) predicts hepatic fat content and ALT in healthy volunteers with normal transaminase concentrations, independently of the other anthropometric and metabolic variables measured.

    View details for DOI 10.1016/j.metabol.2005.05.027

    View details for Web of Science ID 000234127800002

    View details for PubMedID 16311087

  • Effect of a high-carbohydrate versus a high-cis-monounsaturated fat diet on blood pressure in patients with type 2 diabetes DIABETES CARE Shah, M., Adams-Huet, B., Bantle, J. P., Henry, R. R., Griver, K. A., Raatz, S. K., Brinkley, L. J., Reaven, G. M., Garg, A. 2005; 28 (11): 2607-2612

    Abstract

    To investigate whether blood pressure is different in type 2 diabetic patients on a diet rich in carbohydrates versus a diet rich in cis-monounsaturated fatty acids. Data on the dietary effects on these diets' glucose and lipid metabolism have been previously published.The study compared the effect of feeding 42 type 2 diabetic patients a carefully controlled isoenergic high-carbohydrate (high-carb; 55% energy as carbohydrate, 30% as fat, and 10% as monounsaturated fat) and high-monounsaturated fat (high-mono; 45% energy as fat, 25% as monounsaturated fat, and 40% as carbohydrate) diet for 6 weeks each in a four-center, randomized, cross-over study on blood pressure. Twenty-one patients continued the diet they received during the second phase for an additional 8 weeks.According to repeated-measures ANOVA, blood pressure during the last 3 days of each phase was similar after 6 weeks of the high-carb and high-mono diets (systolic blood pressure: 128 +/- 16 vs. 127 +/- 15 mmHg, P = 0.9; diastolic blood pressure: 75 +/- 7 vs. 75 +/- 8 mmHg, P = 0.7). However, after 14 weeks of the high-carb diet (n = 13), there was a significant increase in blood pressure compared with 6 weeks of the high-mono diet (systolic blood pressure: 132 +/- 13 vs. 126 +/- 11 mmHg, P = 0.04; diastolic blood pressure: 83 +/- 6 vs. 76 +/- 7 mmHg, P = 0.002). After 14 weeks of the high-mono diet (n = 8), the reduction in blood pressure was not significant compared with 6 weeks of the high-carb diet (systolic blood pressure: 118 +/- 14 vs. 121 +/- 16 mmHg, P = 0.4; diastolic blood pressure: 71 +/- 8 vs. 75 +/- 10 mmHg, P = 0.3).Although the exchange of carbohydrates with monounsaturated fats may not affect blood pressure in the short term, long-term consumption of a high-carbohydrate diet may modestly raise blood pressure in type 2 diabetic patients.

    View details for Web of Science ID 000234548300001

    View details for PubMedID 16249527

  • Body mass index and waist circumference correlate to the same degree with insulin-mediated glucose uptake METABOLISM-CLINICAL AND EXPERIMENTAL Farin, H. M., Abbasi, F., Reaven, G. M. 2005; 54 (10): 1323-1328

    Abstract

    To compare the relationship between insulin-mediated glucose uptake (IMGU) and excess adiposity as determined by measurement of either body mass index (BMI) or waist circumference (WC), IMGU was quantified by determining the steady-state plasma glucose (SSPG) concentration with the insulin suppression test and the relationship between the SSPG concentration and BMI or WC evaluated in a study of 208 healthy individuals (128 women/80 men). The results indicated that BMI and WC were correlated (P < .001) to a similar degree in both men (r = 0.90) and women (r = 0.86). Steady-state plasma glucose and both indices of excess adiposity were also significantly correlated (P < .001) to an essentially identical extent in men (r values of 0.71 vs 0.70) and women (r values of 0.54 vs 0.53). When the population was divided into tertiles on the basis of SSPG concentrations, 96% of those in the most insulin-resistant tertile were identified as being overweight/obese by BMI criteria and 84% as abdominally obese by WC criteria. However, a substantial number of those in the most insulin-sensitive tertile also demonstrated excess adiposity as defined by either BMI (45%) or WC (33%). To summarize, (1) BMI and WC correlate closely within an individual and equally well with IMGU, and (2) BMI is as effective as WC in identifying insulin-resistant individuals.

    View details for DOI 10.1016/j.metabol.2005.04.021

    View details for Web of Science ID 000232255600009

    View details for PubMedID 16154431

  • Increased aortic stiffness in the insulin-resistant Zucker fa/fa rat AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Sista, A. K., O'Connell, M. K., Hinohara, T., Oommen, S. S., Fenster, B. E., Glassford, A. J., Schwartz, E. A., Taylor, C. A., Reaven, G. M., Tsao, P. S. 2005; 289 (2): H845-H851

    Abstract

    Accumulating clinical evidence indicates increased aortic stiffness, an independent risk factor for cardiovascular and all-cause mortality, in type 2 diabetic and glucose-intolerant individuals. The present study sought to determine whether increased mechanical stiffness, an altered extracellular matrix, and a profibrotic gene expression profile could be observed in the aorta of the insulin-resistant Zucker fa/fa rat. Mechanical testing of Zucker fa/fa aortas showed increased vascular stiffness in longitudinal and circumferential directions compared with Zucker lean controls. Unequal elevations in developed strain favoring the longitudinal direction resulted in a loss of anisotropy. Real-time quantitative PCR and immunohistochemistry revealed increased expression of fibronectin and collagen IV alpha 3 in the Zucker fa/fa aorta. In addition, expression of transforming growth factor-beta and several Smad proteins was increased in vessels from insulin-resistant animals. In rat vascular smooth muscle cells, 12-18 h of exposure to insulin (100 nmol/l) enhanced transforming growth factor-beta1 mRNA expression, implicating a role for hyperinsulinemia in vascular stiffness. Thus there is mechanical, structural, and molecular evidence of arteriosclerosis in the Zucker fa/fa rat at the glucose-intolerant, hyperinsulinemic stage.

    View details for DOI 10.1152/ajpheart.00134.2005

    View details for Web of Science ID 000230458800045

    View details for PubMedID 15833807

  • Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? AMERICAN JOURNAL OF CARDIOLOGY McLaughlin, T., Reaven, G., Abbasi, F., Lamendola, C., Saad, M., Waters, D., Simon, J., Krauss, R. M. 2005; 96 (3): 399-404

    Abstract

    The goal of this study was to evaluate the ability of various routine measures of lipoprotein metabolism to identify patients who were insulin resistant and dyslipidemic, and therefore, at increased risk of cardiovascular disease. For this purpose, insulin resistance was quantified by determining the steady-state plasma glucose concentration during the insulin suppression test in 449 apparently healthy patients. The low-density lipoprotein (LDL) particle diameter and subclass phenotype were measured by gradient gel electrophoresis in 1,135 patients. Pearson's correlation coefficients and receiver-operating characteristic curves were used to evaluate measures of lipoprotein metabolism as potential markers of insulin resistance and LDL phenotype. The results indicated that the ratio of the plasma concentrations of triglyceride to high-density lipoprotein cholesterol was the best predictor of insulin resistance and LDL particle diameter. The optimal triglyceride/high-density lipoprotein cholesterol ratio for predicting insulin resistance and LDL phenotype was 3.5 mg/dl; a value that identified insulin-resistant patients with a sensitivity and specificity comparable to the criteria currently proposed to diagnose the metabolic syndrome. The sensitivity and specificity were even greater for identification of patients with small, dense, LDL particles. In conclusion, a plasma triglyceride/high-density lipoprotein cholesterol concentration ratio > or =3.5 provides a simple means of identifying insulin-resistant, dyslipidemic patients who are likely to be at increased risk of cardiovascular disease.

    View details for DOI 10.1016/j.amjcard.2005.03.085

    View details for Web of Science ID 000231057000017

    View details for PubMedID 16054467

  • Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals DIABETES Kim, S. H., Abbasi, F., Chu, J. W., McLaughlin, T. L., Lamendola, C., Polonsky, K. S., Reaven, G. M. 2005; 54 (8): 2447-2452

    Abstract

    Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means +/- SE from 13.5 +/- 0.62 to 9.8 +/- 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P = 0.008) during the insulin suppression test and by 21% (P = 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR.

    View details for Web of Science ID 000230869500023

    View details for PubMedID 16046313

  • Prevalence of insulin resistance and the metabolic syndrome with alternative definitions of impaired fasting glucose ATHEROSCLEROSIS Ford, E. S., Abbasi, F., Reaven, G. M. 2005; 181 (1): 143-148

    Abstract

    We sought to evaluate the effect of the new definition of impaired fasting glucose (IFG = fasting glucose concentration 100-125 mg/dL among people without diabetes) on the ability to identify insulin resistance, as well as the prevalence of the metabolic syndrome in apparently healthy individuals. From the Stanford General Clinical Research Center data-base, we used data from 230 men and 260 women aged 19-79 years who had had an insulin suppression test to measure insulin resistance. From the Third National Health and Nutrition Examination Survey (1988-1994), we used data from 8814 participants aged > or =20 years to estimate the impact of adopting the new IFG criteria on the prevalence of the metabolic syndrome. Among the 490 participants, the prevalence of IFG increased from 5.5% under the old definition of IFG to 20.4% under the new definition. Using the old definition of IFG, the sensitivity, specificity, and positive predictive value (PPV) of IFG of identifying an individual as being insulin resistant were 10%, 97%, and 63%, respectively. Using the new definition, these parameters were 33%, 88%, and 61%, respectively. If the new IFG criteria were adopted, the prevalence of the metabolic syndrome would increase from 21.8% to 26.3%. The new definition of IFG expands the population with insulin resistance by almost four-fold and could expand the population with the metabolic syndrome by about 20%. The clinical and public health implications of the new IFG definition remain to be elucidated.

    View details for DOI 10.1016/j.atherosclerosis.2005.01.002

    View details for Web of Science ID 000230215300019

    View details for PubMedID 15939066

  • The metabolic syndrome: Requiescat in pace CLINICAL CHEMISTRY Reaven, G. M. 2005; 51 (6): 931-938

    Abstract

    Values for insulin-mediated glucose disposal vary continuously throughout a population of apparently healthy individuals, with at least a sixfold variation between the most insulin sensitive and most insulin resistant of these individuals. The more insulin resistant a person, the more insulin must be secreted to prevent decompensation of glucose tolerance. Insulin resistance is not a disease, but a description of a physiologic state, and approximately one third of an apparently healthy population is sufficiently insulin resistant to be at increased risk to develop a cluster of abnormalities and related clinical syndromes. The primary value of the concept of insulin resistance is that it provides a conceptual framework with which to place a substantial number of apparently unrelated biological events into a pathophysiological construct. In contrast, the metabolic syndrome was introduced as a diagnostic category to identify individuals that satisfy three of five relatively arbitrarily chosen criteria to initiate lifestyle changes with the goal of decreasing risk of cardiovascular disease. Consequently, the value of the notion of the metabolic syndrome must be considered not in pathophysiologic terms, but as a pragmatic approach to obtain a better clinical outcome. In this review, an effort is made to critically evaluate the concept of the metabolic syndrome, the criteria chosen to identify individuals with the syndrome, and the clinical utility of making, or not making, a diagnosis of the metabolic syndrome.

    View details for DOI 10.1373/clinchem.2005.048611

    View details for Web of Science ID 000229452600002

    View details for PubMedID 15746300

  • Hemostatic abnormalities associated with obesity and the metabolic syndrome JOURNAL OF THROMBOSIS AND HAEMOSTASIS Reaven, G. M. 2005; 3 (5): 1074-1085

    View details for Web of Science ID 000229132000040

    View details for PubMedID 15869606

  • Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: The price paid to maintain glucose homeostasis in insulin-resistant individuals ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Reaven, G. M. 2005; 34 (1): 49-?

    Abstract

    The ability of insulin to stimulate glucose disposal varies sixfold to eightfold among apparently healthy individuals. The only way that insulin-resistant persons can prevent the development of type 2 diabetes is by secreting the increased amount of insulin that is necessary to compensate for the resistance to insulin action. The greater the magnitude of muscle and adipose tissue insulin resistance, the more insulin must be secreted to maintain normal or near-normal glucose tolerance. Although compensatory hyperinsulinemia may prevent the development of fasting hyperglycemia in insulin-resistant individuals, the price paid is the untoward physiologic effects of increased circulating insulin concentrations on tissues that retain normal insulin sensitivity. This article focused on the interplay between insulin resistance at the level of the muscle and adipose tissue and normal hepatic insulin sensitivity; this leads to the atherogenic lipoprotein profile that is characteristic of insulin-resistant individuals. It would be inappropriate to minimize the importance of differential insulin sensitivity in the genesis of the changes in lipoprotein metabolism that increase CVD risk in insulin-resistant persons. It would be equally remiss not to emphasize that differential tissue insulin resistance also is necessary to explain why insulin-resistant/hyperinsulinemic individuals are more likely to develop the clinical syndromes (with the exception of type 2 diabetes mellitus) that are listed in Box 1.

    View details for DOI 10.1016/j.ecl.2004.12.001

    View details for Web of Science ID 000228005700004

    View details for PubMedID 15752921

  • Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects. Diabetes & vascular disease research Chu, J. W., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. M., Tsao, P. S. 2005; 2 (1): 37-41

    Abstract

    Thiazolidinedione (TZD) compounds enhance insulin sensitivity and attenuate inflammation. The effect of the TZD compound, rosiglitazone (RSG) on both actions was evaluated in two groups of insulin-resistant subjects with minimal elevations of fasting plasma glucose (PG) concentration: group A (n=15, PG < 7.0 mmol/L) and group B (n=14, PG 7.0-8.3 mmol/L). Insulin action, quantified by the insulin suppression test, improved after three months of treatment in both groups, and concentrations of C-reactive protein, plasminogen activator inhibitor-1 and Eselectin all fell. Significant decreases in L-selectin and P-selectin were confined to group B, and concentrations of interleukin-6, intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 did not fall in either group. Significant relationships were not discerned between enhanced insulin sensitivity and related variables and decreases in inflammatory/vascular markers, suggesting that RSG-induced changes in the latter variables in insulin-resistant individuals might be at least partly independent of the effects of the drug on insulin action.

    View details for PubMedID 16305071

  • Comparative effects of rosuvastatin and gomfibrozil on glucose, insulin, and lipid metabolism in insulin m resistant, nondiabetic patients with combined dyslipidemia AMERICAN JOURNAL OF CARDIOLOGY Lamendola, C., Abbasi, F., Chu, J. W., Hutchinson, H., Cain, V., Leary, E., McLaughlin, T., Stein, E., Reaven, G. 2005; 95 (2): 189-193

    Abstract

    To evaluate the pharmacologic intervention most likely to decrease cardiovascular disease risk in insulin-resistant patients with combined dyslipidemia, 39 patients with this abnormality were assessed before and after 3 months of treatment with gemfibrozil (1,200 mg/day) or rosuvastatin (40 mg/day) with regard to: (1) steady-state plasma glucose concentration at the end of a 180-minute infusion of octreotide, insulin, and glucose; (2) fasting lipid, lipoprotein, and apolipoprotein concentrations; and (3) daylong glucose, insulin, triglyceride, and remnant lipoprotein cholesterol concentrations in response to breakfast and lunch. The 2 groups were similar at baseline in age, gender, body mass index and in measurements of carbohydrate and lipoprotein metabolism. Neither gemfibrozil nor rosuvastatin enhanced insulin sensitivity or lowered daylong glucose and insulin concentrations in insulin-resistant patients with combined dyslipidemia, but both drugs significantly decreased fasting triglyceride concentrations. However, only rosuvastatin treatment significantly (p <0.05 to <0.001) reduced fasting low-density lipoprotein cholesterol, apolipoprotein B-100, apolipoprotein C-III, apolipoprotein C-III:B particles, the apolipoprotein B-100:apolipoprotein A-I ratio, and increased apolipoprotein A-I (p <0.05). The degree of improvement in fasting and postprandial remnant lipoprotein cholesterol concentrations was significantly greater (p <0.05) in rosuvastatin-treated patients, and this difference in the relative effectiveness of the drugs was also true of the decrease in non-high-density lipoprotein cholesterol concentrations.

    View details for DOI 10.1016/j.amjcard.2004.09.005

    View details for Web of Science ID 000226461000006

    View details for PubMedID 15642550

  • Why Syndrome X? From Harold Himsworth to the insulin resistance syndrome CELL METABOLISM Reaven, G. M. 2005; 1 (1): 9-14

    Abstract

    Although the concept of Syndrome X was introduced in the Banting Medal address of 1988 (Reaven, 1988), the notion that led to its genesis had started approximately 50 years earlier. In this short history, an attempt will be made to trace the two paths of scientific discovery that were formally merged in New Orleans in 1988 to form the scientific foundation of Syndrome X. In addition, the developments in the last 16 years that have led from the notion of Syndrome X to the broader concept of an Insulin Resistance Syndrome (IRS) will be briefly summarized.

    View details for DOI 10.1016/j.cmet.2004.12.001

    View details for Web of Science ID 000228830300005

    View details for PubMedID 16054040

  • The insulin resistance syndrome: Definition and dietary approaches to treatment ANNUAL REVIEW OF NUTRITION Reaven, G. M. 2005; 25: 391-406

    Abstract

    The ability of insulin to stimulate glucose disposal varies at least sixfold in apparently healthy individuals, and approximately one-third of the population that is most resistant to this action of insulin is at greatly increased risk to develop a number of adverse clinical outcomes. Type 2 diabetes occurs when insulin resistant individuals are unable to secrete enough insulin to compensate for the defect in insulin action, and this was the first clinical syndrome identified as being related to insulin resistance. Although the majority of insulin-resistant individuals are able to maintain the level of compensatory hyperinsulinemia needed to prevent the development of a significant degree of hyperglycemia, the combination of insulin resistance and hyperinsulinemia greatly increases the likelihood of developing a cluster of closely related abnormalities and the resultant clinical diagnoses that can be considered to make up the insulin resistance syndrome (IRS). Since being overweight/obese and sedentary decreases insulin sensitivity, it is not surprising that the prevalence of the manifestations of the IRS is increasing at a rapid rate. From a dietary standpoint, there are two approaches to attenuating the manifestations of the IRS: (a) weight loss to enhance insulin sensitivity in those overweight/obese individuals who are insulin resistant/hyperinsulinemic; and (b) changes in macronutrient content of diets to avoid the adverse effects of the compensatory hyperinsulinemia. This chapter will focus on defining the abnormalities and clinical syndromes that compose the IRS and evaluating the dietary changes that can ameliorate its adverse consequences.

    View details for DOI 10.1146/annurev.nutr.24.012003.132155

    View details for Web of Science ID 000231710300018

    View details for PubMedID 16011472

  • Relative effects of insulin resistance and protease inhibitor treatment on lipid and lipoprotein metabolism in HIV-infected patients HIV CLINICAL TRIALS Beatty, G., Chu, J., Kulkarni, K., Lipshutz, G., Khalili, M., Abbasi, F., Stansell, J., Reaven, G. M. 2004; 5 (6): 383-391

    Abstract

    The relationship between insulin resistance, dyslipidemia, HIV infection, and antiretroviral therapy remains unclear, and the atherogenic nature of lipid and lipoprotein profiles in HIV-infected patients has not been fully characterized.We measured plasma lipid and lipoprotein subfractions using Vertical Auto Profile-II methodology and directly measured insulin-mediated glucose disposal in 45 protease inhibitor (PI)-treated and non-PI-treated HIV-infected patients.PI-treated patients had higher total, LDL, and narrow-density LDL cholesterol (p <.05) and a trend toward higher triglycerides, whereas HDL cholesterol and LDL particle characteristics were unrelated to PI use or history of lipodystrophy. Insulin sensitivity did not differ on the basis of PI therapy, but decreased insulin sensitivity was associated with lower HDL and HDL-3 cholesterol (p <.01); elevated triglyceride (p <.01), VLDL 1+2, and VLDL 3a+3b lipoproteins (p <.01); and smaller, denser (more atherogenic) LDL particle characteristics (p <.01). Thus, the lipoprotein abnormality associated with PI use was increased LDL cholesterol, whereas changes in TG and HDL metabolism were associated with insulin resistance, independent of PI use.The variables of PI-treatment, dyslipidemia, lipodsytrophy, and insulin resistance do not always cluster together in HIV-infected patients, which suggests that the metabolic phenotype emerging in treated patients results from a complex interplay of drug effects, immune restoration, and baseline insulin sensitivity.

    View details for Web of Science ID 000226800000003

    View details for PubMedID 15682351

  • The metabolic syndrome: one step forward, two steps back. Diabetes & vascular disease research Kim, S. H., Reaven, G. M. 2004; 1 (2): 68-75

    Abstract

    Individuals with insulin resistance are at increased risk of glucose intolerance, dyslipidaemia and essential hypertension. In 1988, it was proposed that this cluster of abnormalities associated with insulin resistance identifies individuals at increased risk for cardiovascular disease. Recently, in an effort to raise awareness of this problem, both the World Health Organisation (WHO) and the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program have suggested a set of clinical criteria to diagnose individuals with what they both refer to as the metabolic syndrome. Although using the same term, the two groups have different goals for creating this diagnosis and different criteria to identify individuals, which relate to their different institutional goals. This review critically evaluates the similarities and differences between the two groups' concepts of the metabolic syndrome and questions the clinical utility of making the diagnosis with either set of definitions.

    View details for PubMedID 16304726

  • Impact of degree of obesity on surrogate estimates of insulin resistance DIABETES CARE Kim, S. H., Abbasi, F., Reaven, G. M. 2004; 27 (8): 1998-2002

    Abstract

    To evaluate the role of adiposity in the relationship between specific and surrogate estimates of insulin-mediated glucose uptake (IMGU) in a large nondiabetic population.Healthy volunteers were classified by BMI into normal weight (<25.0 kg/m(2), n = 208), overweight (25.0-29.9 kg/m(2), n = 168), and obese (>or=30.0 kg/m(2), n = 109) groups. We then assessed how differences in BMI affect the correlation between steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, glucose, and insulin (a specific measure of IMGU) and five surrogate estimates: fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve for insulin in response to oral glucose (I-AUC).Correlation coefficients (r values) between SSPG and surrogate measures of IMGU were all significant (P < 0.05), but the magnitude varied between BMI groups: normal weight: fasting plasma glucose 0.20, fasting plasma insulin 0.33, HOMA-IR 0.36, QUICKI -0.33, and I-AUC 0.69; overweight: fasting plasma glucose 0.19, fasting plasma insulin 0.55, HOMA-IR 0.55, QUICKI -0.54, and I-AUC 0.72; and obese: fasting plasma glucose 0.40, fasting plasma insulin 0.56, HOMA-IR 0.60, QUICKI -0.61, and I-AUC 0.69.The relationship between direct and surrogate estimates of IMGU varies with BMI, with the weakest correlations seen in the normal-weight group and the strongest in the obese group. In general, I-AUC is the most useful surrogate estimate of IMGU in all weight groups. Fasting plasma insulin, HOMA-IR, and QUICKI provide comparable information about IMGU. Surrogate estimates of IMGU based on fasting insulin and glucose account for no more than 13% of the variability in insulin action in the normal-weight group, 30% in the overweight group, and 37% in the obese group.

    View details for Web of Science ID 000223026200023

    View details for PubMedID 15277430

  • Insulin resistance in idiopathic dilated cardiomyopathy - A possible etiologic link JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Tang, W. H., Jamali, A. H., Chu, J. W., Reaven, G. M., Fowler, M. B. 2004; 44 (1): 78-81

    Abstract

    This study was designed to quantify the prevalence of abnormal glucose tolerance and insulin resistance in patients with idiopathic dilated cardiomyopathy (IDCM).Insulin resistance is an independent risk factor for mortality in patients with heart failure (HF) and is a known risk factor for ischemic cardiomyopathy. Though potential physiologic links between insulin resistance and HF have been hypothesized, the relationship between insulin resistance and IDCM remains unclear.A total of 230 consecutive patients from a university HF clinic were screened for IDCM, the absence of diabetes mellitus, and the lack of significant co-morbid conditions. Oral glucose tolerance tests were performed in the 43 patients with IDCM who met these criteria, and their plasma glucose and insulin responses were compared with those of 40 healthy volunteers, matched for age, gender, and body mass index.Plasma glucose responses were higher during the oral glucose tolerance tests in patients with IDCM (p < 0.01), associated with significantly higher plasma insulin concentrations following the oral glucose challenge (p < 0.01). In addition, abnormalities of glucose tolerance were significantly (p < 0.05) more common in patients with IDCM (49% vs. 23%).Insulin resistance and abnormal glucose tolerance are more prevalent in patients with IDCM and represent potentially reversible metabolic derangements in these individuals.

    View details for DOI 10.1016/j.jacc.2004.03.037

    View details for Web of Science ID 000222421500016

    View details for PubMedID 15234411

  • Relationship between plasma nitric oxide concentration and insulin resistance in essential hypertension AMERICAN JOURNAL OF HYPERTENSION Zavaroni, I., Ardigo, D., Rossi, P. C., Zuccarelli, A., Pacetti, E., Monti, L., Piatti, P. M., Reaven, G. M. 2004; 17 (7): 549-552

    Abstract

    Plasma nitric oxide (NOx) concentrations in patients with essential hypertension (EH) have been reported to be higher, lower, or no different than in normotensives. This study was initiated to determine whether these inconsistent findings were related to differences in insulin resistance.Fasting plasma NOx and insulin concentrations were measured in 78 patients with EH and the relationship between these variables evaluated by regression analysis. Patients with hypertension were also divided into tertiles based on their fasting plasma insulin concentration: the highest tertile classified as insulin resistant (EH-IR) and the lowest as insulin sensitive (EH-IS). Plasma NOx concentrations were compared among these two groups and a third group of 21 normotensive, insulin resistant (N-IR) individuals by one-way ANOVA.Plasma insulin and NOx concentrations were correlated (r = 0.31, P <.01) in patients with hypertension, independently of differences in age, body mass index, waist circumference, and blood pressure. Plasma NOx concentrations were different in the three experimental groups (P <.001), being significantly higher (P <.05) in the EH-IR than in either of the other two groups. Despite being hyperinsulinemic, NOx levels in N-IR individuals were lower than in EH-IR subjects and no different from EH-IS individuals.Plasma NOx concentrations are highest in those patients with EH who are also insulin resistant/hyperinsulinemic (EH-IR). Furthermore, because plasma NOx concentrations were as high in the EH-IS as in the N-IR populations, it could be speculated that plasma NOx concentrations are also modulated by EH, per se.

    View details for DOI 10.1016/j.amjhyper.2004.02.009

    View details for Web of Science ID 000222467100001

    View details for PubMedID 15233972

  • The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Reaven, G. 2004; 33 (2): 283-?

    Abstract

    The goal of this article is to differentiate the insulin resistance syndrome from the metabolic syndrome. In the case of the insulin resistance syndrome, the abnormalities and clinical syndromes that are increased in prevalence in insulin-resistant individuals have been summarized, with a brief discussion of the causal relationship between insulin resistance, compensatory hyperinsulinemia, and associated consequences. Discussion of the metabolic syndrome has focused on the five criteria chosen by the adult treatment panel III to diagnose the syndrome, evaluating them in terms of their relationship to insulin resistance and their role as cardiovascular disease risk factors.

    View details for DOI 10.1016/j.ecl.2004.03.002

    View details for Web of Science ID 000221950800003

    View details for PubMedID 15158520

  • Relationship to insulin resistance of the Adult Treatment Panel III diagnostic criteria for identification of the metabolic syndrome DIABETES Cheal, K. L., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. M., Ford, E. S. 2004; 53 (5): 1195-1200

    Abstract

    The Adult Treatment Panel III (ATP III) has published criteria for diagnosing the metabolic syndrome, a cluster of closely related abnormalities related to insulin resistance that increase cardiovascular disease risk. The present analysis was performed to evaluate the ability of these criteria to identify insulin-resistant individuals. The population consisted of 443 healthy volunteers, with measurements of BMI, blood pressure, fasting plasma glucose, triglycerides, HDL cholesterol concentrations, and steady-state plasma glucose (SSPG) concentration. Insulin resistance was defined as being in the top tertile of SSPG concentrations. Of the population, 20% satisfied ATP III criteria for the metabolic syndrome. Although insulin resistance and the presence of the metabolic syndrome were significantly associated (P < 0.001), the sensitivity and positive predictive value equaled 46% (69 of 149) and 76% (69 of 91), respectively. Being overweight, with high triglycerides, low HDL cholesterol, or elevated blood pressure, most often resulted in a diagnosis of the metabolic syndrome. Thus, the ATP III criteria do not provide a sensitive approach to identifying insulin-resistant individuals. The individual components vary both in terms of their utility in making a diagnosis of the metabolic syndrome and their relationship to insulin resistance, with the obesity and lipid criteria being most useful.

    View details for Web of Science ID 000221157300003

    View details for PubMedID 15111486

  • Insulin resistance, cardiovascular disease, and the metabolic syndrome - How well do the emperor's clothes fit? DIABETES CARE Reaven, G. M. 2004; 27 (4): 1011-1012

    View details for Web of Science ID 000220609000028

    View details for PubMedID 15047666

  • Plasma adiponectin concentrations do not increase in association with moderate weight loss in insulin-resistant, obese women METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Lamendola, C., McLaughlin, T., Hayden, J., Reaven, G. M., Reaven, P. D. 2004; 53 (3): 280-283

    Abstract

    Plasma adiponectin concentrations were measured before and after moderate weight loss in 20 obese women, divided at baseline into insulin-resistant (IR) and insulin-sensitive (IS) subgroups on the basis of their steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of octreotide, glucose, and insulin. The groups were similar in age and body weight and lost comparable amounts of weight (8 to 9 kg) during the weight loss period. Fasting plasma insulin and SSPG concentrations were significantly higher (P <.001) and adiponectin concentrations somewhat lower (P =.10) in the IR group (P <.001) at baseline. Both SSPG and plasma insulin concentrations decreased in IR subjects (P <.001), but did not change in IS individuals. Adiponectin concentrations did not change with weight loss in either group. Thus, neither weight loss, per se, nor enhanced insulin sensitivity resulted in a change in plasma adiponectin concentrations.

    View details for DOI 10.1016/j.metabol.2003.10.004

    View details for Web of Science ID 000220333600004

    View details for PubMedID 15015137

  • Discrimination between obesity and insulin resistance in the relationship with adiponectin DIABETES Abbasi, F., Chu, J. W., Lamendola, C., McLaughlin, T., Hayden, J., Reaven, G. M., Reaven, P. D. 2004; 53 (3): 585-590

    Abstract

    Insulin resistance and obesity are both associated with lower plasma adiponectin concentrations. Since insulin resistance and obesity are related, the extent to which the association of adiponectin with insulin resistance is dependent on its relationship with obesity is unclear. To address this issue, fasting plasma adiponectin concentrations were measured in 60 nondiabetic subjects, stratified into four equal groups on the basis of both their degree of adiposity and insulin resistance. Insulin resistance was quantified by determining the steady-state plasma glucose (SSPG) concentration in response to an infusion of octreotide, glucose, and insulin, and degree of adiposity was assessed by BMI. Subjects were defined as obese (BMI >/=30.0 kg/m(2)) or nonobese (<27.0 kg/m(2)) and as either insulin sensitive (SSPG <100 mg/dl) or insulin resistant (>190 mg/dl). Insulin-resistant subjects had significantly (P<0.001) lower (mean +/- SD) adiponectin concentrations, whether they were obese (17.1 +/- 5.9 micro g/ml) or nonobese (16.3 +/- 7.5 micro g/ml) as compared with either obese, insulin-sensitive (34.3 +/- 13.1 micro g/ml) or nonobese, insulin-sensitive (29.8 +/- 15.3 micro g/ml) subjects. Finally, adiponectin levels in insulin-sensitive subjects varied to a significantly greater degree than in insulin-resistant subjects. These results suggest that adiponectin concentrations are more closely related to differences in insulin-mediated glucose disposal than obesity.

    View details for Web of Science ID 000189307500010

    View details for PubMedID 14988241

  • Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Chu, J. W., McLaughlin, T., Lamendola, C., Leary, E. T., Reaven, G. M. 2004; 53 (2): 159-164

    Abstract

    In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 +/- 0.48 v 9.46 +/- 0.47 mmol/L, P <.001) and the combined SU and metformin therapy group (14.09 +/- 0.51 v 10.57 +/- 0.85 mmol/L, P =.001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 +/- 0.09 v 0.34 +/- 0.07 mmol/L, P =.02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 +/- 19 v 446 +/- 18 ng/mL, P =.02) and the combined SU and metformin therapy group (496 +/- 29 v 456 +/- 31 ng/mL, P =.05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.

    View details for DOI 10.1016/j.metabol.2003.07.020

    View details for Web of Science ID 000188797400007

    View details for PubMedID 14767866

  • Obesity, insulin resistance, and cardiovascular disease RECENT PROGRESS IN HORMONE RESEARCH, VOL 59 Reaven, G., Abbasi, F., McLaughlin, T. 2004; 59: 207-223

    Abstract

    The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance - namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations -- is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.

    View details for Web of Science ID 000189490300010

    View details for PubMedID 14749503

  • What is the contribution of differences in three measures of tumor necrosis factor-alpha activity to insulin resistance in healthy volunteers? METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Numeroso, F., Dongiovanni, P., Ardigo, D., Valenti, L., Fracanzani, A. L., Valtuena, S., Delsignore, R., Fargion, S., Reaven, G. M. 2003; 52 (12): 1593-1596

    Abstract

    To address the potential role that tumor necrosis factor-alpha (TNF-alpha) might play in modulation of insulin resistance in healthy, nondiabetic individuals, we compared plasma TNF-alpha and soluble TNF-alpha receptor 2 (sTNF-R2) concentrations, as well as TNF-alpha polymorphisms, in 94 healthy individuals, stratified into insulin-resistant (IR) and insulin-sensitive (IS) groups based on their plasma insulin concentrations 120 minutes after oral glucose on 2 occasions (1993 and 2000). The IR group (n = 50; 29 men and 21 women) was in the upper quartile and the IS group (n = 44; 24 men and 20 women) in the lowest quartile of the distribution of post-glucose challenge insulin concentrations in a large unselected population (>50 v <23 microU/mL). The IR group had significantly higher values for body mass index, waist-to-hip girth, fasting and post-glucose challenge insulin concentrations, and fasting triglyceride concentrations, and lower high-density lipoprotein cholesterol concentrations as compared to the IS group. Despite the fact that they were relatively more obese, and insulin-resistant, plasma concentrations of TNF-alpha were similar in the IR (1.6 +/- 0.6 pg/mL) and IS (1.7 +/- 0.6 pg/mL) groups, as were the concentrations (5.4 +/- 1.4 v 5.8 +/- 2.0 pg/mL) of sTNF-R2. Furthermore, TNF-alpha polymorphisms (detected by polymerase chain reaction [PCR]) were similar in the 2 groups, with essentially identical allelic frequencies of the 238 (10.3% v 9.4%) and 308 polymorphisms (17.9% v 18.7%). In conclusion, plasma TNF-alpha and sTNF-R2 concentrations, as well as TNF-alpha gene polymorphisms, were not different in healthy volunteers stratified into IR and IS groups on the basis of their plasma insulin response to an oral glucose challenge. Given these data, it does not appear that differences in TNF-alpha activity contribute to the marked variations in insulin action that occur in healthy individuals.

    View details for DOI 10.1016/S0026-0495(03)00329-9

    View details for Web of Science ID 000187320600013

    View details for PubMedID 14669161

  • The insulin resistance syndrome. Current atherosclerosis reports Reaven, G. M. 2003; 5 (5): 364-371

    View details for PubMedID 12911846

  • Lipoprotein risk factors for cardiovascular disease in patients with type 2 diabetes mellitus treated with oral antihyperglycaemic agents DIABETES OBESITY & METABOLISM Chu, J. W., Abbasi, F., McLaughlin, T. L., Lamendola, C., Schaaf, P., Carlson, T. H., Leary, E. T., Reaven, G. M. 2003; 5 (5): 333-337

    Abstract

    To compare lipoprotein risk factors for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM) treated with a sulphonylurea (SU) compound only, metformin (MET) only, or combined SU + MET.The study population consisted of 62 patients with type 2 DM, whose antihyperglycaemic treatment program had been stable for at least 3 months, divided into three groups: 26 patients in the SU group, 17 patients in the MET group and 19 patients in the SU + MET group. None of the patients were taking lipid-lowering drugs. Fasting venous blood samples were taken to measure concentrations of glucose, total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and remnant lipoprotein-cholesterol (RLP-C) as well as for determination of LDL particle diameter.The three groups were similar in terms of age, gender, body mass index and fasting plasma glucose concentrations. Total cholesterol concentrations were significantly lower (p < 0.05 for trend) in those treated with SU + MET as compared with the other two groups. However, there were no significant differences between the three groups in their plasma concentrations of TG, LDL-C, HDL-C or RLP-C; furthermore, the proportion of individuals within each treatment group with small LDL particle diameter was also not different.The lipoprotein profile of patients with type 2 DM, matched for level of fasting hyperglycaemia, was similar irrespective of treatment with SU alone, MET alone or SU + MET. Thus, we could not identify any changes in lipoprotein metabolism that could account for differences in risk of CVD as a function of treatment.

    View details for Web of Science ID 000185112800010

    View details for PubMedID 12940871

  • A novel peroxisome proliferator-activated gamma (PPAR gamma) agonist, CLX-0921, has potent antihyperglycemic activity with low adipogenic potential METABOLISM-CLINICAL AND EXPERIMENTAL Dey, D., Medicherla, S., Neogi, P., Gowri, M., Cheng, J., Gross, C., Sharma, S. D., Reaven, G. M., Nag, B. 2003; 52 (8): 1012-1018

    Abstract

    Agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are pharmacologically active antihyperglycemic agents that act by increasing peripheral tissue sensitivity to insulin. Many of these agonists have antihyperglycemic activity that is directly proportional to their ability to bind and activate PPAR gamma; however, recent data bring this relationship into question. In this report we describe a new PPAR gamma agonist, CLX-0921, that is derived from a natural product. This thiazolidinedione (TZD) has a spectrum of activity that differs from commercially available TZDs. It is a weak activator of PPAR gamma (EC(50) of 0.284 micromol/L) compared to rosiglitazone (EC(50) 0.009 micromol/L). Despite this difference, the drug maintains potent glucose uptake activity in vitro and glucose-lowering activity in vivo that is equipotent to that of rosiglitazone. Moreover, CLX-0921 showed a 10-fold reduction in in vitro adipogenic potential compared to rosiglitazone. CLX-0921 also increases glycogen synthesis, an activity not typically associated with rosiglitazone or pioglitazone. Thus CLX-0921 appears to have a distinct spectrum of activity relative to other TZDs.

    View details for DOI 10.1016/S0026-0495(03)00152-5

    View details for Web of Science ID 000185015300011

    View details for PubMedID 12898466

  • Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients METABOLISM-CLINICAL AND EXPERIMENTAL Chu, J. W., Abbasi, F., Beatty, G. W., Khalili, M., KOCH, J., Rosen, A., Schmidt, J. M., Stansell, J. D., Reaven, G. M. 2003; 52 (7): 858-861

    Abstract

    Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (approximately 60 microU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load (r=0.78, P<.01), accounting for approximately two thirds of the variability in SSPG (r2=0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation (r=0.43 to 0.61), thereby possessing limited ability to predict SSPG variability (r2=0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

    View details for DOI 10.1016/S0026-0495(03)00056-8

    View details for Web of Science ID 000184197500010

    View details for PubMedID 12870161

  • Multiple lipoprotein abnormalities associated with insulin resistance in healthy volunteers are identified by the vertical auto profile-II methodology CLINICAL CHEMISTRY Chu, J. W., Abbasi, F., Kulkarni, K. R., Lamendola, C., McLaughlin, T. L., Scalisi, J. N., Reaven, G. M. 2003; 49 (6): 1014-1017

    View details for Web of Science ID 000183088100041

    View details for PubMedID 12766017

  • Insulin resistance/compensatory hyperinsulinemia, essential hypertension, and cardiovascular disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Reaven, G. M. 2003; 88 (6): 2399-2403

    View details for DOI 10.1210/jc.2003-030087

    View details for Web of Science ID 000183318200007

    View details for PubMedID 12788834

  • American College of Endocrinology position statement on the insulin resistance syndrome. Einhorn, D., Reaven, G. M., Cobin, R. H., Ford, E., Ganda, O. P., Handelsman, Y., Hellman, R., Jellinger, P. S., Kendall, D., Krauss, R. M., Neufeld, N. D., Petak, S. M., Rodbard, H. W., Seibel, J. A., Smith, D. A., Wilson, P. W. 2003: 237-252

    View details for PubMedID 12924350

  • Quantification of insulin-mediated glucose disposal in HIV-infected individuals: Comparison of patients treated and untreated with protease inhibitors JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Beatty, G., Khalili, M., Abbasi, T., Chu, J., Reaven, G. M., Rosen, A., Schmidt, J. M., Stansell, J., KOCH, J. 2003; 33 (1): 34-40

    Abstract

    To describe the distribution of insulin sensitivity and glucose tolerance in HIV-infected patients, the authors measured insulin-mediated glucose disposal (IMGD) in 51 subjects (24 protease inhibitor (PI)-treated subjects and 27 non-PI-treated subjects). IMGD was determined by measuring the steady-state plasma glucose (SSPG) concentration during the last 30 minutes of a 180-minute intravenous infusion of octreotide, glucose, and insulin. In addition, oral glucose tolerance testing was performed. SSPG concentrations varied six-fold in both groups, and the mean values +/- SEM did not differ between PI-treated and non-PI-treated groups (8.7 +/- 0.9 vs. 8.0 +/- 0.7 mmol/L, respectively). The mean fasting plasma glucose concentration +/- SEM was higher in the PI-treated subjects than in the non-PI-treated subjects (5.44 +/- 0.11 vs. 5.05 +/- 0.11 mmol/L, respectively; p =.01), whereas fasting plasma insulin concentrations did not differ. PI-treated patients also had significantly higher plasma glucose (p =.001) and insulin (p =.03) responses to the oral glucose challenge. However, whereas the incremental plasma glucose response during the first 30 minutes was significantly higher in PI-treated patients, the incremental insulin response in the two groups was identical. In conclusion, insulin sensitivity varies widely in HIV-infected patients irrespective of PI treatment, and the adverse effect of PIs on insulin sensitivity is likely to be of modest magnitude. Finally, PI treatment may have an inhibitory effect on insulin secretion.

    View details for Web of Science ID 000182805400006

    View details for PubMedID 12792353

  • Beyond type 2 diabetes: The need for a clinically useful way to identify insulin resistance AMERICAN JOURNAL OF MEDICINE McLaughlin, T. L., Reaven, G. M. 2003; 114 (6): 501-502
  • Effect of orlistat added to diet (30% of calories from fat) on plasma lipids, glucose, and insulin in obese patients with hypercholesterolemia AMERICAN JOURNAL OF CARDIOLOGY Lucas, C. P., Boldrin, M. N., Reaven, G. M. 2003; 91 (8): 961-964

    Abstract

    The objective of this study was to quantify the effectiveness of orlistat plus a reduced calorie diet on decreasing cardiovascular disease risk in obese individuals with elevated low-density lipoprotein (LDL) cholesterol concentrations, and to compare the beneficial effects in patients with hypercholesterolemia only (type IIA) with those in subjects with combined dyslipidemia (type IIB). Hypercholesterolemic patients treated with orlistat lost more weight (mean +/- SEM 9.9 +/- 0.4 vs 6.1 +/- 0.5 kg, p = 0.0001) and had greater decreases in plasma cholesterol (p = 0.0001), LDL cholesterol (p = 0.0001), triglycerides (p = 0.06), glucose (p = 0.07), and insulin (p = 0.02) concentrations compared with the diet-only treated patients. The greater degree of weight loss in orlistat-treated subjects was similar irrespective of the form of dyslipidemia, and plasma total and LDL cholesterol and insulin levels decreased to a significantly greater degree (p <0.05) in those patients who received orlistat and who had either type IIA and IIB dyslipidemia. However, triglyceride and insulin concentrations decreased and high-density lipoprotein (HDL) cholesterol increased to a significantly greater degree following orlistat-assisted weight loss in patients with type IIB compared with type IIA subjects, which was associated with a significantly greater decrease in the ratio of LDL/HDL cholesterol. Thus, weight loss in response to a reduced calorie diet in obese hypercholesterolemic patients was associated with a significant decrease in plasma LDL cholesterol levels. The beneficial metabolic effects of weight loss were accentuated in response to orlistat administration, and the improvement was greatest in patients with combined dyslipidemia (type IIB).

    View details for DOI 10.1016/S0002-9149(03)00112-7

    View details for Web of Science ID 000182215300008

    View details for PubMedID 12686336

  • Insulin resistance and compensatory hyperinsulinemia - The key player between cigarette smoking and cardiovascular disease? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Reaven, G., Tsao, P. S. 2003; 41 (6): 1044-1047

    Abstract

    Hyperinsulinemia, dyslipidemia, and endothelial dysfunction are characteristic findings in insulin-resistant individuals, and all of these abnormalities have been identified as increasing cardiovascular disease (CVD) risk. Smokers tend to be relatively insulin resistant, hyperinsulinemic, and dyslipidemic, with evidence of endothelial dysfunction, as compared with nonsmokers, and recent epidemiologic data have suggested that CVD in smokers is primarily seen in those individuals who also have the characteristic findings of insulin resistance. Based on these observations, it is argued that insulin resistance and its consequences represent a major mechanistic link between cigarette smoking and CVD. It is also postulated that the enhanced CVD risk in smokers, resulting from hyperinsulinemia, abnormalities of lipoprotein metabolism, and endothelial dysfunction, will primarily be present in those smokers who are insulin resistant. As a corollary, it is suggested that CVD risk in individuals who cannot, or will not, stop smoking can be reduced by therapeutic efforts aimed at attenuating the adverse effects of insulin resistance and its consequences.

    View details for DOI 10.1016/S0735-1097(02)02982-0

    View details for Web of Science ID 000181552800024

    View details for PubMedID 12651055

  • Importance of identifying the overweight patient who will benefit the most by losing weight ANNALS OF INTERNAL MEDICINE Reaven, G. M. 2003; 138 (5): 420-423

    Abstract

    Because being overweight increases the risk for type 2 diabetes, hypertension, and coronary heart disease, the rapid increase in the prevalence of overweight and obesity in the United States represents a major health problem. The relationship between overweight and obesity and these conditions is probably due to insulin resistance and compensatory hyperinsulinemia. However, although it is known that weight loss in insulin-resistant and hyperinsulinemic persons will be of substantial metabolic benefit, it is equally well established that many overweight and obese persons are not insulin resistant. In the absence of insulin resistance and its manifestations, the risk for type 2 diabetes, hypertension, and coronary heart disease is reduced and the metabolic benefit of weight loss in the substantial number of overweight persons who are insulin sensitive is relatively minimal. Consequently, it is important to identify which overweight persons are most likely to be insulin resistant by considering their family history; blood pressure; and plasma glucose, triglyceride, and high-density lipoprotein cholesterol concentrations. Thoughtful use of this information will help identify the subset of persons who will benefit the most from intense therapeutic efforts to lose weight.

    View details for Web of Science ID 000181257300008

    View details for PubMedID 12614095

  • Comparison in patients with type 2 diabetes of fibric acid versus hepatic hydroxymethyl glutaryl- coenzyme a reductase inhibitor treatment of combined dyslipidemia METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Abbasi, F., Lamendola, C., Leary, E., Reaven, G. M. 2002; 51 (10): 1355-1359

    Abstract

    Patients with combined dyslipidemia are at greatly increased coronary heart disease (CHD) risk. The threat of rhabdomyolysis with dual pharmacologic treatment (hepatic hydroxymethyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors plus fibric acid derivatives) has tended to limit therapy in patients with combined dyslipidemia to a choice of one or the other drug. Judgment of the potential benefits of either agent has rarely taken into account their effect on the postprandial accumulation of highly atherogenic, triglyceride (TG)-rich, remnant lipoprotein particles (RLPs). Because this information could be of substantial clinical relevance, we addressed this question in patients with type 2 diabetes and combined dyslipidemia by comparing the effects of gemfibrozil versus HMG-CoA reductase inhibitors (statins) on both fasting and postprandial lipid and lipoprotein concentrations. For this purpose, 22 patients with type 2 diabetes and combined dyslipidemia were randomized to treatment with either a statin or gemfibrozil for 3 months. Glycemic control was similar in both groups at baseline and did not change in response to treatment. Baseline lipid and lipoprotein concentrations were also similar in the 2 treatment groups, but the responses to therapy were quite different. Statin-treated patients had a statistically significant decrease in low-density lipoprotein (LDL) cholesterol concentration (156 mg/dL to 96 mg/dL, P <.001), whereas there was no change in patients treated with gemfibrozil. In contrast, there was a statistically significant decrease (P <.05) in plasma TG concentrations (116 mg/dL) in gemfibrozil-treated individuals, without any change in subjects treated with statins. However, the decrease in total integrated postprandial plasma RLP response measured hourly from 8 AM to 4 PM was not different in patients treated with either gemfibrozil (-43%) or statins (-34%). These results indicate that statin treatment, in addition to its beneficial effect on hypercholesterolemia, was as effective as gemfibrozil in reducing postprandial accumulation of triglyceride-rich, atherogenic RLPs in patients with type 2 diabetes and combined dyslipidemia. As such, the clinical utility of statin monotherapy in the treatment of combined dyslipidemia may have been underestimated.

    View details for DOI 10.1053/meta.2002.34713

    View details for Web of Science ID 000178587200021

    View details for PubMedID 12370858

  • Relationship between obesity, insulin resistance, and coronary heart disease risk JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Abbasi, F., Brown, B. W., Lamendola, C., McLaughlin, T., Reaven, G. M. 2002; 40 (5): 937-943

    Abstract

    The study goals were to: 1) define the relationship between body mass index (BMI) and insulin resistance in 314 nondiabetic, normotensive, healthy volunteers; and 2) determine the relationship between each of these two variables and coronary heart disease (CHD) risk factors.The importance of obesity as a risk factor for type 2 diabetes and hypertension is well-recognized, but its role as a CHD risk factor in nondiabetic, normotensive individuals is less well established.Insulin resistance was quantified by determining the steady-state plasma glucose (SSPG) concentration during the last 30 min of a 180-min infusion of octreotide, glucose, and insulin. In addition, nine CHD risk factors: age, systolic blood pressure, diastolic blood pressure (DBP), total cholesterol, triglycerides (TG), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein cholesterol concentrations, and glucose and insulin responses to a 75-g oral glucose load were measured in the volunteers.The BMI and the SSPG concentration were significantly related (r = 0.465, p < 0.001). The BMI and SSPG were both independently associated with each of the nine risk factors. In multiple regression analysis, SSPG concentration added modest to substantial power to BMI with regard to the prediction of DBP, HDL cholesterol and TG concentrations, and the glucose and insulin responses.Obesity and insulin resistance are both powerful predictors of CHD risk, and insulin resistance at any given degree of obesity accentuates the risk of CHD and type 2 diabetes.

    View details for Web of Science ID 000177765200014

    View details for PubMedID 12225719

  • Preferential involvement of larger vessels in a rat model of diabetes induced graft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Cantin, B., Zhu, D., Wen, P. Z., Panchal, S. N., Gwathmey, J. K., Reaven, G. M., Valantine, H. A. 2002; 21 (9): 1040-1043

    Abstract

    Using previously described models of diabetes-induced transplant coronary artery atherosclerosis (TxCAD), we quantitatively assessed TxCAD using computer-assisted morphometric measurements. More than 95% of the evaluated vessels were intramyocardial vessels. The first and last tertile of the vessel size distribution were evaluated for the presence of TxCAD. Severe TxCAD, defined as a luminal occlusion > or =75%, was more prevalent in the larger vessels. We observed a differential involvement based on vessel size in diabetes-induced TxCAD.

    View details for Web of Science ID 000177942400013

    View details for PubMedID 12231376

  • Impaired nitric oxide synthase pathway in diabetes mellitus - Role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase CIRCULATION LIN, K. Y., Ito, A., Asagami, T., Tsao, P. S., Adimoolam, S., Kimoto, M., Tsuji, H., Reaven, G. M., Cooke, J. P. 2002; 106 (8): 987-992

    Abstract

    An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM.Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33+/-0.31 versus 0.48+/-0.08 micromol/L; P<0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P<0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol-conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis.A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.

    View details for DOI 10.1161/01.CIR.0000027109.14149.67

    View details for Web of Science ID 000177634600019

    View details for PubMedID 12186805

  • Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes METABOLISM-CLINICAL AND EXPERIMENTAL Asagami, T., Abbasi, F., Stuelinger, M., Lamendola, C., McLaughlin, T., Cooke, J. P., Reaven, G. M., Tsao, P. S. 2002; 51 (7): 843-846

    Abstract

    This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.

    View details for DOI 10.1053/meta.2002.33349

    View details for Web of Science ID 000176578200007

    View details for PubMedID 12077728

  • Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin JOURNAL OF HEART AND LUNG TRANSPLANTATION Cantin, B., Zhu, D., Wen, P., Panchal, S. N., Dai, X., Gwathmey, J. K., Reaven, G. M., Valantine, H. A. 2002; 21 (6): 637-643

    Abstract

    Induction of diabetes in rat heterotopic heart transplantation models leads to an accelerated form of severe transplant coronary artery disease (TxCAD). We undertook this study to determine whether treatment of diabetes with metformin would favorably affect TxCAD.Heterotopic abdominal heart transplantation was performed in rat isograft and allograft models. After transplantation, diabetes was induced with streptozotocin. Fifty percent of the animals received metformin at 500 mg/kg twice daily. We quantitatively assessed TxCAD using histologic sections of harvested hearts at 30 and 60 days with computer-assisted morphometry. We compared vessels in the first tertile of the area distribution with vessels in the last tertile.Fasting glucose levels in metformin-treated animals were 161 +/- 45 mg/dl compared with 400 +/- 120 mg/dl (p < 0.05) in untreated rats. Treatment with metformin led to decreased diabetes-induced TxCAD in the larger vessels. This effect was sustained during the study course in the isografts but not in the allografts. Treatment with metformin did not prevent progression of TxCAD in the smaller vessels at 60 days.Metformin reduced luminal occlusion and severe TxCAD in the larger vessels but did not alter the course of TxCAD in the smaller vessels. These results may have therapeutic implications for patients.

    View details for Web of Science ID 000176074500004

    View details for PubMedID 12057696

  • Relationship between fasting and day-long plasma glucose concentrations in diet-treated patients with type 2 diabetes METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Reaven, G. M. 2002; 51 (4): 457-459

    Abstract

    To define the relationship between fasting and postprandial hyperglycemia, plasma glucose concentrations were determined before and after breakfast and lunch in 42 diet-treated patients with type 2 diabetes. Breakfast was consumed at 8:00 AM and lunch at 12:00 PM, with blood drawn hourly from 8:00 AM to 4:00 PM for measurement of plasma glucose concentration. The results demonstrated highly significant correlation coefficients (r) between fasting plasma glucose concentration and any individual hourly value (r values varying between 0.86 and 0.91). Furthermore, fasting plasma glucose concentrations and the total integrated glucose response areas, post-breakfast (8:00 AM to 12:00 PM), post-lunch (12:00 PM to 4:00 PM), and day-long (8:00 AM to 4:00 PM) were also highly correlated, with r values of 0.95, 0.91, and 0.94, respectively. These results demonstrate that fasting and postprandial glucose concentrations are almost perfectly correlated in diet-treated patients with type 2 diabetes, and that determination of fasting plasma glucose concentrations in these individuals provides an excellent estimate of degree of glycemic control.

    View details for DOI 10.1053/meta.2002.31325

    View details for Web of Science ID 000174820900011

    View details for PubMedID 11912553

  • Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stuhlinger, M. C., Abbasi, F., Chu, J. W., Lamendola, C., McLaughlin, T. L., Cooke, J. P., Reaven, G. M., Tsao, P. S. 2002; 287 (11): 1420-1426

    Abstract

    Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of cardiovascular disease. Several cardiovascular risk factors are associated with reduced sensitivity to insulin, but elevated ADMA concentrations have not been fully linked to the metabolic syndrome.To evaluate the relationship between insulin sensitivity and plasma ADMA concentrations, and to determine whether a pharmacological treatment that increases insulin sensitivity would also modulate ADMA concentrations.Cross-sectional study, containing a nonrandomized controlled trial component, of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal blood pressure and 16 with hypertension), which was conducted at a university medical center between October 2000 and July 2001.Rosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks), an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with hypertension. These subjects were studied before and after 12-week treatment.Insulin sensitivity measured by the insulin suppression test, and fasting plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and ADMA concentrations.Plasma ADMA concentrations were positively correlated with impairment of insulin-mediated glucose disposal in nondiabetic, normotensive subjects (r = 0.73; P<.001). Consistent with the metabolic syndrome, ADMA levels were also positively correlated with fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels (r = 0.19; P =.20). Plasma ADMA concentrations increased in insulin-resistant subjects independent of hypertension. Pharmacological treatment improved insulin sensitivity and reduced mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) micromol/L (P =.001).A significant relationship exists between insulin resistance and plasma concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations may contribute to the endothelial dysfunction observed in insulin-resistant patients.

    View details for Web of Science ID 000174465000024

    View details for PubMedID 11903029

  • Relative impact of low-density lipoprotein-cholesterol concentration and insulin resistance on carotid wall thickening in nondiabetic, normotensive volunteers METABOLISM-CLINICAL AND EXPERIMENTAL Wang, P. W., Liou, C. W., Wang, S. T., Eng, H. L., Liu, R. T., Tung, S. C., Chien, W. Y., Lu, Y. C., Kuo, M. C., Hsieh, C. J., Chen, C. H., Chen, J. F., Chu, J. W., Reaven, G. M. 2002; 51 (2): 255-259

    Abstract

    The relative effect of an increase in low-density lipoprotein-cholesterol (LDL-C) concentration, as compared with insulin resistance and its manifestations, on intimal medial thickening (IMT) of the common carotid artery was defined in 72 healthy men and women. Insulin-mediated glucose disposal was quantified by the insulin suppression tests, in which the height of the steady-state plasma glucose (SSPG) concentration during the last 30 minutes of a 180-minute infusion of octreotide, insulin, and glucose provides an estimate of insulin resistance. IMT was determined by high-resolution B-mode ultrasonography. Univariate analyses defined statistically significant correlation coefficients between IMT and LDL-C concentration (r =.25, P <.05), SSPG concentration (r =.32, P <.01), triglycerides (TG) (r =.25, P <.05), and high-density lipoprotein-cholesterol (HDL-C) (r = -.28, P <.05) concentrations (changes associated with insulin resistance) and ratio of waist-to-hip girth (r =.29, P <.05). When forward step-wise linear regression analysis was used, concentrations of SSPG, LDL-C and HDL-C all emerged as independent predictors of IMT (P <.05). Furthermore, the magnitude of their relationship to IMT values was comparable. These results provide evidence that insulin resistance is as significant a predictor of degree of atherogenesis (estimated by IMT) of the common carotid artery as a high LDL-C concentration.

    View details for DOI 10.1053/meta.2002.29998

    View details for Web of Science ID 000173738800021

    View details for PubMedID 11833058

  • Evaluation of the quantitative insulin sensitivity check index as an estimate of insulin sensitivity in humans METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Reaven, G. M. 2002; 51 (2): 235-237

    Abstract

    The goal of this study was to compare estimates of insulin resistance generated by the quantitative insulin sensitivity check index (QUICKI) with a direct measure of insulin-mediated glucose disposal in healthy, nondiabetic volunteers. For this purpose, the results of measurements of plasma glucose and insulin concentrations in 490 nondiabetic, healthy subjects were used to compute several surrogate estimates of insulin resistance, and these values were compared with a direct measure of insulin-mediated glucose disposal. The results of this analysis showed that estimates of insulin resistance derived from use of QUICKI were significantly correlated (r = -.60, P <.001) with direct measures of insulin-mediated glucose in the 490 subjects studied. It was also noted that QUICKI estimates of insulin resistance were highly correlated with fasting insulin concentrations (r = -.98) and the homeostasis model assessment for insulin resistance (HOMA-IR, r = -.99). On the other hand, the correlation between all 3 of the surrogate methods for estimating insulin resistance and the direct assessment of insulin-mediated glucose disposal was relatively weak, i.e., r =.61, r =.64, and r = -.60) for fasting insulin concentration, HOMA-IR, and QUICKI, respectively. The results of these comparisons do not provide support for the superiority of QUICKI over other commonly used surrogate measures of insulin resistance based upon use of fasting insulin concentration or equations utilizing fasting insulin and glucose concentration. Furthermore, none of the 3 surrogate estimates can account for more than approximately 40% of the variability of the difference in insulin-mediated glucose disposal measured directly in 490 healthy, nondiabetic volunteers.

    View details for DOI 10.1053/meta.2002.28970

    View details for Web of Science ID 000173738800017

    View details for PubMedID 11833054

  • Multiple CHD risk factors in type 2 diabetes: beyond hyperglycaemia Reaven, G. M. WILEY-BLACKWELL PUBLISHING, INC. 2002: S13-S18

    Abstract

    Recent evidence from the United Kingdom Prospective Diabetes Study convincingly demonstrates that good glycaemic control is difficult to achieve and, despite its positive impact on microvascular complications, is not sufficient to reduce the risk of coronary heart disease (CHD). Syndrome X--a cluster of abnormalities associated with resistance to insulin-mediated glucose uptake that have been implicated in accelerating atherogenesis--provides a useful clinical concept to prevent CHD in patients with type 2 diabetes. Components of syndrome X can include hypertension, hyperinsulinaemia, dyslipidaemia, and a procoagulant state, changes that contribute to the development of atherosclerosis. Low-density lipoprotein cholesterol (LDL-C) levels are usually close to normal, but the LDL-C is present in abnormally small and dense particles. Triglyceride levels are elevated and are associated with an increase in postprandial accumulation of atherogenic, remnant lipoprotein particles. High-density lipoprotein cholesterol levels are typically low. This particular dyslipidaemia, along with hyperinsulinaemia, induces expression of plasminogen activator inhibitor-1, contributing to a prothrombotic state. In addition, plaque formation may be accelerated in insulin-resistant subjects by increased expression of adhesion molecules on endothelial cells and increased rate of monocyte adhesion to cultured endothelial cells. Syndrome X and type 2 diabetes are associated with multiple abnormalities that enhance the atherosclerotic process. The opportunities for new therapeutic approaches to reduce cardiovascular risk will undoubtedly evolve along with our understanding of the complex factors responsible for insulin resistance, compensatory hyperinsulinaemia, and CHD.

    View details for Web of Science ID 000173842300003

    View details for PubMedID 11843950

  • Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ai, M., Tanaka, A., Ogita, K., Sekinc, M., Numano, F., Numano, F., Reaven, G. M. 2001; 38 (6): 1628-1632

    Abstract

    The goal of this study was to evaluate the relative effects of hyperglycemia and hyperinsulinemia on postprandial remnant lipoprotein (RLP) concentrations in newly diagnosed type 2 diabetics.Increases in fasting RLP concentration have been described in type 2 diabetics, as well as in insulin-resistant nondiabetics. Given the atherogenicity of RLPs, we have extended these observations by assessing postprandial RLP concentrations and observing that hyperglycemia was necessary for the increase in RLP concentrations.Patients with type 2 diabetes were subdivided on the basis of their plasma insulin response to oral glucose into hyperinsulinemic (H-DM) and normoinsulinemic (N-DM) groups of 15 patients each. Plasma triglyceride (TG), RLP-TG and RLP cholesterol (RLP-C) concentrations were determined before and 2 and 4 h after an oral fat load in these patients and 10 control (CTL) subjects.Plasma TG, RLP-TG and RLP-C concentrations peaked 2 h after the fat load in the CTL group, returning to baseline within 4 h. In contrast, concentrations of these variables increased throughout the 4-h study in both groups of patients with type 2 diabetes. Total integrated plasma RLP-TG and RLP-C responses above baseline after the oral fat load were significantly higher in the H-DM group compared with the CTL (p = 0.019 and 0.009, respectively) or N-DM (p = 0.026 and 0.029, respectively) groups. Post-heparin lipoprotein lipase activities and apo E phenotypes were similar in the H-DM and N-DM groups.Remnant lipoprotein response to an oral fat load is significantly increased in hyperinsulinemic patients with type 2 diabetes. These changes may increase the risk of coronary heart disease in these individuals.

    View details for Web of Science ID 000172254600008

    View details for PubMedID 11704373

  • Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus AMERICAN JOURNAL OF CARDIOLOGY Abbasi, F., Asagmi, T., Cooke, J. P., Lamendola, C., McLaughlin, T., Reaven, G. M., Stuehlinger, M., Tsao, P. S. 2001; 88 (10): 1201-?

    View details for Web of Science ID 000172412300025

    View details for PubMedID 11703973

  • Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone Cataldo, N. A., Abbasi, F., McLaughlin, T. L., Lamendola, C., Reaven, G. M. ELSEVIER SCIENCE INC. 2001: 1057-1059

    Abstract

    To determine the metabolic and reproductive effectiveness of rosiglitazone in polycystic ovary syndrome (PCOS).Case report.Academic clinical practice and General Clinical Research Center.A 25-year-old woman with PCOS.Rosiglitazone maleate, 4 mg daily for 5 months until conception.Insulin sensitivity by steady-state plasma glucose technique; serum androgens, progesterone, and hCG; and pelvic ultrasound images.Rosiglitazone treatment for 5 months improved insulin sensitivity, lowered serum free testosterone, and resulted in spontaneous ovulation and conception.Rosiglitazone is a promising insulin sensitizer for treatment of PCOS. Clinical trials are warranted.

    View details for Web of Science ID 000172083900034

    View details for PubMedID 11704136

  • Effect of insulin resistance on postprandial elevations of remnant lipoprotein concentrations in postmenopausal women AMERICAN JOURNAL OF CLINICAL NUTRITION Kim, H. S., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. M. 2001; 74 (5): 592-595

    Abstract

    Questions remain as to why postmenopausal women are at a higher risk of coronary artery disease (CAD) than are premenopausal women. Studies have shown that plasma concentrations of remnant lipoproteins (RLPs) are elevated in patients with CAD and that increases in plasma RLP concentrations may be related to variations in insulin-mediated glucose disposal.We sought to evaluate the possibility that postprandial accumulation of plasma RLPs will be accentuated in insulin-resistant, postmenopausal women.Postmenopausal women were divided into insulin-sensitive (n = 15) and insulin-resistant (n = 15) groups according to their steady state plasma glucose concentrations in response to a 180-min infusion of octreotide, insulin, and glucose. Plasma insulin, triacylglycerol, and RLP-cholesterol concentrations were measured either hourly (insulin) or every 2 h (triacylglycerol and RLP cholesterol) for 8 h, before and after breakfast (0800) and lunch (1200).By selection, insulin-resistant women had higher steady state plasma glucose concentrations than did insulin-sensitive women (10.8 +/- 0.5 compared with 4.1 +/- 5 mmol/L, respectively; P < 0.001), associated with higher fasting triacylglycerol (1.58 +/- 0.04 compared with 1.00 +/- 0.03 mmol/L; P = 0.01) and lower HDL-cholesterol (1.06 +/- 0.08 compared with 1.34 +/- 0.05; P = 0.01) concentrations. In addition, measurements of daylong concentrations of insulin, triacylglycerol, and RLP cholesterol were also significantly greater in insulin-resistant than in insulin-sensitive women (P < 0.001).Postprandial accumulation of RLPs is accentuated in insulin-resistant, postmenopausal women. This may contribute to the increased risk of CAD in these individuals.

    View details for Web of Science ID 000171779500009

    View details for PubMedID 11684526

  • Insulin resistance as a predictor of age-related diseases JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Facchini, F. S., Hua, N., Abbasi, F., Raven, G. M. 2001; 86 (8): 3574-3578

    Abstract

    The current study was initiated to evaluate the ability of insulin resistance to predict a variety of age-related diseases. Baseline measurements of insulin resistance and related variables were made between 1988-1995 in 208 apparently healthy, nonobese (body mass index < 30 kg/m2) individuals, who were then evaluated 4-11 yr later (mean +/- SEM = 6.3 +/- 0.2 yr) for the appearance of the following age-related diseases: hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. The effect of insulin resistance on the development of clinical events was evaluated by dividing the study group into tertiles of insulin resistance at baseline and comparing the events in these 3 groups. Clinical endpoints (n = 40) were identified in 37 individuals (18%) of those evaluated, including 12 with hypertension, 3 with hypertension + type 2 diabetes, 9 with cancer, 7 with coronary heart disease, 4 with stroke, and 2 with type 2 diabetes. Twenty-eight out of the total 40 clinical events were seen in 25 individuals (36%) in the most insulin-resistant tertile, with the other 12 occurring in the group with an intermediate degree of insulin resistance. Furthermore, insulin resistance was an independent predictor of all clinical events, using both multiple logistic regression and Cox's proportional hazards analysis. The fact that an age-related clinical event developed in approximately 1 out of 3 healthy individuals in the upper tertile of insulin resistance at baseline, followed for an average of 6 yr, whereas no clinical events were observed in the most insulin-sensitive tertile, should serve as a strong stimulus to further efforts to define the role of insulin resistance in the genesis of age-related diseases.

    View details for Web of Science ID 000170430200017

    View details for PubMedID 11502781

  • Metabolic changes following sibutramine-assisted weight loss in obese individuals: Role of plasma free fatty acids in the insulin resistance of obesity METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Abbasi, F., Lamendola, C., Kim, H. S., Reaven, G. M. 2001; 50 (7): 819-824

    Abstract

    The relationship between insulin-mediated glucose disposal and daylong free fatty acid (FFA) concentrations before and after sibutramine-assisted weight loss was investigated in 24 healthy, normotensive, nondiabetic, obese women (body mass index [BMI] >30.0 kg/m(2)). The 24 volunteers were defined as being insulin-resistant (IR) or insulin-sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration in response to a 180-minute continuous intravenous infusion of octreotide, insulin, and glucose. The mean (+/- SEM) SSPG concentrations were significantly higher (P <.001) in the IR group (219 +/- 7 v 69 +/- 6 mg/dL) at baseline. The IR group also had significantly higher plasma glucose (P =.002), insulin (P <.001), and FFA (P =.02) concentrations measured at hourly intervals from 8 AM to 4 PM, before and after breakfast (8 AM) and lunch (noon). Weight loss in response to an energy-restricted diet for 4 months and sibutramine (15 mg/d) was comparable in the 2 experimental groups (8.6 +/- 1.3 v 7.9 +/- 1.4 kg). SSPG concentrations decreased significantly (P <.001) following weight loss (219 +/- 7 to 144 +/- mg/dL) in the IR group, but there was no change in the SSPG of the IS group (69 +/- 6 to 73 +/- 7 mg/dL. The improvement in insulin sensitivity in the IR group after weight loss was associated with a significant decline in daylong plasma glucose (P >.001) and insulin (P =.02) concentrations, without a weight-loss-associated decrease in daylong plasma FFA responses. In contrast, there was no significant change in plasma glucose, insulin, and FFA concentrations following weight loss in the IS group. These results indicate that daylong FFA concentrations vary substantially in obese individuals as a function of whether they are IR or IS. Furthermore the observation that the IR group was more insulin-sensitive after weight loss, associated with lower daylong insulin concentrations in the absence of a significant decrease in circulating FFA concentrations, suggests that resistance to insulin-mediated glucose disposal in obese individuals cannot be entirely due to high FFA levels.

    View details for DOI 10.1053/meta.2001.24220

    View details for Web of Science ID 000169829600014

    View details for PubMedID 11436188

  • Insulin resistance, dietary cholesterol, and cholesterol concentration in postmenopausal women METABOLISM-CLINICAL AND EXPERIMENTAL Reaven, G. M., Abbasi, F., Bernhart, S., Coulston, A., Darnell, B., Dashti, N., Kim, H. S., Kulkarni, K., Lamendola, C., McLaughlin, T., Osterlund, L., Schaff, P., Segrest, J. 2001; 50 (5): 594-597

    Abstract

    Questions remain concerning the effect of variations in cholesterol intake on plasma cholesterol concentration, as well as on the role of factors modulating the metabolic impact of this dietary intervention. To define the impact of wide variations in dietary cholesterol intake on plasma total and low-density lipoprotein (LDL) cholesterol concentrations, as well as testing the hypothesis that resistance to insulin-mediated glucose disposal would accentuate the increase in plasma total and LDL cholesterol concentrations in response to a given increment in dietary cholesterol intake, we performed a prospective, randomized study comparing diets varying in cholesterol content in 65 healthy, postmenopausal women, 31 defined as insulin-resistant and 34 as insulin-sensitive. The changes in total and LDL cholesterol in response to increments in dietary cholesterol of up to approximately 800 mg/day were modest in magnitude, without evidence of a statistically significant diet-induced increase in cholesterol concentration, or of any difference in the responses of insulin-resistant as compared with insulin-sensitive women. These results indicate that relatively large increments in dietary cholesterol intake had little effect on total or LDL cholesterol concentrations in healthy, postmenopausal women, irrespective of whether they were insulin-resistant or insulin-sensitive.

    View details for Web of Science ID 000168444100014

    View details for PubMedID 11319723

  • Insulin resistance: why is it important to treat? DIABETES & METABOLISM Reaven, G. M. 2001; 27 (2): 247-253

    Abstract

    The ability of insulin to stimulate muscle glucose disposal and inhibit adipose tissue lipolysis is impaired in patients with type 2 diabetes. The progression from normal glucose tolerance and/or impaired glucose tolerance to type 2 diabetes only occurs when insulin secretory function declines to a degree that circulating insulin concentrations are no longer able to overcome muscle and adipose tissue insulin resistance. Although, ambient plasma insulin concentrations are not sufficiently high to maintain euglycaemia in patients with type 2 diabetes, absolute plasma insulin concentrations in these individuals are as high, if not higher, than in nondiabetic subjects. Since the plasma concentrations of insulin, or free fatty acids (FFAs), or both, are elevated in patients with type 2 diabetes secondary to muscle and adipose tissue insulin resistance, hypertriglyceridaemia is common in these individuals. Improvement in glycaemic control with insulin or insulin secretagogues is achieved by raising plasma insulin concentrations to a level high enough to overcome the insulin resistance. This is not the case with thiazolidinediones (TZDs): glycaemic control is associated with lower plasma insulin concentration. Compounds that improve insulin sensitivity and lead to lower glucose and insulin concentrations may have unique clinical benefit in the treatment of patients with type 2 diabetes.

    View details for Web of Science ID 000168531500010

    View details for PubMedID 11452218

  • Why is it important to be insulin sensitive? Diabetes & metabolism Reaven, G. M. 2001; 27 (2): 189-192

    View details for PubMedID 11452209

  • Familial factors in the antihypertensive response to lisinopril AMERICAN JOURNAL OF HYPERTENSION Hollenberg, N. K., Anzalone, D. A., Falkner, B., Fisher, N. D., Hopkins, P. N., Hsueh, W., Hutchinson, H., Krauss, R. M., Price, D. A., Raskin, P., Reaven, G. M. 2001; 14 (3): 218-223

    Abstract

    Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents.This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable.Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein.Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

    View details for Web of Science ID 000167285000005

    View details for PubMedID 11281232

  • Hyperinsulinemia: The missing link among oxidative stress and age-related diseases? FREE RADICAL BIOLOGY AND MEDICINE Facchini, F. S., Hua, N. W., Reaven, G. M., Stoohs, R. A. 2000; 29 (12): 1302-1306

    Abstract

    Mounting evidence supports Harman's hypothesis that aging is caused by free radicals and oxidative stress. Although it is known that oxidant species are produced during metabolic reactions, it is largely unknown which factor(s), of physiological or pathophysiological significance, modulate their production in vivo. In this hypothesis paper, it is postulated that hyperinsulinemia may have such function and therefore promote aging, independently of elevations of glycemia. Hyperinsulinemia is secondary to impaired insulin stimulated glucose metabolism at the level of skeletal muscle (insulin resistance) and is seen in about one third of glucose tolerant humans following dietary carbohydrate intake. If other insulin-stimulated (or inhibited) pathways retain normal sensitivity to the hormone, hyperinsulinemia could, by its effects on antioxidative enzymes and on free radical generators, enhance oxidative stress. Other proaging effects of insulin involve the inhibition of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a metabolic explanation for the life-prolonging effect of calorie restriction and of mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans.

    View details for Web of Science ID 000165834600010

    View details for PubMedID 11118820

  • A new rat model of type 2 diabetes: The fat-fed, streptozotocin-treated rat METABOLISM-CLINICAL AND EXPERIMENTAL Reed, M. J., Meszaros, K., Entes, L. J., Claypool, M. D., Pinkett, J. G., Gadbois, T. M., Reaven, G. M. 2000; 49 (11): 1390-1394

    Abstract

    This study was initiated to develop an animal model of type 2 diabetes in a non-obese, outbred rat strain that replicates the natural history and metabolic characteristics of the human syndrome and is suitable for pharmaceutical research. Male Sprague-Dawley rats (n = 31), 7 weeks old, were fed normal chow (12% of calories as fat), or high-fat diet (40% of calories as fat) for 2 weeks and then injected with streptozotocin (STZ, 50 mg/kg intravenously). Before STZ injection, fat-fed rats had similar glucose concentrations to chow-fed rats, but significantly higher insulin, free fatty acid (FFA), and triglyceride (TG) concentrations (P < .01 to .0001). Plasma insulin concentrations in response to oral glucose (2 g/kg) were increased 2-fold by fat feeding (P < .01), and adipocyte glucose clearance under maximal insulin stimulation was significantly reduced (P < .001), suggesting that fat feeding induced insulin resistance. STZ injection increased glucose (P < .05), insulin (P < .05), FFA (P < .05), and TG (P < .0001) concentrations in fat-fed rats (Fat-fed/STZ rats) compared with chow-fed, STZ-injected rats (Chow-fed/STZ rats). Fat-fed/STZ rats were not insulin deficient compared with normal chow-fed rats, but had hyperglycemia and a somewhat higher insulin response to an oral glucose challenge (both P < .05). In addition, insulin-stimulated adipocyte glucose clearance was reduced in Fat-fed/STZ rats compared with both chow-fed and Chow-fed/STZ rats (P < .001). Finally, Fat-fed/STZ rats were sensitive to the glucose lowering effects of metformin and troglitazone. In conclusion, Fat-fed/STZ rats provide a novel animal model for type 2 diabetes, simulates the human syndrome, and is suitable for the testing of antidiabetic compounds.

    View details for Web of Science ID 000165220900003

    View details for PubMedID 11092499

  • Diet and Syndrome X. Current atherosclerosis reports Reaven, G. M. 2000; 2 (6): 503-507

    Abstract

    Syndrome X is a cluster of abnormalities, associated with resistance to insulin-mediated glucose uptake, that increases risk of coronary heart disease. Increased carbohydrate intake (with reciprocal decreased fat intake) within the boundaries of menus that can be followed in the free-living state have not been shown to decrease insulin resistance directly, by enhancing insulin sensitivity, or indirectly, by producing and maintaining weight loss. Moreover, such diets accentuate the metabolic abnormalities that constitute Syndrome X. Substitution of monounsaturated fat, polyunsaturated fat, or both for saturated fat results in the same reduction in low-density lipoprotein-cholesterol concentration as seen in diets low in fat and high in carbohydrates but without any untoward effects on the various manifestations of Syndrome X. Consequently, substituting unsaturated fat for saturated fat, without increasing intake of dietary protein or carbohydrate, may be useful for patients with hypercholesterolemia, Syndrome X, or both.

    View details for PubMedID 11122785

  • Relationship between hyperinsulinemia and remnant lipoprotein concentrations in patients with impaired glucose tolerance JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Ai, M., Tanaka, A., Ogita, K., Sekine, M., Numano, F., Numano, F., Reaven, G. M. 2000; 85 (10): 3557-3560

    Abstract

    This study was performed to explore further the association between insulin resistance and plasma remnant lipoprotein (RLP) concentration. For this purpose we used the sum of the plasma insulin concentrations before and 30, 60, 90, 120, and 180 min after a 75-g oral glucose load (sigmaIRI) as a surrogate measure of insulin resistance in 61 subjects with impaired glucose tolerance. SigmaIRI was determined on 2 occasions, before and 16 weeks after initiation of a diet and exercise program. At baseline, sigmaIRI correlated with the sum of the plasma glucose concentrations in response to the 75-g oral glucose load (r = 0.26; P < 0.04) as well as plasma concentrations of triglyceride (r = 0.21; P = 0.09), RLP-cholesterol (r = 0.41; P < 0.001), and RLP-triglyceride (r = 0.46; P < 0.001). In contrast, neither total (r = 0.07) nor high density lipoprotein (HDL) cholesterol (r = 0.04) concentrations correlated with sigmaIRI. SigmaIRI was lower in 42 subjects following life-style intervention, associated with significant (P < 0.005) reductions in sigmaglucose, and fasting glucose, insulin, triglyceride, RLP-cholesterol, and RLP-triglyceride concentrations. However, none of these variables decreased in the 19 subjects whose sigmaIRI did not fall. Finally, the change in sigmaIRI following intervention with diet and exercise was significantly associated with differences in sigmaglucose (r = 0.63; P < 0.001) and fasting glucose (r = 0.26; P < 0.05), insulin (r = 0.79; P < 0.001), triglyceride (r = 0.29; P < 0.03), RLP-cholesterol (r = 0.71; P < 0.001), and RLP-triglyceride (r = 0.49; P < 0.001) concentrations. These results demonstrate that variations in concentrations of RLPs are highly correlated with changes in sigmaIRI, consistent with the possibilities that 1) RLP measurements are useful estimates of insulin resistance; and 2) an increase in RLP concentrations may provide the mechanistic link between insulin resistance and coronary heart disease.

    View details for Web of Science ID 000089820800015

    View details for PubMedID 11061501

  • Masoprocol decreases serum triglyceride concentrations in rats with fructose-induced hypertriglyceridemia METABOLISM-CLINICAL AND EXPERIMENTAL Scribner, K. A., Gadbois, T. M., Gowri, M., Azhar, S., Reaven, G. M. 2000; 49 (9): 1106-1110

    Abstract

    Historically, extracts of the creosote bush have been used by native healers of the Southwest region of North America to treat symptoms of type 2 diabetes. More recently, we have shown that masoprocol (nordihydroguaiaretic acid), a pure compound isolated from the creosote bush (Larrea tridentata), decreases serum glucose and triglyceride (TG) levels when administered orally in rodent models of type 2 diabetes. The present studies were undertaken to determine if masoprocol also decreases TG concentrations in rats with fructose-induced hypertriglyceridemia (HTG), a nondiabetic model of HTG associated with insulin resistance and hyperinsulinemia. Serum TG levels, which were significantly higher after rats ate a fructose-enriched (60% by weight) diet for 14 days as compared with chow-fed controls (411 v 155 mg/dL, P < .01), decreased in a stepwise fashion in fructose-fed rats treated orally with masoprocol for 4 to 8 days over a dose range of 10 to 80 mg/kg twice daily. Using the nonionic detergent Triton WR 1339 to compare TG secretion rates in masoprocol- and vehicle-treated rats, masoprocol at a dose of 40 or 80 mg/kg twice daily, significantly reduced hepatic TG secretion (P < .01) and liver TG content (P < .001), whereas lower doses of masoprocol decreased serum TG without an apparent reduction in hepatic TG secretion. Administration of Intralipid (a fat emulsion) showed that the half-time for removal of TG from serum was also shorter in masoprocol-treated rats versus vehicle-treated controls (31 v 64 minutes, P < .05). In addition adipose tissue lipoprotein lipase (LPL) activity was increased in masoprocol-treated rats and adipose tissue hormone-sensitive lipase (HSL) activity was decreased. We conclude that masoprocol administration to rats with fructose-induced HTG results in lower serum TG levels associated with reduced hepatic TG secretion and increased peripheral TG clearance.

    View details for Web of Science ID 000089325300002

    View details for PubMedID 11016888

  • Carbohydrate-induced hypertriglyceridemia: An insight into the link between plasma insulin and triglyceride concentrations JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Abbasi, F., Lamendola, C., Yeni-Komshian, H., Reaven, G. 2000; 85 (9): 3085-3088

    Abstract

    This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.

    View details for Web of Science ID 000089166200016

    View details for PubMedID 10999790

  • Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols AMERICAN JOURNAL OF CLINICAL NUTRITION Facchini, F. S., Humphreys, M. H., DoNascimento, C. A., Abbasi, F., Reaven, G. M. 2000; 72 (3): 776-779

    Abstract

    It is not known whether total circulating lipid hydroperoxides are increased in insulin-resistant individuals and whether this correlates with depletion of liposoluble antioxidant vitamins that are consumed during lipid peroxidation.The goal of this study was to define the relation between resistance to insulin-mediated glucose disposal and plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins in healthy volunteers.Insulin-mediated glucose disposal was determined in 36 healthy, nondiabetic volunteers by measuring their steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a 180-min constant infusion of octreotide, insulin, and glucose. In addition, fasting plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins were determined by using the FOX 2 assay and liquid chromatography.Statistically significant direct relations were observed between SSPG and mean arterial blood pressure (r = 0.44, P: = 0.008) and plasma lipid hydroperoxide concentrations (r = 0.42, P: = 0.01), whereas significant inverse correlations were found between SSPG and alpha-carotene (r = -0.58, P: = 0.0002), beta-carotene (r = -0.49, P: = 0.004), lutein (r = -0.35, P: = 0.04), alpha-tocopherol (r = -0. 36, P: = 0.04), and delta-tocopherol (r = -0.45, P: = 0.007).Variations in insulin-mediated glucose disposal in healthy individuals are significantly related to plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins. These findings suggest that total plasma lipid peroxidation is increased in insulin-resistant individuals at an early, preclinical stage, ie, well before the development of glucose intolerance and type 2 diabetes.

    View details for Web of Science ID 000089021300018

    View details for PubMedID 10966898

  • Masoprocol decreases rat lipolytic activity by decreasing the phosphorylation of HSL AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Gowri, M. S., Azhar, R. K., Kraemer, F. B., Reaven, G. M., Azhar, S. 2000; 279 (3): E593-E600

    Abstract

    Masoprocol (nordihydroguaiaretic acid), a lipoxygenase inhibitor isolated from the creosote bush, has been shown to decrease adipose tissue lipolytic activity both in vivo and in vitro. The present study was initiated to test the hypothesis that the decrease in lipolytic activity by masoprocol resulted from modulation of adipose tissue hormone-sensitive lipase (HSL) activity. The results indicate that oral administration of masoprocol to rats with fructose-induced hypertriglyceridemia significantly decreased their serum free fatty acid (FFA; P < 0.05), triglyceride (TG; P < 0.001), and insulin (P < 0.05) concentrations. In addition, isoproterenol-induced lipolytic rate and HSL activity were significantly lower (P < 0.001) in adipocytes isolated from masoprocol compared with vehicle-treated rats and was associated with a decrease in HSL protein. Incubation of masoprocol with adipocytes from chow-fed rats significantly inhibited isoproterenol-induced lipolytic activity and HSL activity, associated with a decrease in the ability of isoproterenol to phosphorylate HSL. Masoprocol had no apparent effect on adipose tissue phosphatidylinositol 3-kinase activity, but okadaic acid, a serine/threonine phosphatase inhibitor, blocked the antilipolytic effect of masoprocol. The results of these in vitro and in vivo experiments suggest that the antilipolytic activity of masoprocol is secondary to its ability to inhibit HSL phosphorylation, possibly by increasing phosphatase activity. As a consequence, masoprocol administration results in lower serum FFA and TG concentrations in hypertriglyceridemic rodents.

    View details for Web of Science ID 000088830300015

    View details for PubMedID 10950827

  • The relationship between plasma glucose and insulin responses to oral glucose, LDL oxidation, and soluble intercellular adhesion molecule-1 in healthy volunteers ATHEROSCLEROSIS Chen, N. G., Azhar, S., Abbasi, F., Carantoni, M., Reaven, G. M. 2000; 152 (1): 203-208

    Abstract

    This study was initiated to describe the relationships between plasma glucose and insulin responses to oral glucose and the concentrations of partially oxidized low density lipoprotein (poxLDL) and soluble intercellular adhesion molecule-1 (sICAM-1) in 23 healthy, non-diabetic volunteers. Results demonstrated that plasma glucose (r=0.65, P<0.002) and insulin (r=0.58, P<0.007) responses to a 75-g oral glucose challenge were highly correlated to poxLDL concentrations. Plasma glucose (r=0.63, P<0.002) and insulin (r=0.68, P<0.001) concentrations also significantly correlated with sICAM-1 concentrations. Furthermore, concentrations of poxLDL and sICAM-1 were significantly related (r=0.55, P<0.001). These relationships remained statistically significant when adjusted for differences in age, gender, body mass index, and lipoprotein concentrations. These results provide further evidence that circulating LDL particles are more highly oxidized in insulin resistant states, and demonstrate the presence of an in vivo relationship between insulin resistance, LDL oxidized state, and sICAM-1 concentrations. These results help explain why soluble forms of adhesion molecules are increased in clinical conditions characterized by insulin resistance, and support the possibility that LDL oxidizability is increased in insulin resistant subjects, and that the increase in sICAM-1 results from stimulation of cellular adhesion molecules by more highly oxidized LDL.

    View details for Web of Science ID 000089447700024

    View details for PubMedID 10996356

  • Plasma nitric oxide concentrations are elevated in insulin-resistant healthy subjects METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Platti, P. M., Monti, L. D., Gasparini, P., Barilli, L. A., Massironi, P., Ardigo, D., Valsecchi, G., Delsignore, R., Reaven, G. M. 2000; 49 (8): 959-961

    Abstract

    The goal of this study was to compare plasma nitric oxide (NO) concentrations in healthy subjects, defined as either insulin-resistant or insulin-sensitive on the basis of the plasma insulin response to a 75-g oral glucose challenge. For this purpose, 404 healthy subjects were divided into quartiles on the basis of the plasma insulin response to glucose, and 49 individuals were selected from the quartile with the lowest insulin response and 49 from the quartile with the highest insulin response. The two groups of 49 each were selected to be essentially identical in terms of age, gender distribution, body mass index (BMI), and waist to hip ratio (WHR). The quartile with the greatest insulin response also had a significantly higher plasma glucose response to oral glucose, faster heart rate, higher blood pressure, and the combination of higher triglyceride and lower high-density lipoprotein (HDL) cholesterol concentrations. In addition to the latter changes, previously shown to be associated with hyperinsulinemia, NO concentrations were also higher in the hyperinsulinemic group. It is speculated that this increase in the NO concentration in hyperinsulinemic and presumably insulin-resistant, subjects represents a compensatory effort to overcome the untoward effects of insulin resistance and/or hyperinsulinemia.

    View details for Web of Science ID 000089019100001

    View details for PubMedID 10954010

  • Erythrocyte insulin receptor tyrosine kinase activity is increased in glyburide-treated patients with type 2 diabetes in good glycaemic control DIABETES OBESITY & METABOLISM Santos, R. F., Nomizo, R., Oliveira, E., Ursich, M., Wajchenberg, B., Reaven, G. M., Azhar, S. 2000; 2 (4): 237-241

    Abstract

    The goal of this study was to test the hypothesis that insulin receptor tyrosine kinase activity of isolated erythrocytes would be greater in glyburide-treated patients with type 2 diabetes in good glycaemic control (n = 13) than in untreated patients (n = 12) with significant fasting hyperglycaemia.The two groups were similar in age, sex distribution, and body mass index. By selection, glyburide-treated patients had significantly (p < 0.001) lower (mean +/- s.e.m.) fasting glucose (6.9+/-0.4 vs. 13.9+/-0.8 mmol/l) and HbA(IC) (7.4+/-0.2 vs. 11.8+/-0.9%) concentrations. In addition, insulin-stimulated tyrosine kinase activity was increased in erythrocytes from glyburide -treated patients (p < 0.01).Although insulin receptor number was similar in solubilized erythrocytes from the two groups, tyrosine kinase activity per insulin receptor was significantly (p < 0.02) greater in erythrocytes from glyburide-treated patients with type 2 diabetes.These findings are quite similar to previously published data in metformin-treated patients. As such, it is suggested that decreases in insulin receptor tyrosine kinase activity may contribute to the loss of insulin sensitivity in hyperglycaemic subjects (glucotoxicity), and that an improvement in glycaemic control, irrespective of how it is achieved, will help rectify this abnormality.

    View details for Web of Science ID 000088302800005

    View details for PubMedID 11225657

  • Are the results really different? DIABETES CARE Reaven, G. M. 2000; 23 (7): 1040-1040

    View details for Web of Science ID 000087890200045

    View details for PubMedID 10895876

  • Insulin resistance and hypertension - Patients in double jeopardy for cardiovascular disease GERIATRICS McLaughlin, T., Reaven, G. 2000; 55 (6): 28-?

    Abstract

    Essential hypertension is prevalent among older individuals, and approximately 50% of persons with hypertension can be considered to have insulin resistance and hyperinsulinemia. It appears likely that insulin resistance and hyperinsulinemia predispose to, rather than result from, hypertension. Insulin resistance is associated with abnormalities in lipoprotein metabolism, hypercoagulability, and endothelial function, which probably account in part for the increased cardiovascular risk among hypertensive patients. To identify this subset of patients, all hypertensive patients should be screened for diabetes and lipid abnormalities. The presence of impaired glucose tolerance, diabetes, or hypertriglyceridemia and low HDL suggest the presence of insulin resistance. Insulin resistant patients, in particular, will benefit from exercise and weight loss.

    View details for Web of Science ID 000087657800008

    View details for PubMedID 10872343

  • Plasma insulin concentration is more tightly linked to plasma leptin concentration than is the body mass index METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Carantoni, M., McLaughlin, T., Reaven, G. M. 2000; 49 (4): 544-547

    Abstract

    This study tested the hypothesis that the integrated plasma insulin response to oral glucose is a more sensitive predictor of the fasting plasma leptin concentration than the body mass index (BMI) or waist to hip ratio (WHR). For this purpose, we determined the fasting plasma leptin concentration and plasma insulin response to a 75-g oral glucose challenge in 76 healthy female subjects, with a BMI of 19.1 to 36.6 kg/m2 and a WHR of 0.57 to 1.1. The results demonstrated that fasting plasma leptin concentrations were significantly correlated with both the BMI (r = .64, P < .001) and the plasma insulin response to glucose (r = .61, P < .001), but not with the WHR (r = .27). Since the BMI and the insulin response were also significantly related (r = .34, P = .003), multivariate analysis was performed to determine if the BMI and insulin response were independent determinants of the fasting leptin concentration. This analysis indicated that both the BMI and insulin response were significantly related to plasma leptin (P < .001). To pursue this issue further, the population was divided into tertiles on the basis of the (1) plasma leptin concentration, (2) BMI, and (3) integrated insulin response. The two variables that were most closely linked to each other were the leptin concentration and insulin response. In contrast, the BMI was relatively easily disassociated from the other two variables. These results indicate that while both the plasma insulin response to glucose and the BMI are significantly associated with the fasting plasma leptin concentration, the plasma insulin response appears more closely associated with the plasma leptin concentration.

    View details for Web of Science ID 000086444800023

    View details for PubMedID 10778883

  • Comparison of fasting plasma leptin concentrations in healthy subjects with high and low plasma insulin METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Gasparini, P., Barilli, A. I., Massironi, P., Campanini, C., Carantoni, M., Delsignore, R., Reaven, G. M. 2000; 49 (4): 499-502

    Abstract

    This study was initiated to evaluate the role of hyperinsulinemia in the regulation of fasting plasma leptin. We measured plasma leptin and insulin concentrations in 404 healthy nondiabetic subjects. For analytical purposes, the population was divided into quartiles on the basis of the lowest (quartile 1) and highest (quartile 4) plasma insulin response to oral glucose, and fasting plasma leptin values in these 2 dichotomous groups were compared. The total plasma integrated insulin response was 4-fold greater in quartile 4, associated with significantly higher (P < .001) fasting plasma leptin (12.60+/-0.85 v8.53+/-0.56 ng/mL). Fasting plasma leptin concentrations remained significantly higher in the hyperinsulinemic quartile when comparisons were made after subdividing the population on the basis of gender, body mass index (BMI), or waist to hip ratio (WHR). These results demonstrate that fasting plasma leptin concentrations are significantly higher in hyperinsulinemic individuals, and this difference is independent of either overall or central obesity.

    View details for Web of Science ID 000086444800015

    View details for PubMedID 10778875

  • The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Abbasi, F., McLaughlin, T., Lamendola, C., Reaven, G. M. 2000; 85 (3): 1251-1254

    Abstract

    This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.

    View details for Web of Science ID 000088387000057

    View details for PubMedID 10720071

  • Insulin-mediated glucose disposal is decreased in normal subjects with relatively low plasma magnesium concentrations METABOLISM-CLINICAL AND EXPERIMENTAL Rosolova, H., Mayer, O., Reaven, G. M. 2000; 49 (3): 418-420

    Abstract

    The relationship between the plasma magnesium (Mg) concentration and steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations at the end of a 180-minute infusion of octreotide, insulin, and glucose was determined in 98 healthy nondiabetic subjects. For the purposes of data analysis, the population was divided into tertiles on the basis of the plasma Mg concentration: I, plasma Mg 0.83 mmol/L; II, plasma Mg 0.84 to 0.91 mmol/L; and III, plasma Mg 0.92 mmol/L. The three groups were identical in terms of age, gender distribution, and degree of obesity. However, both fasting plasma insulin (P < .05) and SSPG (P < .05) concentrations were significantly higher in the tertile (I) with the lowest plasma Mg concentration. Furthermore, there was a significant inverse correlation between plasma Mg and SSPG concentrations (r = -.27, P < .01) in the entire population. These results indicate that variations in the plasma Mg concentration have a relatively modest but significant effect on insulin-mediated glucose disposal in healthy subjects, with lower plasma Mg concentrations associated with increased insulin resistance.

    View details for Web of Science ID 000085809300022

    View details for PubMedID 10726923

  • Roles of insulin resistance and obesity in regulation of plasma insulin concentrations AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Jones, C. N., Abbasi, F., Carantoni, M., Polonsky, K. S., Reaven, G. M. 2000; 278 (3): E501-E508

    Abstract

    Plasma glucose, insulin, and C-peptide concentrations were determined in response to graded infusions of glucose, and insulin secretion rates were calculated over each sampling period. Measurements were also made of insulin clearance, resistance to insulin-mediated glucose, uptake, and the plasma glucose, insulin, and C-peptide concentrations at hourly intervals from 8:00 AM to 4:00 PM in response to breakfast and lunch. Plasma glucose, insulin, and C-peptide concentrations were significantly (P < 0.01) higher in obese women in response to the graded intravenous glucose infusion, associated with a 40% (P < 0.005) greater insulin secretory response. Degree of insulin resistance correlated positively (P < 0.05) with the increase in insulin secretion rate in both nonobese (r = 0.52) and obese (r = 0.58) groups and inversely (P < 0.05) with the decrease in insulin clearance in obese (r = -0.46) and nonobese (r = -0.39) individuals. Weight loss was associated with significantly lower plasma glucose, insulin, and C-peptide concentrations in response to graded glucose infusions and in day-long insulin concentrations. Neither insulin resistance nor the insulin secretory response changed after weight loss, whereas there was a significant increase in the rate of insulin clearance during the glucose infusion. It is concluded that 1) obesity is associated with a shift to the left in the glucose-stimulated insulin secretory dose-response curve as well as a decrease in insulin clearance and 2) changes in insulin secretion and insulin clearance in obese women are more a function of insulin resistance than obesity.

    View details for Web of Science ID 000085819900017

    View details for PubMedID 10710505

  • Insulin regulation of plasma free fatty acid concentrations is abnormal in healthy subjects with muscle insulin resistance METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., McLaughlin, T., Lamendola, C., Reaven, G. M. 2000; 49 (2): 151-154

    Abstract

    This study evaluated the ability of insulin to regulate free fatty acid (FFA) concentrations in healthy nondiabetic subjects selected to be either insulin-resistant or -sensitive on the basis of insulin-mediated glucose disposal by muscle. Comparisons of steady-state plasma glucose (SSPG), insulin (SSPI), and FFA concentrations were made at the end of 3 infusion periods: (1) under basal insulin conditions (approximately 10 microU/mL), (2) in response to isoproterenol-induced stimulation of lipolysis at the same basal insulin concentration, and (3) following inhibition of isoproterenol-induced lipolysis by a 2-fold increase in the insulin concentration. The results showed that steady-state FFA concentrations were significantly higher under basal conditions (360 +/- 73 v 158 +/- 36 microEq/L, P = .02), in response to isoproterenol-induced lipolysis (809 +/- 92 v433 +/- 65 microEq/L, P = .005), and following insulin inhibition of isoproterenol-induced lipolysis (309 +/- 65 v 159 +/- 37 microEq/L, P = .06). These differences were found despite the fact that SSPG concentrations were also higher in insulin-resistant individuals during all 3 infusion periods. These results demonstrate that the ability of insulin to regulate plasma FFA concentrations is impaired in healthy subjects with muscle insulin resistance, indicating that insulin-resistant individuals share defects in the ability of insulin to stimulate muscle glucose disposal and to inhibit adipose tissue lipolysis.

    View details for Web of Science ID 000085340800002

    View details for PubMedID 10690936

  • Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers DIABETES CARE Yeni-Komshian, H., Carantoni, M., Abbasi, F., Reaven, G. M. 2000; 23 (2): 171-175

    Abstract

    The goal of this study was to define the relationship between a quantitative measure of the ability of physiological hyperinsulinemia to stimulate glucose disposal and several surrogate measures of insulin resistance.Insulin-mediated glucose disposal was quantified in 490 healthy nondiabetic volunteers by determining the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose. Because the steady-state plasma insulin concentration was similar in all subjects during the infusion (approximately 60 microU/ml), the SSPG concentration provided a direct estimate of insulin-mediated glucose disposal. Relationships between this specific measure of insulin resistance and several surrogate estimates of insulin resistance based on plasma glucose and insulin concentrations were then defined.The surrogate measure of insulin resistance most closely related to the direct determination of insulin action was the total integrated insulin response to a 75-g oral glucose challenge with correlation coefficients (r) varying from 0.67 to 0.79. Fasting plasma insulin concentration was significantly correlated (r = 0.61, P<0.001) to the specific estimate of insulin action. Two other surrogate estimates of insulin action, the ratio of fasting glucose-to-fasting insulin concentration and the homeostasis model assessment for insulin resistance, were no more closely related to SSPG than the fasting plasma insulin concentration.The total integrated insulin response to oral glucose is the best surrogate measure of insulin resistance, accounting for approximately two-thirds of the variability in insulin-mediated glucose disposal. Fasting insulin concentration accounted for approximately one-third of the variability in insulin-mediated glucose disposal, and the use of fasting plasma glucose and insulin concentrations to calculate more sophisticated estimates of insulin resistance appears to offer little advantage over the fasting plasma insulin concentration. Given the large number of nondiabetic individuals in this study, the results should have general application in population-based studies, providing evidence for both the utility and limitation of the use of these surrogate measures.

    View details for Web of Science ID 000085037300008

    View details for PubMedID 10868826

  • High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk AMERICAN JOURNAL OF CARDIOLOGY Abbasi, F., McLaughlin, T., Lamendola, C., Kim, H. S., Tanaka, A., Wang, T., Nakajima, K., Reaven, G. M. 2000; 85 (1): 45-48

    Abstract

    In this study we compared the effects of variations in dietary fat and carbohydrate (CHO) content on concentrations of triglyceride-rich lipoproteins in 8, healthy, nondiabetic volunteers. The diets contained, as a percentage of total calories, either 60% CHO, 25% fat, and 15% protein, or 40% CHO, 45% fat, and 15% protein. They were consumed in random order for 2 weeks, with a 2-week washout period in between. Measurements were obtained at the end of each dietary period of plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, remnant lipoprotein (RLP) cholesterol, and RLP triglyceride concentrations, both after an overnight fast and throughout an 8-hour period (8 A.M. to 4 P.M.) in response to breakfast and lunch. The 60% CHO diet resulted in higher (mean +/- SEM) fasting plasma triglycerides (206 +/- 50 vs 113 +/- 19 mg/dl, p = 0.03), RLP cholesterol (15 +/- 6 vs 6 +/- 1 mg/dl, p = 0.005), RLP triglyceride (56 +/- 25 vs 16 +/- 3 mg/dl, p = 0.003), and lower HDL cholesterol (39 +/- 3 vs 44 +/- 3 mg/dl, p = 0.003) concentrations, without any change in LDL cholesterol concentration. Furthermore, the changes in plasma triglyceride, RLP cholesterol, and RLP triglyceride persisted throughout the day in response to breakfast and lunch. These results indicate that the effects of lowfat diets on lipoprotein metabolism are not limited to higher fasting plasma triglyceride and lower HDL cholesterol concentrations, but also include a persistent elevation in RLPs. Given the atherogenic potential of these changes in lipoprotein metabolism, it seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO.

    View details for Web of Science ID 000084555000009

    View details for PubMedID 11078235

  • Fasting remnant lipoprotein cholesterol and triglyceride concentrations are elevated in nondiabetic, insulin-resistant, female volunteers JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Abbasi, F., McLaughlin, T., Lamendola, C., Yeni-Komshian, H., Tanaka, A., Wang, T., Nakajima, K., Reaven, G. M. 1999; 84 (11): 3903-3906

    Abstract

    This study was initiated to test the hypothesis that plasma concentrations of remnant lipoproteins would be higher after an overnight fast in insulin-resistant compared to insulin-sensitive volunteers. Forty-three healthy nonobese women were studied, divided into insulin-resistant (n = 21) and insulin-sensitive (n = 22) groups on the basis of their steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide acetate, insulin, and glucose. Under these conditions, steady state plasma insulin concentrations are similar in all subjects (approximately 60 microU/mL), and the higher the SSPG concentrations, the more insulin resistant the individual. By selection, mean (+/-SEM) SSPG concentrations were significantly higher (P < 0.001) in the insulin-resistant group (210 +/- 7 vs. 78 +/- 3 mg/dL). In addition, the insulin-resistant group had higher triglycerides (198 +/- 27 vs. 101 +/- 12 mg/dL; P < 0.005) and lower high density lipoprotein cholesterol (48 +/- 4 vs. 60 +/- 4 mg/dL; P < 0.05) concentrations. Finally, insulin resistance was associated with higher remnant lipoprotein particle concentrations of cholesterol (7.2 +/- 0.8 vs. 4.4 +/- 0.3; P < 0.005) and triglycerides (22.2 +/- 3.4 vs. 8.5 +/- 1.0; P < 0.001). All of these differences were seen despite the fact that the two groups were similar in terms of age and body mass index. These results identify additional abnormalities in lipoprotein metabolism that may contribute to the increased risk of coronary heart disease seen in insulin-resistant, nondiabetic subjects (syndrome X).

    View details for Web of Science ID 000083555800007

    View details for PubMedID 10566626

  • Comparison of plasminogen activator inhibitor-1 concentration in insulin-resistant versus insulin-sensitive healthy women ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Abbasi, F., McLaughlin, T., Lamendola, C., Lipinska, I., Tofler, G., Reaven, G. M. 1999; 19 (11): 2818-2821

    Abstract

    The primary goal of this investigation was to see whether plasminogen activator inhibitor-1 (PAI-1) concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable that might play a role in regulation of PAI-1. For this purpose, we recruited 32 healthy women, divided on the basis of their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test into an insulin-resistant (SSPG=216+/-12 mg/dL, n=16) and an insulin-sensitive (94+/-6 mg/dL, n=16) group. PAI-1 antigen concentrations were significantly higher (26+/-4 versus 14+/-3 ng/mL, P<0.02) in the insulin-resistant group. In addition, fasting plasma insulin (18+/-3 versus 11+/-2 microU/mL, P<0.02) and triglyceride (160+/-19 versus 93+/-10 mg/dL, P<0.001) concentrations were higher in the insulin-resistant individuals, whereas HDL concentrations were lower (44+/-3 versus 58+/-3 mg/dL, P<0.005). However, the 2 groups were essentially identical in terms of age, menopausal status, hormone replacement therapy, body mass index (BMI), ratio of waist-to-hip girth, and blood pressure. When the experimental population was considered as 1 group, there were statistically significant correlations between PAI-1 antigen and the following variables: adjusting for differences in age and BMI, SSPG (r=0.56, P<0.001); triglyceride (r=0.39, P<0.05); and HDL cholesterol (r=-0. 65, P<0.001) concentrations. Finally, multiple regression analysis revealed the major determinants of PAI-1 to be insulin resistance, or insulin concentration, and HDL cholesterol. These results: 1) demonstrate that PAI-1 concentrations are higher in healthy, insulin-resistant women as compared with insulin-sensitive individuals, independent of differences in BMI or ratio of waist-to-hip girth; and 2) provide another mechanism by which insulin-resistant individuals are at increased thrombotic cardiovascular risk.

    View details for Web of Science ID 000083725700035

    View details for PubMedID 10559032

  • PPAR gamma agonists enhance human vascular endothelial adhesiveness by increasing ICAM-1 expression BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Chen, N. G., Sarabia, S. F., Malloy, P. J., Zhao, X. Y., Feldman, D., Reaven, G. M. 1999; 263 (3): 718-722

    Abstract

    Early atherosclerotic lesions are characterized by increased monocyte adhesion to the overlying endothelium. Oxidized LDL (oxLDL) stimulates the adhesion of human monocytes to endothelial cells, in part, by increasing expression of ICAM-1. However, the cellular role of oxLDL in endothelial adhesiveness is not well understood. The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is expressed in vascular endothelial cells. Whether it can be activated by a synthetic ligand, troglitazone, as well as by natural ligands, oxLDL and its lipid components (i.e., 9- and 13-HODE), has not yet been explored. This study was undertaken to determine whether PPARgamma is expressed in ECV304 human vascular endothelial cells and if so to define the biological effects of its activation by these agonists. Our results demonstrate that PPARgamma mRNA is expressed in ECV304 cells, and transfected cells with a PPARE luciferase construct respond to these agonists. In addition, ligand-dependent PPARgamma activation increased ICAM-1 protein expression and enhanced adherence of monocytes to ECV304 cells by two- to threefold. These findings suggest that the PPARgamma signaling pathway might contribute to the atherogenicity of oxLDL in vascular endothelial cells.

    View details for Web of Science ID 000083018100023

    View details for PubMedID 10512746

  • Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Chen, N. G., Holmes, M., Reaven, G. M. 1999; 84 (10): 3485-3489

    Abstract

    The relationship between insulin resistance, soluble adhesion molecules E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1), and vascular adhesion molecule-1 (sVCAM-1), mononuclear cell binding to cultured endothelium, and lipoprotein concentrations were evaluated in 28 healthy, nondiabetic, and normotensive individuals. The mean (+/-SEM) lipid and lipoprotein concentrations were within the normal rage: cholesterol (199 +/- 18 mg/dL); triglyceride (128 +/- 12 mg/dL); low-density cholesterol (127 +/- 8 mg/dL; and high-density cholesterol (47 +/- 3 mg/dL). The results indicated that degree of insulin resistance was significantly correlated with concentrations of sE-selectin (r = 0.54, P < 0.005), sICAM-1 (r = 0.67, P < 0.001), and sVCAM-1 (r = 0.41, P < 0.05). Furthermore, the relationship between insulin resistance and both sE-selectin and sI-CAM-1 remained statistically significant when adjusted for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Finally, mononuclear cell binding correlated significantly with concentrations of sE-selectin (r = 0.54, P < 0.005) and sICAM-1 (r = 0.47, P < 0.01). These findings raise the possibility that previously described relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and suggests that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules.

    View details for Web of Science ID 000083013300013

    View details for PubMedID 10522984

  • Fatty acid inhibition of glucose-stimulated insulin secretion is enhanced in pancreatic islets from insulin-resistant rats METABOLISM-CLINICAL AND EXPERIMENTAL Chen, N. G., Reaven, G. M. 1999; 48 (10): 1314-1317

    Abstract

    A study was initiated to test two hypotheses. The first was the postulate that glucose-stimulated insulin secretion would be enhanced in pancreatic islets isolated from normal non-obese rats made insulin-resistant by dietary means. The second, related hypothesis was that glucose-stimulated insulin secretion by pancreatic islets isolated from insulin-resistant rats would be more vulnerable to inhibition following culture in the presence of fatty acids. For this purpose, insulin resistance was induced in normal Sprague-Dawley rats by feeding fat-enriched and fructose-enriched diets. The results indicate that islets isolated from either fat-fed or fructose-fed rats secreted significantly more insulin at a glucose concentration of 2.5 to 10.0 mmol/L. In addition, the mean maximal glucose (27 mmol/L)-stimulated insulin secretion rate was significantly lower (15.3 +/- 2.5 ng/islet/h) in islets from fructose-fed rats versus chow-fed rats (25.2 +/- 3.1 ng/islet/h) following culture for 48 hours in the presence of palmitate (0.125 micromol/L). These results support the view that glucose-stimulated insulin secretion is enhanced in islets from insulin-resistant rats, and that these islets are more vulnerable to the inhibitory effects of free fatty acid (FFA) on insulin secretion.

    View details for Web of Science ID 000083117800018

    View details for PubMedID 10535396

  • Plasma homocysteine concentrations in healthy volunteers are not related to differences in insulin-mediated glucose disposal ATHEROSCLEROSIS Abbasi, F., Facchini, F., Humphreys, M. H., Reaven, G. R. 1999; 146 (1): 175-178

    Abstract

    This study was initiated to test the hypothesis that plasma homocysteine concentrations are increased in insulin resistant individuals. For this purpose, the relationship between insulin resistance, as assessed by the steady-state plasma glucose (SSPG) concentration during the insulin suppression test, and fasting plasma homocysteine concentration was defined in 55 healthy volunteers. The results indicated that homocysteine concentrations did not vary as a function of SSPG concentrations (r = 0.02, P = 0.88). Furthermore, mean (+/- S.E.M.) plasma homocysteine concentrations were similar (8.2+/-0.4 vs. 8.7+/-0.7 micromol/l) in individuals classified as being either insulin sensitive (SSPG <100 mg/dl) or insulin resistant (SSPG >180 mg/dl). On the other hand, SSPG concentration was significantly correlated with fasting plasma insulin (r = 0.58, P<0.001), triglycerides (r = 0.34, P<0.05), and HDL-cholesterol (r = -0.36, P = 0.04) concentrations. These data strongly suggest that the increased risk of atherosclerosis associated with increased plasma homocysteine concentrations is unrelated to insulin resistance and/or the metabolic abnormalities associated with it.

    View details for Web of Science ID 000082257900022

    View details for PubMedID 10487501

  • Enhanced monocyte adherence to thoracic aortae from rats with two forms of experimental hypertension AMERICAN JOURNAL OF HYPERTENSION Asagami, T., Reaven, G. M., Tsao, P. S. 1999; 12 (9): 890-893

    Abstract

    To extend our previous observation that thoracic aortae from rats with spontaneous hypertension (SHR) bind monocytoid cells with enhanced avidity, we isolated thoracic aortae from two different forms of rodent hypertension: Dahl salt-sensitive (Dahl-S) rats fed a high salt diet and Sprague-Dawley (S-D) rats fed a fructose-enriched diet. Blood pressure was determined 14 days after feeding normal chow or chow containing 8% NaCl to Dahl-S and Dahl salt-resistant (Dahl-R) rats, and either chow or a fructose-enriched diet to S-D and Fischer 344 (F-344) rats. Blood pressure was similar in Dahl-S and Dahl-R rats on the chow diet, but higher in Dahl-S rats in response to the 8% NaCl diet (188 +/- 7 v 137 +/- 3 mm Hg, P < .001). Blood pressure also increased when S-D rats consumed fructose as compared with chow (149 +/- 4 v 128 +/-2, P < .05), whereas blood pressure did not change with diet in F-344. Thoracic aortae were removed from rats in each experimental group, and their ability to bind murine monocytoid cells quantified. Measurements of monocyte binding were performed on one experimental and one control rat simultaneously, and results presented as the ratio of cells bound by thoracic aortae from the experimental compared with the control rat. With this approach, the ratio of monocyte binding (8% NaCl/chow) was increased in Dahl-S versus Dahl-R rats (1.7 +/- 0.1 v 1.3 +/- 0.1, P < .05), as well as in S-D as compared with F-344 rats (1.7 +/- 0.2 v 1.1 +/-0.1, P < .05). These results provide evidence that hypertension in Dahl-S and fructose-fed S-D rats was associated with changes in the endothelium that favor atherogenesis.

    View details for Web of Science ID 000082738300006

    View details for PubMedID 10509546

  • Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and insulin resistance in healthy nondiabetic volunteers CIRCULATION Chen, N. G., Abbasi, F., Lamendola, C., McLaughlin, T., Cooke, J. P., Tsao, P. S., Reaven, G. M. 1999; 100 (9): 940-943

    Abstract

    This study was initiated to compare the adherence to cultured endothelial cells of mononuclear cells isolated from normotensive and hypertensive individuals.Mononuclear cell binding to endothelium was greater in patients with hypertension (32+/-1 versus 25+/-2; P<0.001) than in normal volunteers. There was a significant relationship (r=0.42, P<0. 01) between mononuclear cell binding and mean arterial pressure, independent of differences in age, sex, and body mass index. A significant relationship also existed between insulin resistance (estimated by the steady-state plasma glucose concentration during the insulin suppression test) and mononuclear cell binding in both the normotensive (r=0.86, P<0.001) and hypertensive (r=0.74, P<0. 001) groups. Furthermore, multiple regression analysis demonstrated an independent relationship (P<0.001) between mononuclear cell binding and both steady-state plasma glucose and hypertensive status.These results indicate that both hypertension and insulin resistance lead to changes in mononuclear cells that increase their adherence to cultured endothelial cells.

    View details for Web of Science ID 000082353000009

    View details for PubMedID 10468524

  • Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The barilla factory revisited METABOLISM-CLINICAL AND EXPERIMENTAL Zavaroni, I., Bonini, L., Gasparini, P., Barilli, A. L., Zuccarelli, A., Dall'Aglio, E., Delsignore, R., Reaven, G. M. 1999; 48 (8): 989-994

    Abstract

    The study was initiated to evaluate the ability of hyperinsulinemia (as a surrogate measure of insulin resistance) to predict the development in a previously healthy population of three putative outcomes of this abnormality--glucose intolerance, hypertension, and coronary heart disease (CHD). The study involved defining the incidence at which these changes occurred between 1981 and 1993 to 1996 in 647 individuals who were free of any disease when initially studied. The study population consisted of approximately 90% of the subjects evaluated in 1981, divided into quartiles on the basis of the plasma insulin response to a glucose challenge as determined in 1981. The results indicated that the 25% of the population with the highest insulin response in 1981 had significant (P < .001) increases in the incidence of impaired glucose tolerance (IGT) or type 2 diabetes (eightfold), hypertension (twofold), or CHD (threefold). Furthermore, the ability of hyperinsulinemia to predict the three clinical endpoints was independent of differences in age, gender, or body mass index (BMI). Finally, if CHD is considered the clinical endpoint, multiple logistic regression analysis indicates that the values for plasma triglyceride (TG) and mean arterial blood pressure ([MAP] as measured in 1981) also predict the development of CHD. These results indicate that the untoward clinical effects of insulin resistance and/or compensatory hyperinsulinemia, glucose intolerance, hypertension, and CHD clearly can develop in less than 15 years.

    View details for Web of Science ID 000081925500011

    View details for PubMedID 10459563

  • Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance DIABETIC MEDICINE Morel, Y., Golay, A., Perneger, T., Lehmann, T., Vadas, L., Pasik, C., Reaven, G. M. 1999; 16 (8): 650-655

    Abstract

    This study was initiated to test the hypothesis that metformin treatment leads to enhanced glucose disposal at ambient insulin concentrations.Nineteen obese patients with impaired glucose tolerance (IGT) were treated with either metformin or placebo in a randomized, double-blind, placebo-controlled, cross-over study. Insulin secretion and insulin resistance were quantified using the homeostasis model assessment (HOMA) and insulin-stimulated glucose disposal were measured by determining the steady-state plasma glucose (SSPG).The average benefit of metformin was 0.6 mmol/l for glucose (95% confidence interval (CI) 0.2-0.9 P = 0.002), 2.8 pmol/l for insulin (95% CI 0.2-5.4, P = 0.019). Insulin resistance, as quantified by HOMA, was improved by 1.1 (95% CI 0.2-2.0, P = 0.004), without any change in insulin secretion. Basal and insulin-stimulated glucose oxidation were comparable in the placebo and metformin-treated groups at the end of each treatment period, as was the SSPG concentration. However, both systolic and diastolic blood pressures fell significantly following metformin administration as compared to treatment with placebo.These results indicate that metformin administration to patients with IGT is associated with enhanced glucose disposal at baseline insulin concentrations and a fall in blood pressure. In contrast, neither glucose oxidation nor glucose disposal were increased in association with metformin treatment under conditions of physiological hyperinsulinaemia.

    View details for Web of Science ID 000082298600006

    View details for PubMedID 10477209

  • Masoprocol lowers blood pressure in rats with fructose-induced hypertension AMERICAN JOURNAL OF HYPERTENSION Gowri, M. S., Reaven, G. M., Azhar, S. 1999; 12 (7): 744-746

    Abstract

    Rats with fructose-induced hypertension were treated by oral gavage with either masoprocol (nordihydroguaiaretic acid) or vehicle. Masoprocol treatment resulted in significantly (P < .05 to .001) lower values for systolic blood pressure (120 +/- 3 v 164 +/- 5 mm Hg), as well as plasma insulin (30 +/- 5 v 44 +/- 4 microU/mL), free fatty acid (551 +/- 20 v 692 +/- 22 microEq/L), and triglyceride (79 +/- 5 v 219 +/- 32 mg/dL) concentrations. These results indicate that masoprocol, a lipoxygenase inhibitor, is able to lower blood pressure, as well as improve the metabolic abnormalities present in a rodent model of hypertension that simulates the characteristic of many patients with essential hypertension.

    View details for Web of Science ID 000080947200012

    View details for PubMedID 10411373

  • Measurements of insulin-mediated glucose disposal are stable over time JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Facchini, F., Humphreys, M. H., Jeppesen, J., Reaven, G. M. 1999; 84 (5): 1567-1569

    Abstract

    To evaluate the stability of insulin-mediated glucose disposal, over time, we measured the steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations in response to a continuous infusion of SRIF (5 microg/min), insulin (25 microU/m2 x min), and dextrose (240 microg/m2 x min). These measurements were made in 15 healthy volunteers, studied before and after a mean (+/-SEM) interval of 48 +/- 2 months. The mean (+/-SEM) weight of the volunteers did not increase with time (75.4 +/- 3.1 vs. 76.6 +/- 3.2 kg), and there was no significant variation between the 2 mean (+/-SEM) values of either SSPI (324 +/- 18 vs. 372 +/- 24 pmol/L) or SSPG (8.4 +/- 1.0 vs. 8.2 +/- 1.0 mmol/L). Given the similarity of both SSPI and SSPG concentrations at baseline and follow-up, it can be concluded that insulin-mediated glucose disposal was stable in these 15 individuals over an interval of approximately 4 yr.

    View details for Web of Science ID 000080141600015

    View details for PubMedID 10323381

  • Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion HYPERTENSION Facchini, F. S., DoNascimento, C., Reaven, G. M., Yip, J. W., Ni, X. P., Humphreys, M. H. 1999; 33 (4): 1008-1012

    Abstract

    The objective of this study was to investigate the relationships among various humoral factors thought to be involved in the regulation of blood pressure during high NaCl intake. Nineteen healthy subjects underwent sequential 5-day periods ingesting a low-sodium (25 mmol/d) or high-sodium (200 mmol/d) diet. Insulin resistance was assessed by the steady-state plasma glucose concentration at the end of a 3-hour insulin suppression test. Insulin resistance correlated inversely with natriuresis (P=0.04) and directly with increase in weight (P=0.03). The increase in mean arterial pressure associated with the high-sodium diet correlated directly with the gain in weight (P<0.05) and inversely with the increase in urinary nitrate excretion (P<0.0001). In a multiple regression model, more than 2/3 of the variance in mean arterial pressure was accounted for by the gain in weight and change in urinary nitrate excretion. The steady-state plasma glucose concentrations obtained with the 2 diets were similar, indicating that insulin resistance was unaffected by sodium intake. During high sodium intake, plasma renin activity and aldosterone decreased and plasma atrial natriuretic peptide increased; these changes did not correlate with the change in mean arterial pressure, insulin resistance, or change in urinary nitrate excretion. To the extent that urinary nitrate excretion reflects activity of the endogenous nitric oxide system, these results suggest that the salt sensitivity of mean arterial pressure may be related to blunted generation of endogenous nitric oxide. The results also demonstrate that insulin-resistant individuals have an impaired natriuretic response to high sodium intake.

    View details for Web of Science ID 000079843100017

    View details for PubMedID 10205239

  • Intensive blood pressure glucose control in type 2 diabetes: Why is it so difficult to decrease coronary heart disease? JOURNAL OF HUMAN HYPERTENSION Reaven, G. M. 1999; 13: S19-S23

    View details for Web of Science ID 000080404400004

    View details for PubMedID 10335853

  • Effect of masoprocol on glucose transport and lipolysis by isolated rat adipocytes METABOLISM-CLINICAL AND EXPERIMENTAL Gowri, M. S., Reaven, G. M., Azhar, S. 1999; 48 (4): 411-414

    Abstract

    Masoprocol (nordihydroguaiaretic acid) is a lipoxygenase inhibitor isolated from the creosote bush and used by native healers to treat type 2 diabetes. It has been recently shown to decrease serum glucose, free fatty acid (FFA), and triglyceride (TG) concentrations in rodent models of type 2 diabetes. The current study was initiated to quantify the effects of masoprocol incubation of adipocytes isolated from normal rats. The results indicate that masoprocol significantly increased glucose uptake by adipocytes in both the absence and presence of insulin. In addition, the maximal rate of insulin-stimulated glucose transport was increased in adipocytes incubated with masoprocol and the insulin concentration resulting in a half-maximal glucose transport rate (ED50) decreased. Finally, isoproterenol-stimulated increases in FFA and glycerol release were significantly decreased in the presence of masoprocol. These results provide an explanation at the cellular level for the observation that masoprocol decreases serum glucose, insulin, and FFA concentrations in rodent models of type 2 diabetes.

    View details for Web of Science ID 000079809300001

    View details for PubMedID 10206430

  • Can changes in plasma insulin concentration explain the variability in leptin response to weight loss in obese women with normal glucose tolerance? JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Carantoni, M., Abbasi, F., Azhar, S., Schaaf, P., Reaven, G. M. 1999; 84 (3): 869-872

    Abstract

    The aim of this study was to test the hypothesis that the fall in circulating insulin concentration associated with moderate weight loss determines the associated decrease in plasma leptin concentration. For this purpose, 12 healthy, nondiabetic, obese women were studied before and after an average weight loss of 9.5 kg (11.2% of initial body weight). Plasma leptin concentrations fell from a mean (+/-SE) value of 35 +/- 3 to 17 +/- 2 ng/mL (P < 0.001) in association with the loss of weight. However, there was no correlation between the decline in leptin concentration and the associated fall in weight, body mass index, fat mass, or percent body fat. Furthermore, no correlation was seen among changes in fasting plasma glucose or insulin concentrations, the 8-h integrated plasma glucose response to breakfast and lunch, or the estimate of insulin-mediated glucose disposal. The only measured variable that correlated with the fall in plasma leptin concentration (r = 0.78; P < 0.005) was the decline in the 8-h integrated plasma insulin response after weight loss (from 304 +/- 44 to 232 +/- 36 microU/8 h x mL; P < 0.001). Finally, multivariate regression analysis, using various estimates of degree of obesity, insulin resistance, integrated glucose response, and integrated insulin response as dependent variables, indicated that only the insulin response was independently related to the decrease in leptin concentration (P = 0.035). The fall in integrated insulin response accounted for 66% of the variance in leptin concentrations after weight loss, and this was true no matter what the estimate of change in degree of obesity. In addition to offering an explanation for the variance in postweight loss leptin concentrations, these data provide further evidence of the importance of ambient insulin concentrations in the regulation of plasma leptin concentrations.

    View details for Web of Science ID 000079147100008

    View details for PubMedID 10084563

  • Insulin resistance, the key to survival: a rose by any other name DIABETOLOGIA Reaven, G. M. 1999; 42 (3): 384-385

    View details for Web of Science ID 000078998000021

    View details for PubMedID 10096797

  • Novel terpenoid-type quinones isolated from Pycnanthus angolensis of potential utility in the treatment of type 2 diabetes JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Luo, J. A., Cheung, J., Yevich, E. M., Clark, J. P., Tsai, J., Lapresca, P., Ubillas, R. P., Fort, D. M., Carlson, T. J., Hector, R. F., King, S. R., Mendez, C. D., Jolad, S. D., Reaven, G. M. 1999; 288 (2): 529-534

    Abstract

    Using an ethnomedical-based drug discovery program, two previously unknown compounds (SP-18904 and SP-18905) from Pycnanthus angolensis were isolated that lower glucose concentrations in mouse models of type 2 diabetes. SP-18904 and SP-18905 are terpenoid-type quinones that significantly lowered plasma glucose concentration (p <.05) when given orally to either ob/ob or db/db mice, both of which are hyperglycemic and hyperinsulinemic. The antihyperglycemic actions of SP-18904 and SP-18905 were associated with significant decreases in plasma insulin concentrations (p <.05), suggesting that both compounds lowered glucose by enhancing insulin-mediated glucose uptake. This was supported by the insulin suppression test in ob/ob mice. Studies in hyperglycemic, insulin-deficient mice and in vitro experiments on 3T3-L1 adipocytes further supported this conclusion. As such, these two terpenoid-type quinones represent a new class of compounds of potential use in the treatment of type 2 diabetes.

    View details for Web of Science ID 000078286700019

    View details for PubMedID 9918555

  • Differences in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Abbasi, F., Carantoni, M., Schaaf, P., Reaven, G. 1999; 84 (2): 578-581

    Abstract

    The current study was initiated to determine whether insulin resistance and/or hyperinsulinemia affected the ability of obese individuals to lose weight in response to hypocaloric diets. Thirty-one obese, nondiabetic women, with values for body mass index ranging from 28.0-35.0 kg/m2, volunteered for this program. Resistance to insulin-mediated glucose disposal was assessed by determining their steady state plasma insulin and glucose concentration during the last 30 min of a 180-min infusion of somatostatin, insulin, and glucose. The total integrated insulin response to breakfast and lunch was also determined. After the baseline measurements, volunteers were placed on a hypocaloric diet calculated to lead to a minimum weekly loss of 1% of ideal body weight. Individuals who met the criteria after 30 days of dieting were defined as weight loss successes (n = 20) and continued on the diet for another 30 days. Individuals not meeting the criteria were designated as weight loss failures (n = 12) and were discharged from the study. There was a mean (+/-SEM) weight loss at 60 days of 9.2 +/- 0.4 kg in the 20 individuals defined as weight loss successes, but there was no correlation between weight loss and either steady state plasma glucose or the total integrated insulin response (r < 0.1; P > 0.83). Furthermore, using the same criteria to define insulin sensitivity and insulin resistance as those for therapeutic successes, the therapeutic failures comprised six insulin-sensitive and five insulin-resistant subjects. In summary, insulin-mediated glucose disposal varied widely in nondiabetic, obese women, and there was no relationship between baseline insulin resistance or total integrated insulin response and weight loss. It is concluded that the ability to lose weight on a calorie-restricted diet over a short time period does not vary in obese, healthy women as a function of insulin resistance or hyperinsulinemia.

    View details for Web of Science ID 000078464000031

    View details for PubMedID 10022419

  • Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes DIABETOLOGIA Reed, M. J., Meszaros, K., Entes, L. J., Claypool, M. D., Pinkett, J. G., Brignetti, D., Luo, J., Khandwala, A., Reaven, G. M. 1999; 42 (1): 102-106

    Abstract

    Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20% fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16-33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35% compared with vehicle (14.2+/-1.1 vs 21.7+/-1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8+/-0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80% compared with vehicle (1.0+/-0.1 vs 4.8+/-0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6+/-0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65% by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol kg x min(-1)) and insulin (30 pmol x kg x min(-1)) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30% in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 micromol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p <0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis.

    View details for Web of Science ID 000078261300018

    View details for PubMedID 10027587

  • Insulin resistance: A chicken that has come to roost Reaven, G. M. NEW YORK ACAD SCIENCES. 1999: 45-57

    Abstract

    Insulin-mediated glucose disposal varies approximately 10-fold in apparently healthy human beings. Insulin (I)-resistant individuals can remain glucose tolerant if the pancreas compensates for this defect by secreting large amounts of I. Type 2 diabetes develops when I-resistant persons cannot sustain this state of compensatory hyperinsulinemia (increases I). However, the ability of increases I to prevent decompensation of glucose tolerance is a mixed blessing, and the combination of I resistance and increases I predisposes such individuals to develop a series of abnormalities that increase risk of coronary heart disease (CHD). Given the health-related consequences of I resistance and increases I, it has been suggested that a "thrifty" genotype exists that favored evolutionary survival by enhancing I secretion and thereby promoting energy accumulation. An alternative view is that conservation of muscle mass was necessary for survival, and that muscle I resistance was the "thrifty" genotype. This latter hypothesis is more consistent with current data, and there is evidence of a genetic basis for I resistance. In either case, there is little question as to the importance of I resistance and related abnormalities in diseases of Western civilization. However, the strength of the association between I resistance and its consequences varies in magnitude, and it is necessary to emphasize that development of a clinical end-point will vary as a function of (1) degree of I resistance; (2) "closeness" of I resistance to the end-point; and (3) the ability to compensate for the effects of I resistance. I resistance is a physiological characteristic, genetically determined, that helped primitive humans to survive. It is greatly aggravated by obesity and physical inactivity, and represents a modern scourge.

    View details for Web of Science ID 000084392400004

    View details for PubMedID 10842651

  • Insulin resistance may or may not play a role in blood pressure regulation JOURNAL OF INTERNAL MEDICINE Reaven, G. M. 1998; 244 (4): 359-360

    View details for Web of Science ID 000076535900016

    View details for PubMedID 9817631

  • Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration? JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Zavaroni, I., Zuccarelli, A., Gasparini, P., Massironi, P., Barilli, A., Reaven, G. M. 1998; 83 (10): 3498-3500

    Abstract

    In this study, we have evaluated the effect, over approximately 14 yr, of differences in baseline degree of hyperinsulinemia on weight gain in 647 healthy, nonobese factory workers. The subjects were divided into 4 quartiles, on the basis of their plasma insulin response to an oral glucose challenge, in 1981. At that time, the mean (+/-SD) plasma insulin concentration, 2 h after the glucose challenge, varied from 18+/-5 to 106+/-42 microU/mL. Despite this approximate 6-fold difference in plasma insulin response at baseline, the weight gain over the period of observation was similar in all quartiles, with mean (+/-SD) increments (kg) of 1.8+/-5.1, 1.6+/-5.3, 2.3+/-5.2, and 2.3+/-5.7, going from the lowest quartile to the highest quartile, in terms of insulin concentration. Furthermore, when the population was considered as a whole, there was no correlation between baseline degree of hyperinsulinemia and change in either absolute (r = 0.004) or percent (r = 0.003) weight gain. Finally, there was no difference in the number of individuals who gained more than 4.5 kg, as a function of their baseline insulin response. Consequently, we conclude that 6-fold differences in plasma insulin responses to glucose do not predict weight gain in a healthy, nonobese population.

    View details for Web of Science ID 000076275500019

    View details for PubMedID 9768653

  • Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin DIABETES CARE Abbasi, F., Carantoni, M., CHEN, Y. D., Reaven, G. M. 1998; 21 (8): 1301-1305

    Abstract

    To evaluate further the relative roles played by liver and adipose tissue in the therapeutic response to metformin in patients with type 2 diabetes.A total of 11 patients with diet-treated type 2 diabetes were given metformin for approximately 3 months. Measurements were made before and after treatment of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance (Ra) and disappearance (Rd) rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 195-min infusion period at relatively low insulin (approximately 12-24 microU/ml) concentrations.Mean +/- SEM fasting plasma glucose concentration was significantly lower (175 +/- 11 vs. 224 +/- 15 mg/dl; P < 0.01) after treatment with metformin. Mean +/- SEM insulin concentrations measured from 8:00 A.M. to 5:00 P.M. did not change with treatment. However, both glucose and FFA concentrations were significantly lower (P < 0.01) when measured over the same time period, and the decreases in plasma FFA and glucose concentration were highly correlated (r = 0.81; P = 0.03). Overnight glucose turnover studies indicated that neither Ra (hepatic glucose production [HGP]) nor Rd changed significantly with treatment in association with metformin treatment. Since plasma glucose concentration was much lower after metformin treatment, the overnight glucose metabolic clearance rate (MCR) was significantly lower (P < 0.01). Finally, the ability of insulin to inhibit isoproterenol-stimulated increases in plasma FFA concentration was enhanced in metformin-treated patients (P < 0.05).Metformin treatment was associated with significantly lower fasting plasma glucose concentrations and lower day-long plasma glucose and FFA concentrations. Although overnight HGP was unchanged after treatment with metformin, the overnight glucose MCR was significantly increased, and the antilipolytic activity of insulin was also enhanced. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to a decrease in release of FFA from adipose tissue, leading to lower circulating FFA concentrations and an increase in glucose uptake.

    View details for Web of Science ID 000075177900017

    View details for PubMedID 9702437

  • Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Yip, J., Facchini, F. S., Reaven, G. M. 1998; 83 (8): 2773-2776

    Abstract

    Resistance to insulin-mediated glucose disposal has been postulated to predispose individuals to a cluster of associated abnormalities (Syndrome X) known to increase risk of cardiovascular disease (CVD). Although several abnormalities subsumed under the rubric of Syndrome X have been shown to predict CVD, there has been no prospective study evaluating the power of insulin resistance, the putative fundamental defect in the syndrome, in this context. Therefore, this study was initiated to evaluate the hypothesis that resistance to insulin-mediated glucose disposal would predict the development of CVD in healthy volunteers. To accomplish this goal, 147 normal, healthy, nonobese, volunteers were evaluated [4.7 +/- 0.1 yr (mean +/- SEM)] after baseline measurements of steady state plasma glucose concentration (an estimate of insulin-mediated glucose disposal), as well as other CVD risk factors. Clinical end points developed in 13 subjects during the follow-up period; hypertension in 5, coronary artery disease in 4, cerebrovascular accident in 3, and peripheral vascular disease in 1. There was a significant univariate relationship between SSPG and CVD (P < 0.002), with the majority of the events taking place in the tertile of subjects with the highest SSPG concentration, i.e. the greatest degree of insulin resistance. In contrast, no CVD events were observed in the tertile with the lowest SSPG concentrations; the most insulin sensitive. SSPG was also related significantly to diastolic blood pressure, triglyceride, and low-density lipoprotein and high-density lipoprotein cholesterol concentrations, and the glucose and insulin responses to oral glucose. All of these relationships were independent of age, gender, body mass index, estimates of physical activity, and smoking history. When SSPG was paired with each of the other variables in a series of multiple regression models, only SSPG, or insulin response, were independent predictors of CVD events. In conclusion, approximately one of every five healthy, nonobese subjects in the most insulin-resistant tertile, followed for approximately 5 yr, had a serious clinical event. These data highlight the importance of insulin resistance as a predictor of CVD.

    View details for Web of Science ID 000075265300026

    View details for PubMedID 9709945

  • Antihyperglycemic activities of cryptolepine analogues: An ethnobotanical lead structure isolated from Cryptolepis sanguinolenta JOURNAL OF MEDICINAL CHEMISTRY Bierer, D. E., Dubenko, L. G., Zhang, P. S., Lu, Q., Imbach, P. A., Garofalo, A. W., Phuan, P. W., Fort, D. M., Litvak, J., Gerber, R. E., Sloan, B., Luo, J., Cooper, R., Reaven, G. M. 1998; 41 (15): 2754-2764

    Abstract

    Cryptolepine (1) is a rare example of a natural product whose synthesis was reported prior to its isolation from nature. In the previous paper we reported the discovery of cryptolepine's antihyperglycemic properties. As part of a medicinal chemistry program designed to optimize natural product lead structures originating from our ethnobotanical and ethnomedical field research, a series of substituted and heterosubstituted cryptolepine analogues was synthesized. Antihyperglycemic activity was measured in vitro and in an NIDDM mouse model to generate the first structure-bioactivity study about the cryptolepine nucleus.

    View details for Web of Science ID 000074878000013

    View details for PubMedID 9667966

  • Hematocrit and hemoglobin are independently related to insulin resistance and compensatory hyperinsulinemia in healthy, non-obese men and women METABOLISM-CLINICAL AND EXPERIMENTAL Facchini, F. S., Carantoni, M., Jeppesen, J., Reaven, G. M. 1998; 47 (7): 831-835

    Abstract

    In this study, we evaluated the relationship between resistance to insulin-mediated glucose disposal and hematocrit (Hct) and hemoglobin (Hgb) concentrations in 150 normal, healthy volunteers: 100 men and 50 women. Insulin resistance was defined as the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Since the steady-state plasma insulin (SSPI) concentrations are similar in all individuals, the SSPG concentrations provide a direct measure of insulin resistance: the higher the SSPG, the more insulin-resistant the subject. The results indicated that SSPG was significantly (P < .001) related to Hct and Hgb in both men and women, with correlation coefficients (r) ranging from 0.38 to 0.43. A series of other variables were also related to Hct and Hgb, including blood pressure, plasma glucose and insulin responses to oral glucose, and plasma triglyceride and high-density lipoprotein (HDL) concentrations. When multiple regression analysis was used to evaluate these relationships, the only variables that were consistently found to be associated with Hct and Hgb were insulin resistance and plasma insulin response to oral glucose. Thus, these results suggest that Hct and Hgb concentrations be added to the cluster of variables related to insulin resistance and compensatory hyperinsulinemia.

    View details for Web of Science ID 000074627200012

    View details for PubMedID 9667230

  • Diabetes and dyslipidemia - A new model for transplant coronary artery disease CIRCULATION Hoang, K., Chen, I., Reaven, G., Zhang, L. N., Ross, H., Billingham, M., Valantine, H. 1998; 97 (21): 2160-2168

    Abstract

    Clinical observations suggest that transplant coronary artery disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic heart transplantation in the presence of diabetes and dyslipidemia to further study their role in TxCAD development.Major histocompatibility complex-mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts). Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transplantation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (+F). Allograft transplants were divided into four groups: (1) +DM/+F; (2) +DM/-F; (3) -DM/+F; and (4) -DM/-F. Isograft transplants (Lewis to Lewis, +DM/+/-F) were controls. All animals received daily cyclosporine (5 mg/kg). Grafts surviving > 30 days were evaluated for TxCAD on histological sections and graded 0 to 5 for intimal thickness. All streptozotocin-treated animals were diabetic within 2 weeks, with fourfold increases in plasma glucose concentrations versus nondiabetics. Severe TxCAD was observed in diabetic allografts only. The mean grade of TxCAD in diabetic allografts was 3.2 +/- 0.5 versus 1.1 +/- 0.4 in diabetic isografts (P < 0.03) and zero TxCAD in nondiabetic allografts (P < or = 0.0001). Fructose feeding resulted in a 1.5-fold higher triglyceride and a 1.3-fold higher cholesterol level versus the regular diet (-F) but showed no independent contribution to the development of TxCAD.These findings suggest that metabolic derangements associated with diabetes play an important role in TxCAD development in heterotopic ACI-to-Lewis rat heart transplantation. In this model of TxCAD in major histocompatibility complex-mismatched, diabetic, and dyslipidemic rats, immunologic and metabolic mechanisms that contribute to TxCAD can be further delineated and approaches to its prevention assessed.

    View details for Web of Science ID 000073959900012

    View details for PubMedID 9626177

  • Interaction of diabetes and hypertension on determinants of endothelial adhesiveness ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Tsao, P. S., Niebauer, J., Buitrago, R., Lin, P. S., Wang, B. Y., Cooke, J. P., CHEN, Y. D., Reaven, G. M. 1998; 18 (6): 947-953

    Abstract

    Epidemiological studies have established that diabetes mellitus and hypertension are independent risk factors for atherosclerosis. One of the earliest abnormalities seen in atherogenesis is enhanced monocyte adherence to the endothelium. The mechanisms by which diabetes mellitus or hypertension enhances monocyte-endothelial cell interactions are incompletely characterized. It is not known whether there are additive interactions between these risk factors on endothelial adhesiveness for monocytes. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were fed a normal or fructose-enriched diet. In some cases, animals were injected with streptozotocin (35 mg/kg body weight) to induce diabetes. After 2 weeks, plasma was drawn for biochemical measurements, and thoracic aortas were harvested, opened longitudinally, and exposed to fluorescently labeled mouse monocytoid cells (WEHI 78/24, 2 x 10(6)/mL) for 30 minutes on a rocking platform. Adherent cells were counted by epifluorescence microscopy. WEHI 78/24 binding to aortic segments from SHR animals was elevated compared with segments from WKYs. Fructose feeding alone had no effect on endothelial adhesiveness. When WKYs were made hyperglycemic by STZ injection, monocyte binding was 160% of the control value. Elevated monocyte binding was also observed in aortas derived from SHR animals injected with STZ, indicating an additive effect of hypertension and hyperglycemia. To determine whether alterations in oxidative state played a role in the endothelial adhesiveness, aortic segments were exposed to lucigenin (250 micromol/L) for measurement of superoxide anion. Aortic segments from SHR elaborated 120% more superoxide anion than did controls. Elevated free-radical production was also observed in aortas from diabetic WKYs. Furthermore, thoracic aortas derived from diabetic SHR animals elaborated more superoxide anion than did any of the other groups (374%, P<0.05). Immunohistochemical staining for monocyte chemotactic protein-1 demonstrated increased expression in aortas isolated from diabetic WKY and SHR compared with control vessels. These studies demonstrate that both diabetes and hypertension lead to increased monocyte adherence to the endothelium. This abnormality is associated with increased vascular superoxide production and monocyte chemotactic protein-1 expression. Furthermore, there appears to be an additive interaction between hyperglycemia and hypertension in their effects on endothelial adhesiveness and its determinants.

    View details for Web of Science ID 000074175500014

    View details for PubMedID 9633936

  • Nongenetic mouse models of non-insulin-dependent diabetes mellitus METABOLISM-CLINICAL AND EXPERIMENTAL Luo, J., Quan, J., Tsai, J., Hobensack, C. K., Sullivan, C., Hector, R., Reaven, G. M. 1998; 47 (6): 663-668

    Abstract

    The purpose of the study was to develop a mouse model of non-insulin-dependent diabetes mellitus (NIDDM) that closely simulates the metabolic abnormalities of the human disease and is also cost-effective compared with the genetic models currently available. For this purpose, insulin resistance was induced in male C57BL/6J or Institute of Cancer Research (ICR) mice by feeding diets enriched in either fructose or fat, and hyperglycemia was induced by injecting these mice with a dose of streptozotocin (STZ) that does not cause diabetes in chow-fed mice. In the case of C57BL/6J mice, insulin levels initially increased in response to the fructose- and fat-enriched diets and then decreased to levels comparable to or still higher than those in chow-fed mice following STZ injection. Associated with the decrease in insulin levels following STZ, fat-fed and fructose-fed C57BL/6J mice became significantly hyperglycemic, reaching values of 388 +/- 38 and 366 +/- 58 mg/dL, respectively. In contrast, neither plasma glucose nor insulin concentrations changed in chow-fed mice injected with an identical amount of STZ. Essentially identical findings were seen before and after STZ injection in fat-fed compared with chow-fed ICR mice. Although a direct comparison was not made, sensitivity to the diabetogenic effects of STZ appeared to be greater in fat-fed ICR compared with fat-fed C57BL/6J mice. Finally, plasma glucose decreased when mice with these experimental models of NIDDM were treated with either metformin or tolbutamide. Given these results, it seems reasonable to suggest that the combination of dietary-induced insulin resistance and relatively low-dose STZ results in mouse models that should be of use in studying the pathophysiology of NIDDM or in evaluating therapeutic compounds for the treatment of NIDDM.

    View details for Web of Science ID 000074071200007

    View details for PubMedID 9627363

  • Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent DIABETIC MEDICINE Luo, J., Fort, D. M., Carlson, T. J., NOAMESI, B. K., nii-Amon-Kotei, D., King, S. R., Tsai, J., Quan, J., Hobensack, C., Lapresca, P., Waldeck, N., Mendez, C. D., Jolad, S. D., Bierer, D. E., Reaven, G. M. 1998; 15 (5): 367-374

    Abstract

    Evidence has been published that a wide array of plant-derived active principles, representing numerous classes of chemical compounds, demonstrate activity consistent with their possible use in the treatment of patients with Type 2 diabetes mellitus (DM). Despite these interesting observations, to date, metformin is the only ethical drug approved for treatment of Type 2 DM derived from a medicinal plant. Why is this so, given the fact that higher plants are such a potential source of new drugs? The answer to this rhetorical question may lie in the reliance of most pharmaceutical companies on random, in vitro, mechanism-based, high throughput screening in the initial phases of plant drug research. In this article we describe an alternative pathway to discovery of drugs for the treatment of Type 2 DM: on based on an ethnomedical approach, involving ethnobotany and traditional medicine. In particular, we present evidence that cryptolepine, an indoloquinolone alkaloid isolated from Cryptolepis sanguinolenta, significantly lowers glucose when given orally to a mouse model of diabetes. The antihyperglycaemic effect of cryptolepine leads to a significant decline in plasma insulin concentration, associated with evidence of an enhancement in insulin-mediated glucose disposal. Finally, cryptolepine increases glucose uptake by 3T3-L1 cells. These data permit us to conclude that an ethnobotanical approach to drug discovery can identify a potentially useful drug for the treatment of Type 2 DM.

    View details for Web of Science ID 000073549200003

    View details for PubMedID 9609357

  • Relationship between insulin resistance and partially oxidized LDL particles in healthy, nondiabetic volunteers ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Carantoni, M., Abbasi, F., Warmerdam, F., Klebanov, M., Wang, P. W., CHEN, Y. D., Azhar, S., Reaven, G. M. 1998; 18 (5): 762-767

    Abstract

    This study was performed in 36 healthy volunteers to define the relationship between plasma concentrations of partially oxidized low density lipoprotein (poxLDL), plasma glucose and insulin responses to oral glucose, and steady-state plasma glucose (SSPG) concentrations after a 180-minute infusion of somatostatin, insulin, and glucose. The concentration of poxLDL was estimated by determining the amount of conjugated dienes formed during in vitro LDL oxidation in the presence or absence of alanine. Under these conditions, the greater the in vitro antioxidant effect of alanine, the lower the amount of poxLDL that was present in plasma. The results demonstrated that plasma poxLDL concentration was significantly correlated with plasma glucose (r=.53, P<.001) and insulin (r=.43, P<.01) responses, SSPG concentrations (r=.53, P<.001), and plasma triglyceride (r=.42, P<.01) and HDL cholesterol (r=-.50, P<.002) concentrations. Furthermore, these relationships persisted when the data were corrected for differences in age, sex, body mass index, and the ratio of waist to hip girth. Of note, there was no correlation between poxLDL and LDL cholesterol concentration. When SSPG was entered along with age, sex, body mass index, and waist-to-hip ratio in a multiple regression model, SSPG alone was a significant prediction of poxLDL (r-=.37, P<.02). The addition of plasma glucose and insulin responses and triglyceride and HDL cholesterol concentrations increased the r2 to only .47. These results show that the amount of poxLDL in plasma is significantly correlated with insulin resistance (ie, SSPG) and its metabolic consequences.

    View details for Web of Science ID 000073770100012

    View details for PubMedID 9598835

  • Masoprocol (nordihydroguaiaretic acid): a new antihyperglycemic agent isolated from the creosote bush (Larrea tridentata) EUROPEAN JOURNAL OF PHARMACOLOGY Luo, J., Chuang, T., Cheung, J., Quan, J., Tsai, J., Sullivan, C., Hector, R. F., Reed, M. J., Meszaros, K., King, S. R., Carlson, T. J., Reaven, G. M. 1998; 346 (1): 77-79

    Abstract

    An ethnomedically-driven approach was used to evaluate the ability of a pure compound isolated from the creosote bush (Larrea tridentata) to lower plasma glucose concentration in two mouse models of type 2 diabetes. The results indicated that plasma glucose concentration fell approximately 8 mmol/l in male C57BL/ks-db/db or C57BL/6J-ob/ob mice following the oral administration of masoprocol (nordihydroguaiaretic acid), a well known lipoxygenase inhibitor. The decline in plasma glucose concentration following masoprocol treatment in the mice was achieved without any change in plasma insulin concentration. In addition, oral glucose tolerance improved and the ability of insulin to lower plasma glucose concentrations was accentuated in masoprocol-treated db/db mice. These data raise the possibility that masoprocol, or other lipoxygenase inhibitors, represents a new approach to the pharmacological treatment of Type 2 diabetes.

    View details for Web of Science ID 000073348600010

    View details for PubMedID 9617755

  • Individuals with high total cholesterol HDL cholesterol ratios are insulin resistant JOURNAL OF INTERNAL MEDICINE Jeppesen, J., Facchini, F. S., Reaven, G. M. 1998; 243 (4): 293-298

    Abstract

    To define the pathophysiologic characteristics of patients at high risk for coronary heart disease due to an increased ratio of total cholesterol (TC) to high density lipoprotein-cholesterol (HDL-C).Cross-sectional.Clinical Research Center.One hundred-20 healthy, non-diabetic, normotensive, volunteers were screened for this study. From this pool, 40 individuals (20 females and 20 males) with the highest and the lowest TC/HDL-C ratios were selected for comparison.Values for body mass index (BMI), ratio of waist to hip girth (WHR), and blood pressure were obtained on all patients. In addition, measurements were made of fasting lipid and lipoprotein concentrations, plasma glucose and insulin responses to an oral glucose challenge, and insulin resistance as assessed by the insulin suppression test.Age, BMI, and WHR were the same in the two groups. However, the group with a high TC/HDL-C ratio had higher (P < 0.05) systolic and diastolic blood pressures. In addition, patients with a high TC/HDL-C ratio had significantly higher (P < 0.001) very low density (VLDL) and low density lipoprotein (LDL)-cholesterol concentrations and lower HDL-cholesterol concentrations, with significant (P < 0.001) correlations between the TC/HDL-C ratio and VLDL (r = 0.60), LDL (r = 0.54), and HDL (r = -0.73) cholesterol concentrations. Patients with a high TC/HDL-C ratio were also significantly (P < 0.05-0.001) more insulin resistant, glucose intolerant with a greater plasma insulin response to oral glucose, and hypertriglyceridemic.The results indicate that an increase in LDL-cholesterol concentration is not necessarily the major contributor to a high ratio of TC/HDL-C. Furthermore, individuals with this epidemiologic designation are insulin resistant, and liable to all the other abnormalities associated with this metabolic defect.

    View details for Web of Science ID 000073808300005

    View details for PubMedID 9627143

  • Hypothesis: muscle insulin resistance is the ("not-so") thrifty genotype DIABETOLOGIA Reaven, G. M. 1998; 41 (4): 482-484

    View details for Web of Science ID 000072869800015

    View details for PubMedID 9562354

  • Plasma leptin concentrations do not appear to decrease insulin-mediated glucose disposal or glucose-stimulated insulin secretion in women with normal glucose tolerance DIABETES Carantoni, M., Abbasi, F., Azhar, S., CHEN, Y. D., Klebanov, M., Wang, P. W., Warmerdam, F., Reaven, G. M. 1998; 47 (2): 244-247

    Abstract

    The aim of this study was to test the hypothesis that plasma leptin concentrations contributed to the pathophysiology of NIDDM by decreasing both insulin-mediated glucose disposal and glucose-stimulated insulin secretion. The study was performed in 60 women with normal oral glucose tolerance. Differences in insulin-mediated glucose disposal were determined by comparing the steady-state plasma glucose (SSPG) concentrations attained at the end of a 180-min constant infusion of somatostatin, glucose, and insulin, while comparisons of glucose-stimulated insulin secretion were based on the incremental increase in insulin concentration 30 min after an oral glucose challenge (deltaIns) as compared with the fasting value. The results showed that the higher the fasting plasma leptin concentration, the greater the degree of insulin resistance (r = 0.47, P < 0.01). Furthermore, multiple regression analysis indicated that the relationship between leptin and SSPG was independent of age and degree of obesity as estimated by BMI. However, since the total integrated plasma insulin response was highly correlated with both SSPG (r = 0.80, P < 0.001) and leptin (r = 0.55, P < 0.01), multiple regression analysis was repeated, adding total insulin response to the model. When this was done, the significant relationship between leptin and SSPG disappeared, whereas both BMI (P < 0.03) and insulin response (P < 0.001) were correlated with SSPG. A significant relationship between leptin and deltaIns was seen, but it was a positive one (r = 0.31, P < 0.02), not a negative one as would be expected if circulating levels of leptin inhibited glucose-stimulated insulin secretion. Furthermore, multiple regression analysis could only confirm an independent relationship between deltaIns and SSPG, but not between deltaIns and leptin. The results of these studies do not support the view that circulating leptin has a primary effect on either insulin action or secretion in normal female volunteers. It seems more likely that chronic hyperinsulinemia in insulin-resistant individuals acts to increase adipose tissue leptin synthesis and secretion, leading to higher ambient leptin concentrations.

    View details for Web of Science ID 000071689400014

    View details for PubMedID 9519720

  • Insulin resistance and human disease: a short history. Journal of basic and clinical physiology and pharmacology Reaven, G. M. 1998; 9 (2-4): 387-406

    Abstract

    The notion that tissue resistance to insulin might play an important role in certain disease states is approximately 60 years old. However, recognition of its central role in this regard is a relatively recent phenomenon. In this review an effort has been made to trace a brief history of insulin resistance from its inception to its current position as the fundamental abnormality in both type 2 diabetes and Syndrome X.

    View details for PubMedID 10212844

  • Results of a placebo-controlled study of the metabolic effects of the addition of metaformin to sulfonylurea-treated patients - Evidence for a central role of adipose tissue DIABETES CARE Abbasi, F., Kamath, V., Rizvi, A. A., Carantoni, M., CHEN, Y. D., Reaven, G. M. 1997; 20 (12): 1863-1869

    Abstract

    To define the metabolic effects of metformin in the treatment of NIDDM and to evaluate potential mechanisms for its ability to improve glycemic control.Sulfonylurea-treated patients, with inadequate glycemic control, were treated with metformin in either a placebo-controlled or open fashion. Measurements were made of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance and disappearance rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 45-min infusion period at relatively low (approximately 60 pmol/l) insulin concentrations.Mean +/- SE hourly plasma glucose, insulin, and FFA concentrations were similar before and after treatment in the placebo group. In contrast, mean hourly plasma glucose concentrations were significantly lower (P < 0.005) after metformin treatment in both the placebo-controlled and open-label groups (-3.9 +/- 1.0 and -4.4 +/- 0.8 mmol/l, respectively). Similarly, day-long hourly FFA levels were lower (P < 0.005) following metformin in the placebo-controlled and open-label groups (-87 +/- 35 and -136 +/- 31 mumol/l, respectively). Plasma insulin concentrations did not change with treatment in any group. Overnight glucose turnover studies indicated that neither the rate of glucose appearance (hepatic glucose production) or glucose disappearance changed significantly with treatment in the placebo or metformin groups. Because plasma glucose concentration was much lower after metformin treatment, overnight glucose metabolic clearance rate was significantly (P < 0.001) lower in this group. Finally, plasma FFA concentrations in response to a low-dosage insulin infusion (5 mU.m-2.min-1) were significantly lower after metformin as compared with the placebo-treated group (P < 0.001).Metformin treatment was associated with significantly lower day-long plasma glucose and FFA concentrations. Although overnight hepatic glucose production was unchanged following treatment with metformin, the overnight glucose metabolic clearance rate significantly increased. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to an increase in glucose uptake, secondary to a decrease in release of FFA from adipose tissue, and lower circulating FFA concentrations.

    View details for Web of Science ID A1997YH35900012

    View details for PubMedID 9405908

  • The kidney: An unwilling accomplice in syndrome X Reaven, G. M. W B SAUNDERS CO. 1997: 928-931

    Abstract

    The ability of insulin to stimulate glucose disposal by muscle varies widely within the population at large. Individuals with muscle insulin resistance develop type 2 diabetes if they cannot compensate for this defect by secreting large amounts of insulin. Although this philanthropic effort on the part of the pancreatic B-cell may prevent gross decompensation of glucose homeostasis, it renders such individuals at increased risk to develop a cluster of abnormalities (syndrome X) associated with coronary heart disease. Although the kidney is not considered to be an insulin sensitive tissue, two features of syndrome X, hyperuricemia and hypertension, are likely to be dependent on the retention of normal insulin action on the kidney. More specifically, there is evidence to support the hypothesis that elevated plasma insulin concentrations may enhance renal sodium retention and decrease urinary uric acid clearance. As such, it is possible that a normal kidney response to the compensatory hyperinsulinemia associated with insulin resistance in nondiabetic subjects contributes to the development of hyperuricemia and hypertension in such individuals.

    View details for Web of Science ID A1997YK71400032

    View details for PubMedID 9398143

  • Effects of a quick-release form of bromocriptine (ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women DIABETES CARE Kamath, V., Jones, C. N., Yip, J. C., VARASTEH, B. B., Cincotta, A. H., Reaven, G. M., CHEN, Y. D. 1997; 20 (11): 1697-1701

    Abstract

    To assess the effect on various aspects of carbohydrate and lipid metabolism of administering a quick-release formulation of bromocriptine (Ergoset) to obese, nondiabetic, hyperinsulinemic women.Hourly concentrations of prolactin, glucose, insulin, free fatty acid (FFA), and triglyceride were measured for 24 h before and after approximately 8 weeks of treatment with Ergoset. In addition, fasting lipid and lipoprotein concentrations and the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose were determined before and after Ergoset administration.Circulating prolactin concentrations were dramatically decreased (P < 0.001) following treatment, associated with a significant fall (P < 0.05) in 24-h-long plasma glucose, FFA, and triglyceride concentrations. Neither circulating plasma insulin concentrations nor the ability of insulin to mediate glucose disposal changed with treatment. Finally, fasting total cholesterol fell (P < 0.05) and the ratio of total to HDL cholesterol decreased (P = 0.06) in association with Ergoset treatment.The fact that significant metabolic improvement was seen in the obese nondiabetic hyperinsulinemic women studied suggests that Ergoset could be of therapeutic benefit in clinical conditions of hyperglycemia and/or dyslipidemia.

    View details for Web of Science ID A1997YC34300015

    View details for PubMedID 9353611

  • Evidence that insulin can directly inhibit hepatic glucose production DIABETOLOGIA Maheux, P., CHEN, Y. D., Polonsky, K. S., Reaven, G. M. 1997; 40 (11): 1300-1306

    Abstract

    In order to evaluate the role of portal insulin in the modulation of hepatic glucose production (HGP), measurements of plasma glucose and insulin concentrations and both HGP and peripheral glucose disappearance rates were made following an infusion of a dose of tolbutamide (0.74 mg x m(-2) x min[-1]) in healthy volunteers that does not result in an increase in peripheral vein insulin concentrations or metabolic clearance rate of glucose. The results showed that the infusion of such a dose of tolbutamide was associated with a significant and rapid decline in both HGP (from 9.0 +/- 0.5 to 7.7 +/- 0.5 micromol x kg(-1) x min(-1) or delta = -13.8 +/- 4.5%; p < 0.001 compared to saline) and plasma glucose concentration (from 5.1 +/- 0.2 to 4.4 +/- 0.1 mmol/l or delta = -13.0 +/- 2.1%; p < 0.01 compared to saline). Since neither HGP nor fasting glucose fell when tolbutamide-stimulated insulin secretion was inhibited by the concurrent administration of somatostatin, it indicated that tolbutamide by itself, does not directly inhibit HGP. Finally, HGP fell by 26.3 +/- 6.0% at 10 min after a dose of tolbutamide that elevated both peripheral and portal insulin concentrations, at a time when HGP had barely increased (delta = +6.9 +/- 5.3%). The difference in the magnitude of the two responses was statistically significant (p < 0.03), providing further support for the view that insulin can directly inhibit HGP, independent of any change in flow of substrates from periphery to liver.

    View details for Web of Science ID A1997YF77300009

    View details for PubMedID 9389422

  • Insulin resistance does not change the ratio of proinsulin to insulin in normal volunteers JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Wang, P. W., Abbasi, F., Carantoni, M., CHEN, Y. D., Azhar, S., Reaven, G. M. 1997; 82 (10): 3221-3224

    Abstract

    Plasma glucose, insulin, and proinsulin concentrations were measured before and after an oral glucose challenge in 57 nondiabetic individuals. In addition, insulin-mediated glucose disposal was estimated by determining the steady state plasma glucose (SSPG) concentration after a 180-min iv infusion of somatostatin, insulin, and glucose. The plasma glucose concentration after oral glucose administration was used to divide the population into those with normal (n = 36) or impaired glucose tolerance (IGT; n = 21), and the 36 normal glucose-tolerant individuals were further subdivided into an insulin-sensitive (SSPG, < 9.0 mmol/L; n = 15) and an insulin-resistant (SSPG, > 10 mmol/L; n = 21) group. Fasting and postglucose load insulin concentrations were similar in the normal glucose-tolerant insulin-resistant and IGT groups, but were significantly higher (P < 0.02- < 0.001) than those in normal glucose-tolerant insulin-sensitive individuals. Fasting proinsulin concentrations were also higher (P < 0.002) in the normal glucose-tolerant insulin-resistant (15.1 +/- 1.5 pmol/L) and IGT (15.8 +/- 1.8 pmol/L) groups compared to those in normal glucose-tolerant insulin-sensitive volunteers (9.3 +/- 1.2 pmol/ L). However, the ratio of fasting proinsulin to insulin was identical in all three groups (0.12). When the three groups were combined, significant relationships (P < 0.001) existed between SSPG (degree of insulin resistance) and both fasting proinsulin (r = 0.59) and insulin (r = 0.66) concentrations, but not with the ratio of proinsulin to insulin (r = 0.03). These results demonstrate that fasting proinsulin and insulin concentrations are increased in insulin-resistant, nondiabetic subjects, and the more insulin resistant, the greater the increase. In contrast, the ratio of proinsulin to insulin did not vary as a function of insulin resistance. Thus, neither insulin resistance nor the need to secrete more insulin to maintain glucose tolerance necessarily leads to abnormal insulin processing by the beta-cell.

    View details for Web of Science ID A1997YA00200008

    View details for PubMedID 9329342

  • Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM DIABETES CARE Carantoni, M., Abbasi, F., Chu, L., CHEN, Y. D., Reaven, G. M., Tsao, P. S., Varasteh, B., Cooke, J. P. 1997; 20 (9): 1462-1465

    Abstract

    To compare the binding to cultured endothelial cells of mononuclear cells isolated from healthy volunteers and patients with NIDDM.Mononuclear cells were isolated from healthy volunteers (n = 11) and patients with NIDDM (n = 14) and incubated with ECV 304 cells, a human umbilical endothelial cell-derived transformed cell line. Following a period of incubation, the adherence of mononuclear cells to endothelial cells was determined.Adherence of mononuclear cells from patients with NIDDM was significantly greater (P < 0.05) than that of cells isolated from the healthy volunteers, and this difference persisted when adjusted for age, sex, and degree of obesity. Mononuclear cell binding to ECV 304 cells correlated significantly with fasting plasma glucose (r = 0.52, P < 0.01), insulin (r = 0.51, P < 0.01), triglyceride (r = 0.54, P < 0.01), and VLDL (r = 0.54, P < 0.01) and HDL cholesterol (r = -0.45, P < 0.05) levels, but not with either total or LDL cholesterol levels or blood pressure.Since the adherence of mononuclear cells to the endothelium represents the earliest step in atherogenesis, the observation that mononuclear cells from patients with NIDDM bind more avidly to cultured endothelial cells may help explain why accelerated atherosclerosis occurs in patients with NIDDM. The metabolic abnormality, or abnormalities, present in patients with NIDDM that is responsible for the enhanced adhesiveness of mononuclear cells requires further examination.

    View details for Web of Science ID A1997XT09100023

    View details for PubMedID 9283798

  • Relationship between insulin-mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase DIABETOLOGIA Maheux, P., Azhar, S., Kern, P. A., CHEN, Y. D., Reaven, G. M. 1997; 40 (7): 850-858

    Abstract

    The relationship between insulin-mediated glucose disposal and fasting insulin and triglyceride (TG) concentrations, plasma post-heparin lipoprotein lipase (PH-LPL) activity and mass, and adipose tissue LPL activity, mass, and mRNA content was defined in 19 non-diabetic men. Insulin-mediated glucose uptake [as assessed by determining the steady-state plasma glucose (SSPG) concentration during a continuous infusion of somatostatin, insulin, and glucose] was significantly correlated with fasting TG concentration (r = 0.54, p < 0.02), plasma PH-LPL activity (r = -0.52, p < 0.03) and mass (r = -0.49, p < 0.03), and adipose tissue LPL mRNA content (r = -0.68, p < 0.001). Comparable relationships were also seen when fasting insulin concentration was substituted for SSPG. Although adipose tissue LPL and mass correlated with each other (r = 0.76, p < 0.001) in a fasting state, they were not related to any other variable measured. Using in vivo and molecular biology techniques, these data demonstrate that the more insulin resistant an individual, the lower the level of plasma PH-LPL activity and mass, and the higher the plasma TG concentration. Since lower concentrations of adipose tissue mRNA were also directly correlated with plasma PH-LPL mass (r = 0.57, p < 0.01), and inversely with plasma TG concentration (r = -0.68, p < 0.001) as well as SSPG (r = -0.68, p < 0.001), it can be postulated that the relationship between insulin resistance and LPL activity and plasma TG concentration is associated with the inability of insulin to stimulate the transcription or to increase the intracellular mRNA stability of adipose tissue LPL in insulin resistant individuals.

    View details for Web of Science ID A1997XJ15300015

    View details for PubMedID 9243108

  • Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Jones, C. N., Pei, D., Staris, P., Polonsky, K. S., CHEN, Y. D., Reaven, G. M. 1997; 82 (6): 1834-1838

    Abstract

    Plasma glucose and insulin responses to a graded i.v. infusion of glucose were compared in two groups of glucose-tolerant women divided on the basis of their insulin sensitivity. Resistance to insulin-mediated glucose disposal was measured using the insulin suppression test, and the women studied were chosen to represent the highest and lowest quartiles of insulin resistance seen in the normal population. The sensitivity of the pancreatic beta-cell to glucose was assessed by measuring the glucose, insulin, and C peptide concentrations in response to continuous graded i.v. infusions of glucose at rates of 1, 2, 3, 4, 6, and 8 mg/kg x min for 40 min each. In addition, insulin secretion rates in response to the graded glucose infusion, calculated over each sampling period, were derived from deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance. Although plasma glucose concentrations were only slightly higher throughout the glucose infusion, the insulin concentrations were approximately doubled in the insulin-resistant subjects. When expressed as a function of the molar increments in plasma glucose achieved during the glucose infusion studies, the insulin-resistant women had a 90% higher (684 +/- 55 vs. 360 +/- 36 pmol/L x mmol/L; P < 0.001) total integrated plasma insulin response as the glucose concentration was increased from 5 to 9 mmol/L. However, the total integrated insulin secretory rate was only increased by 37% (1494 +/- 133 vs. 1093 +/- 125 pmol/mmol/L x min; P < 0.05) in the insulin-resistant group. This discrepancy suggested that insulin clearance was lower in the insulin-resistant subjects, and the calculation of this value, as the ratio of the total secretion of insulin to the area under the plasma insulin curve, was significantly lower in the insulin-resistant group (1.25 +/- 0.05 vs. 1.87 +/- 0.16 L/min x m2; P < 0.005). These results show that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as a decrease in insulin clearance.

    View details for Web of Science ID A1997XC08000036

    View details for PubMedID 9177392

  • From plant to patient: An ethnomedical approach to the identification of new drugs for the treatment of NIDDM DIABETOLOGIA Oubre, A. Y., Carlson, T. J., King, S. R., Reaven, G. M. 1997; 40 (5): 614-617

    View details for Web of Science ID A1997WX27400019

    View details for PubMedID 9165233

  • Identification of an age-related defect in glucose-stimulated insulin secretion in non-diabetic women ENDOCRINOLOGY AND METABOLISM Jones, C. N., Pei, D., Sturis, J., Polonsky, K. S., CHEN, Y. D., Reaven, G. M. 1997; 4 (3): 193-200
  • Effect of metformin on insulin-stimulated tyrosine kinase activity of erythrocytes from obese women with normal glucose tolerance DIABETES & METABOLISM Santos, R. F., Nomizo, R., Bopsco, A., Wajchenberg, B. L., Reaven, G. M., Azhar, S. 1997; 23 (2): 143-148

    Abstract

    The purpose of this study was to document the possible effect of solubilised erythrocytes on insulin-receptor binding and tyrosine kinase activity after 12 weeks of metformin administration to 13 healthy obese women with no history of diabetes and normal glucose as evaluated by conventional criteria. Subjects were given metformin 850 mg twice a day for 12 weeks. The results showed that plasma glucose response to an oral glucose challenge did not change following metformin, but that insulin response was significantly lower (p < 0.0001). In addition, both the number of insulin receptors and the tyrosine kinase activity per receptor of solubilised erythrocytes were significantly greater following metformin administration. Since both body weight and plasma glucose concentrations were similar before and after treatment, the effect of metformin on insulin-receptor binding and tyrosine kinase activity appeared to be independent of either of these variables. In summary, oral administration of metformin led to an increase in tyrosine kinase activity or erythrocyte insulin receptors, suggesting that such action occurs in the absence of any significant change in plasma glucose concentration.

    View details for Web of Science ID A1997WU68000004

    View details for PubMedID 9137903

  • Effects of low-fat, high-carbohydrate diets on risk factors for ischemic heart disease in postmenopausal women AMERICAN JOURNAL OF CLINICAL NUTRITION Jeppesen, J., Schaaf, P., Jones, G., Zhou, M. Y., CHEN, Y. D., Reaven, G. M. 1997; 65 (4): 1027-1033

    Abstract

    The effects of variations in dietary carbohydrate and fat on various aspects of carbohydrate and lipoprotein metabolism were evaluated in 10 healthy, postmenopausal women. The two diets were isoenergetic, assigned in random fashion, and consisted (as a % of total energy) of 15% protein, 60% carbohydrate, and 25% fat (60%-carbohydrate diet) or 15% protein, 40% carbohydrate, and 45% fat (40%-carbohydrate diet). Fasting plasma triacylglycerol, very-low-density-lipoprotein (VLDL) triacylglycerol, and VLDL-cholesterol concentrations were higher (P < 0.05-0.001) after the 60%-carbohydrate diet, whereas high-density-lipoprotein (HDL) cholesterol was lower (P < 0.05). Plasma insulin and triacylglycerol concentrations were also higher (P < 0.001) from 0800 to 0000 with the 60%-carbohydrate diet than with the 40%-carbohydrate diet. In addition, when vitamin A was given with the noon meal, the ensuing concentrations of retinyl palmitate were also higher after ingestion of the 60%-carbohydrate diet. Resistance to insulin-mediated glucose disposal, quantified at baseline by determining the steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of somatostatin, insulin, and glucose, correlated with the incremental increases in postprandial concentrations of plasma glucose (r = 0.68, P = 0.06), insulin (r = 0.82, P < 0.02), triacylglycerol (r = 0.77, P < 0.05), and retinyl palmitate (r = 0.68, P = 0.06) and with the Sf > 400 triacylglycerol (r = 0.77, P < 0.05), Sf 20-400 triacylglycerol (r = 0.72, P < 0.05), and Sf > 400 retinyl palmitate (r = 0.75, P < 0.01) lipoprotein fractions. Because all of these changes would increase risk of ischemic heart disease in postmenopausal women, it seems reasonable to question the wisdom of recommending that postmenopausal women consume low-fat, high-carbohydrate diets.

    View details for Web of Science ID A1997WQ77900020

    View details for PubMedID 9094889

  • Editorial: Growth hormone-ready for prime time? JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Marcus, R., Reaven, G. M. 1997; 82 (3): 725-726

    View details for Web of Science ID A1997WM24500004

    View details for PubMedID 9062472

  • Much ado about (almost) nothing DIABETES CARE Coulston, A. M., Reaven, G. M. 1997; 20 (3): 241-243

    View details for Web of Science ID A1997WJ36600002

    View details for PubMedID 9051364

  • Do high carbohydrate diets prevent the development or attenuate the manifestations (or both) of syndrome X? A viewpoint strongly against CURRENT OPINION IN LIPIDOLOGY Reaven, G. M. 1997; 8 (1): 23-27

    Abstract

    Syndrome X refers to a cluster of abnormalities, associated with resistance to insulin-mediated glucose uptake that increase risk of coronary heart disease. Increases in carbohydrate intake (with reciprocal decreases in fat content) within the boundaries of menus that can be followed in the free-living state have not been shown to decrease insulin resistance, either directly by enhancing insulin sensitivity or indirectly by producing and maintaining weight loss. However, such diets accentuate the metabolic abnormalities that constitute syndrome X. Because substitution of monounsaturated or polyunsaturated fat, or both, for saturated fat results in the same fall in LDL-cholesterol concentration as seen with low fat/high carbohydrate diets, it is concluded that low fat/high carbohydrate diets should be avoided in the treatment of syndrome X.

    View details for Web of Science ID A1997WR27300006

    View details for PubMedID 9127707

  • Ethnic differences in insulin resistance and its consequences in older Mexican American and non-hispanic white women JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Aguirre, M. A., Jones, C. N., Pei, D., Villa, M. L., Reaven, G. M. 1997; 52 (1): M56-M60

    Abstract

    This study was initiated to test the hypothesis that older, healthy, nondiabetic Mexican American women would be relatively resistant to insulin-mediated glucose disposal, hyperinsulinemic, and dyslipidemic as compared to a matched group of non-Hispanic White (NHW) women.The study, cross-sectional in nature, involved 14 Mexican American and 19 NHW healthy, normotensive nondiabetic, postmenopausal women of similar age and body mass index. It took place in the General Clinical Research Center at Stanford Medical Center. Measurements were made of fasting plasma glucose, insulin and lipid concentrations, and plasma glucose and insulin concentrations following a 75 gram oral glucose challenge. Resistance to insulin-mediated glucose disposal was estimated by the steady-state plasma glucose (SSPG) concentration achieved at the end of a 3-hour constant infusion of glucose, insulin, and somatostatin.Mexican American women had significantly greater glucose (p < .001) and insulin (p < .001) responses to the oral glucose challenge than did the NHW women. Resistance to insulin-mediated glucose disposal was increased in Mexican American women (SSPG 195 +/- 25 mg/dl compared to 137 +/- 18 mg/dl in NHW; p < .001). While total cholesterol, low density lipoprotein (LDL)-cholesterol, and triglyceride concentrations were not significantly different in the two ethnic groups, high density lipoprotein (HDL)-cholesterol was significantly lower in the Mexican American women (51 mg/dl vs 61 mg/dl; p = .04).Older Mexican American women are more insulin resistant, glucose intolerant, and hyperinsulinemic, and have a lower HDL-cholesterol than a matched group of non-Hispanic White peers. These results were observed despite the exclusion of individuals with non-insulin dependent diabetes mellitus (NIDDM).

    View details for Web of Science ID A1997WC11300019

    View details for PubMedID 9008670

  • Insulin resistance and atherosclerosis DIABETES REVIEWS CHEN, Y. D., Reaven, G. M. 1997; 5 (4): 331-342
  • Banting Lecture 1988. Role of insulin resistance in human disease. 1988. Nutrition Reaven, G. M. 1997; 13 (1): 65-?

    View details for PubMedID 9058458

  • Enhanced sympathetic nervous system activity - The Linchpin between insulin resistance, hyperinsulinemia, and heart rate AMERICAN JOURNAL OF HYPERTENSION Facchini, F. S., Stoohs, R. A., Reaven, G. M. 1996; 9 (10): 1013-1017

    Abstract

    This study was undertaken to see whether insulin resistant individuals, who are chronically hyperinsulinemic, have a higher heart rate (HR) than insulin sensitive, normoinsulinemic subjects. A total of 45 normotensive, nondiabetic individuals had insulin-mediated glucose disposal quantified by the insulin suppression test. In an effort to minimize variables known to modify heart rate, such as diet, exercise, and emotional distress, heart rate was continuously monitored during sleep by an electronic device measuring RR intervals. The average heart rate (as calculated by a mean of 30,720 +/- 208 beats per subject over a monitoring time of 6.9 +/- 0.6 h) was significantly related (r = 0.61; P < .001) to insulin resistance as expressed by the steady-state plasma glucose (SSPG) response to a continuous infusion of glucose, insulin and somatostatin and to the plasma insulin response to a 75 g of oral glucose challenge (r = 0.51; P < .001). These significant relationships between HR and both SSPG and plasma insulin response persisted after adjustment by stepwise regression analysis for age, gender distribution, body mass index, physical activity, and family history of either diabetes or hypertension. These results show that insulin resistant individuals, with compensatory hyperinsulinemia, have a higher nocturnal heart rate: a finding consistent with the possibility that the increased nocturnal heart rates are secondary to insulin-induced sympathetic activity.

    View details for Web of Science ID A1996VL72600010

    View details for PubMedID 8896654

  • Insulin resistance in patients with essential hypertension can occur in the absence of microalbuminuria AMERICAN JOURNAL OF HYPERTENSION Yip, J. W., Jones, C., Facchini, F., Chen, I., Reaven, G. M. 1996; 9 (10): 959-963

    Abstract

    This study was initiated to see if the presence of resistance to insulin-mediated glucose disposal, glucose intolerance, and hyperinsulinemia in healthy patients with hypertension was dependent upon the coexistence of microalbuminuria. For this purpose we compared these variables in 68 individuals: 34 patients with hypertension and 34 normal volunteers. The two groups were similar in terms of age, gender distribution, body mass index, and ratio of waist to hip girth. Furthermore, although four patients with hypertension satisfied the criteria for microalbuminuria, as compared to one normal volunteer, the urinary albumin excretion (UAE) rates were similar in the two groups (8.07 +/- 1.08 v 7.67 +/- 1.12 micrograms/min). Despite the similarities, both the plasma glucose and insulin responses to a 75 g oral glucose challenge were significantly higher (P < .01) in those with high blood pressure. In addition, the steady-state plasma glucose (SSPG) concentrations at the end of a 180 min continuous infusion of somatostatin, insulin, and glucose was significantly higher in those with hypertension (156 +/- 13 v 107 +/- 10 mg/dL, P < .01). Since the steady-state plasma insulin levels were also somewhat higher in those with hypertension, the higher SSPG values indicate that these individuals were relatively insulin resistant as compared to the control population. Finally, UAE rates were not correlated with either the plasma glucose or insulin responses to oral glucose or to the SSPG concentrations--either in the entire group of 68, or when the 34 patients in each group were considered separately. These results demonstrate that insulin resistance, glucose intolerance, and hyperinsulinemia can occur independently of microalbuminuria in patients with hypertension.

    View details for Web of Science ID A1996VL72600003

    View details for PubMedID 8896647

  • Lack of a relationship between urinary albumin excretion rate and insulin resistance in patients with non-insulin-dependent diabetes mellitus METABOLISM-CLINICAL AND EXPERIMENTAL Rizvi, A., Varasteh, B., CHEN, Y. D., Reaven, G. M. 1996; 45 (9): 1062-1064

    Abstract

    The study was performed to determine the relationship between urinary albumin excretion (UAE) and resistance to insulin-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty-five non-obese male patients were enrolled; UAE rates were determined on two 24-hour urine collections, and resistance to insulin-mediated glucose disposal was quantified by measurement of steady-state plasma glucose (SSPG) and steady-state plasma insulin concentrations during the last 30 minutes of a 180-minute infusion of somatostatin, insulin, and glucose. Twenty-four-hour urine UAE rates varied from 6 to 112 microgram/min, and microalbuminuria (> 20 microgram/min) was present in seven of 25 patients. SSPG concentration ranged from 158 to 419 mg/dL, and there was no relationship between UAE rates and SSPG concentration (r = .16, P = NS). Furthermore, the mean SSPG concentration was not significantly different in seven patients with microalbuminuria compared with 18 normoalbuminuric subjects (318 +/- 20 v 298 +/- 17 mg/dL). Thus, resistance to insulin-mediated glucose disposal occurs in patients with NIDDM in the absence of microalbuminuria, and we could not detect any relationship between UAE and insulin resistance in this population.

    View details for Web of Science ID A1996VF48100004

    View details for PubMedID 8781291

  • Dissociation between urinary albumin excretion and variables associated with insulin resistance in a healthy population JOURNAL OF INTERNAL MEDICINE Zavaroni, I., Bonini, L., Gasparini, P., Zuccarelli, A., DALLAGLIO, E., Barilli, L., CIONI, F., Strata, A., Reaven, G. M. 1996; 240 (3): 151-156

    Abstract

    To see if the cluster of metabolic and haemodynamic variables defined as comprising Syndrome X varied as a function of urinary albumin excretion (UAE) rate in a healthy population.A cross-sectional, population-based study.A factory in Italy.Two hundred and twenty-five healthy volunteers, 115 men and 110 women. OUTCOME MEASURES. Measurements were made of the plasma glucose and insulin responses to oral glucose, fasting triglyceride (TG) and high density lipoprotein (HDL)-cholesterol concentrations, blood pressure, and UAE rates.Only five of the 225 volunteers had micro-albuminuria, defined as a UAE rate > 2 micrograms min-1, and the UAE rate was < 5 micrograms min-1 in 80% of the volunteers. Significant variations in the metabolic and haemodynamic variables measured were not associated with any differences in UAE. Finally, significant relationships were found between various measures of plasma insulin concentration and plasma glucose response to oral glucose, plasma TG and HDL-cholesterol concentrations, and mean arterial blood pressure, independent of variations in age, body mass index, ratio of waist-to-hip girth, and UAE rates.The widespread variability in plasma glucose and insulin responses, plasma TG and HDL-cholesterol concentrations, and blood pressure that are seen in the population at large cannot be attributed to variations in UAE rate.

    View details for Web of Science ID A1996VJ71400006

    View details for PubMedID 8862124

  • Gemfibrozil treatment of endogenous hypertriglyceridemia: Effect on insulin-mediated glucose disposal and plasma insulin concentrations JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Jeng, C. Y., Sheu, W. H., Fuh, M. M., Shieh, S. M., CHEN, Y. D., Reaven, G. M. 1996; 81 (7): 2550-2553

    Abstract

    Gemfibrozil or placebo was administered for 3 months to 24 individuals with endogenous hypertriglyceridemia and normal glucose tolerance. Mean ( +/- SEM) fasting plasma triglyceride (TG) concentrations decreased (4.01 +/- 0.55 to 1.34 +/- 0.12 mmol/L; P < 0.001) and high density lipoprotein cholesterol concentrations increased (0.54 +/- 0.03 to 0.67 +/- 0.04 mmol/L; P < 0.001) in gemfibrozil-treated patients, associated with lower (P < 0.01-0.001) plasma free fatty acid and TG concentrations when measured at hourly intervals in response to breakfast (0800 h) and lunch (1200 h). However, day-long plasma glucose and insulin responses to meals in the 2 groups were similar before and after treatment, as were the steady state plasma glucose and insulin concentrations at the end of a 180-min infusion of somatostatin, insulin, and glucose. Thus, marked decreases in both plasma TG and free fatty acid concentrations seen in association with gemfibrozil neither enhanced insulin-mediated glucose disposal nor lowered ambient plasma insulin concentrations in patients with endogenous hypertriglyceridemia.

    View details for Web of Science ID A1996UW84200025

    View details for PubMedID 8675576

  • Relation between dietary vitamin intake and resistance to insulin-mediated glucose disposal in healthy volunteers AMERICAN JOURNAL OF CLINICAL NUTRITION Facchini, F., Coulston, A. M., Reaven, G. M. 1996; 63 (6): 946-949

    Abstract

    The relation between the self-reported intake of various dietary constituents and insulin-mediated glucose disposal was evaluated in 52 healthy volunteers. Insulin-mediated glucose uptake was independently associated with degree of obesity (inversely) and estimates of level of physical activity (directly). An independent relation between increased intake of vitamin A and insulin action was shown, ie, the greater the intake of vitamin A, the more effective was insulin in stimulating glucose disposal. However, there was no independent relation noted between insulin-mediated glucose disposal and estimates of the intake of carbohydrate, protein, amount or kind of fat, fiber, or vitamins C and E. Furthermore, the 20 individuals with estimates of vitamin A consumption > 10 000 IU/d had significantly lower plasma glucose (P < 0.01) and insulin (P < 0.05) responses to oral glucose, and insulin-mediated glucose disposal values that were higher (P < 0.005) than those of the 20 individuals whose estimated vitamin A intake was < 8000 IU/d. These results suggest that vitamin A intake, but not intakes of vitamin C and E, fiber, fat, or carbohydrate is associated with enhanced insulin-mediated glucose disposal.

    View details for Web of Science ID A1996UP71500015

    View details for PubMedID 8644691

  • Insulin resistance, its consequences, and coronary heart disease - Must we choose one culprit? CIRCULATION Reaven, G. M., CHEN, Y. D. 1996; 93 (10): 1780-1783

    View details for Web of Science ID A1996UK79500004

    View details for PubMedID 8635254

  • Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22 JOURNAL OF CLINICAL INVESTIGATION Wu, D. A., Bu, X. D., Warden, C. H., SHEN, D. D., Jeng, C. Y., Sheu, W. H., Fuh, M. M., Katsuya, T., Dzau, V. J., Reaven, G. M., Lusis, A. J., Rotter, J. I., CHEN, Y. D. 1996; 97 (9): 2111-2118

    Abstract

    Resistance to insulin-mediated glucose disposal is a common finding in patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as in nondiabetic individuals with hypertension. In an effort to identify the generic loci responsible for variations in blood pressure in individuals at increased risk of insulin resistance, we studied the distribution of blood pressure in 48 Taiwanese families with NIDDM and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. We found no evidence for linkage of the angiotensin converting enzyme locus on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures. In contrast, we obtained significant evidence for linkage or systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (LPL) locus on the short arm of chromosome 8 (P = 0.002, n = 125 sib-pairs, for the haplotype generated from two simple sequence repeat markers within the LPL gene). Further strengthening this linkage observation, two flanking marker loci for LPL locus, D8S261 (9 cM telomeric to LPL locus) and D8S282 (3 cM centromeric to LPL locus), also showed evidence for linkage with systolic blood pressure (P = 0.02 and 0.0002 for D8S261 and D8S282, respectively). Two additional centromeric markers (D8S133, 5 cM from LPL locus, and NEFL, 11 cM from LPL locus) yielded significant P values of 0.01 and 0.001, respectively. Allelic variation around the LPL gene locus accounted for as much as 52-73% of the total interindividual variation in systolic blood pressure levels in this data set. Thus, we have identified a genetic locus at or near the LPL gene locus which contributes to the variation of systolic blood pressure levels in nondiabetic family members at high risk for insulin resistance and NIDDM.

    View details for Web of Science ID A1996UJ39900016

    View details for PubMedID 8621801

  • Resistance to insulin-mediated glucose disposal in patients with noninsulin-dependent diabetes mellitus in the absence of obesity or microalbuminuria - A clinical research center study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM SHEU, W., Jeng, C. Y., Fuh, M., CHEN, Y. D., Reaven, G. M. 1996; 81 (3): 1156-1159

    Abstract

    To challenge the view that resistance to insulin-mediated glucose uptake in noninsulin-dependent diabetes mellitus (NIDDM) is limited to patients with microalbuminuria, high blood pressure, or obesity, we compared measurements of insulin resistance in 29 normal volunteers and 31 normotensive patients with NIDDM (mean +/- SE fasting plasma glucose, 160 +/- 10 mg/dL). The patients with NIDDM were nonobese (body mass index, < 27 kg/m2), with urinary albumin excretion (UAE) less than 20 micrograms/min on the basis of two overnight urine collections. The two groups were similar in age and body mass index. Although patients with NIDDM had neither high blood pressure nor microalbuminuria; both their blood pressure (125 +/- 2/79 +/- 1 vs, 113 - 2/73 +/- 2 mm Hg) and UAE excretion (4.7 +/- 0.58 vs. 2.12 +/- 0.17 micrograms/min) were somewhat higher than those in the control population. Resistance to insulin-mediated glucose disposal was quantified by measurement of the steady state plasma glucose (SSPG) and insulin (SSPI) concentrations during the last 30 min of an 180-min infusion of somatostatin (5 micrograms/min), insulin (25 mU/min-m2), and glucose (240 mg/min-m2). The results showed that SSPI concentrations were similar in the two groups (64 +/- 3 vs. 62 +/- 3 microU/mL), but SSPG concentrations were approximately twice as high in patients with NIDDM (258 +/- 15 vs. 139 +/- 11 mg/dL;P < 0.001); demonstrating the presence of severe insulin resistance. Furthermore, the magnitude of the differences in the SSPG values of the two groups did not change and remained highly significant when adjusted for small differences in age, body mass index, blood pressure, and UAE. Finally, SSPG did not correlate with age, body mass index, blood pressure, or UAE in either group. These data again demonstrate that insulin resistance exists in patients with NIDDM, and that this defect is present in the absence of obesity, high blood pressure, or microalbuminuria.

    View details for Web of Science ID A1996TZ90600052

    View details for PubMedID 8772592

  • Mechanisms of disease - Hypertension and associated metabolic abnormalities - The role of insulin resistance and the sympathoadrenal system NEW ENGLAND JOURNAL OF MEDICINE Reaven, G. M., Lithell, H., Landsberg, L. 1996; 334 (6): 374-381
  • Similar weight loss with low- or high-carbohydrate diets AMERICAN JOURNAL OF CLINICAL NUTRITION Golay, A., Allaz, A. F., Morel, Y., DETONNAC, N., Tankova, S., Reaven, G. 1996; 63 (2): 174-178

    Abstract

    The goal of this study was to evaluate the effect of diets that were equally low in energy but widely different in relative amounts of fat and carbohydrate on body weight during a 6-wk period of hospitalization. Consequently, 43 adult, obese persons were randomly assigned to receive diets containing 4.2 MJ/d (1000 kcal/d) composed of either 32% protein, 15% carbohydrate, and 53% fat, or 29% protein, 45% carbohydrate, and 26% fat. There was no significant difference in the amount of weight loss in response to diets containing either 15% (8.9 +/- 0.6 kg) or 45% (7.5 +/- 0.5 kg) carbohydrate. Furthermore, significant decreases in total body fat and waist-to-hip circumference were seen in both groups, and the magnitude of the changes did not vary as a function of diet composition. Fasting plasma glucose, insulin, cholesterol, and triacylglycerol concentrations decreased significantly in patients eating low-energy diets that contained 15% carbohydrate, but neither plasma insulin nor triacylglycerol concentrations fell significantly in response to the higher-carbohydrate diet. The results of this study showed that it was energy intake, not nutrient composition, that determined weight loss in response to low-energy diets over a short time period.

    View details for Web of Science ID A1996TR79300005

    View details for PubMedID 8561057

  • Coronary artery intimal thickening in the transplanted heart - An in vivo intracoronary ultrasound study of immunologic and metabolic risk factors TRANSPLANTATION Rickenbacher, P. R., Kemna, M. S., Pinto, F. J., Hunt, S. A., Alderman, E. L., Schroeder, J. S., Stinson, E. B., Popp, R. L., Chen, I., Reaven, G., Valantine, H. A. 1996; 61 (1): 46-53

    Abstract

    This study examined the hypothesis that immunologic factors are the major correlates of coronary artery intimal thickening and luminal stenosis. The study population included 116 adult heart transplant recipients with a mean age of 44.7 +/- 12.0 years (89 men and 27 women) undergoing annual coronary angiography and intracoronary ultrasound 3.4 +/- 2.7 (range, 1.0-14.6) years after transplantation. Mean intimal thickness was obtained from several distinct sites along the left anterior descending and/or left circumflex coronary artery by intracoronary ultrasound. Coronary artery stenosis defined by angiography was classified as mild (< 30% luminal stenosis), moderate (> or = 30-70% luminal stenosis), or severe (> 70% luminal stenosis or diffuse pruning of distal vessels). Prevalence of any transplant coronary artery disease (TxCAD) was 85% by intracoronary ultrasound and 15% by angiography. By multiple regression analysis, only average fasting plasma triglyceride level (P < 0.006) and average weight (P < 0.007) were significantly correlated with severity of intimal thickening (R = 0.54, P < 0.0001). Donor age (P < 0.006) and average fasting plasma triglyceride level (P < 0.009) were significantly correlated with stenosis by angiography. Correlation of multiple immunologic and metabolic factors with intimal thickness by univariate analysis suggests a multifactorial etiology for TxCAD. Among the multiple univariate correlates of TxCAD, higher fasting plasma triglyceride levels and body weight are the only independent correlates of TxCAD. The absence of acute rejection as an independent predictor of intimal thickening suggests that mechanisms beyond those mediating typical cellular rejection should be targeted for advancing our understanding of Tx-CAD.

    View details for Web of Science ID A1996TQ20100011

    View details for PubMedID 8560573

  • EFFECT OF GLIPIZIDE TREATMENT ON RESPONSE TO AN INFUSED GLUCOSE-LOAD IN PATIENTS WITH NIDDM DIABETES CARE Sheu, W. H., Jeng, C. Y., Fuh, M. M., CHEN, Y. D., Reaven, G. M. 1995; 18 (12): 1582-1587

    Abstract

    This study was initiated to compare the effect of sulfonylurea treatment on the response to an infused glucose load of patients with non-insulin-dependent diabetes mellitus (NIDDM) at a basal insulin concentration and in response to physiological hyperinsulinemia.We used the insulin suppression test, in which subjects were infused for 180 min with somatostatin, exogenous insulin, and glucose. Since similar steady-state plasma insulin (SSPI) concentrations are reached in all subjects, the resultant steady-state plasma glucose (SSPG) concentration permits comparison of the ability of a given individual to maintain glucose homeostasis in response to the infused glucose load.We studied 15 nonobese patients at two different SSPI concentrations, before and after glipizide treatment, at basal (68 +/- 4 pmol/l) and high (470 +/- 31 pmol/l) levels. Values for SSPG concentrations were lower after treatment at both the basal (15.3 +/- 0.5 vs. 18.5 +/- 0.6 mmol/l; P < 0.001) and the high (10.6 +/- 0.7 vs. 14.2 +/- 0.7 mmol/l; P < 0.001) SSPI concentrations. To compare the responses of each patient before and after treatment, we calculated the fractional glucose metabolic rate, i.e., (glucose infusion rate--urinary glucose loss) divided by SSPG. To provide an alternative method of comparing the effect of sulfonylurea treatment, we divided the incremental increase in fractional metabolic glucose rate between the studies done at the low and high SSPI by the incremental increase in SSPI between the two studies (insulin sensitivity index [SI]).The results of these calculations indicated that glipizide treatment was associated with a significant increase in fractional glucose metabolic rate at a basal insulin concentration (29 +/- 3 to 42 +/- 2 ml.m-2.min-1, P < 0.001), and in response to the incremental change in SSPI (14 +/- 4 to 23 +/- 3 ml.m-2.min-1, P < 0.02). Finally, SI also increased in association with sulfonylurea (0.24 +/- 0.06 to 0.43 +/- 0.07 ml.m-2.min-1/microU.ml-1, P < 0.001).

    View details for Web of Science ID A1995TG47600009

    View details for PubMedID 8722055

  • EFFECT OF VARIATIONS IN ORAL FAT AND CARBOHYDRATE LOAD ON POSTPRANDIAL LIPEMIA AMERICAN JOURNAL OF CLINICAL NUTRITION Jeppesen, J., CHEN, Y. D., Zhou, M. Y., Wang, T., Reaven, G. M. 1995; 62 (6): 1201-1205

    Abstract

    In this study we assessed the acute effects of the consumption of varying amounts of fat and fructose on the magnitude of postprandial lipemia. Subjects were studied after an overnight fast on four separate mornings, ingesting in random order 5, 40, or 80 g fat, or 5 g fat plus 50 g fructose. Vitamin A (36 mg, or 120,000 U retinol) was also given and blood was drawn at frequent intervals over the next 10 h for measurement of triacylglycerol and retinyl palmitate (RP) concentrations in plasma and the Sf > 400 and Sf 20-400 lipoprotein fractions. (Sf denotes flotation units.) In general, the postprandial triacylglycerol response increased in plasma and in both lipoprotein fractions as a function of both the baseline fasting triacylglycerol concentration and the amount of fat ingested. However, no matter how high the fasting plasma triacylglycerol concentration, there was no increase in the postprandial triacylglycerol concentration in plasma or either lipoprotein fraction after the 5-g oral fat load. The results of the measurements of RP concentration were somewhat similar in that there was a dose-dependent increase in the plasma and the Sf > 400 lipoprotein fraction in response to the higher fat loads. However, just the opposite was true in the Sf 20-400 lipoprotein fraction, for which the increase in RP concentration was inversely related to the size of the fat load.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995TJ28400004

    View details for PubMedID 7491880

  • EFFECT OF WEIGHT-LOSS ON BLOOD-PRESSURE AND INSULIN-RESISTANCE IN NORMOTENSIVE AND HYPERTENSIVE OBESE INDIVIDUALS AMERICAN JOURNAL OF HYPERTENSION Su, H. Y., Sheu, W. H., Chin, H. M., Leng, C. Y., CHEN, Y. D., Reaven, G. M. 1995; 8 (11): 1067-1071

    Abstract

    In this study, the effect of weight loss on blood pressure and various facets of glucose and insulin metabolism was examined in 22 subjects with mild to moderate obesity; 11 with high blood pressure (diastolic blood pressure > 95 mm Hg) and 11 with normal blood pressure (diastolic blood pressure < 90 mm Hg). The two groups were similar in mean (+/- SEM) body mass index at baseline (30.2 +/- 1.0 v 31.6 +/- 1.1 kg/m2), and each group lost approximately 8 kg during the 3-month study period. Blood pressure fell significantly (P < .003) following the 8 kg weight loss in both the normotensive (122 +/- 3/81 +/- 3 to 110 +/- 3/74 +/- 2 mm Hg) and hypertensive (149 +/- 3/98 +/- 1 to 135 +/- 3/86 mm Hg) subjects. Furthermore, the plasma glucose and insulin responses to a 75 g oral glucose load were significantly lower (P < .001) following weight loss. Finally, insulin resistance, as assessed by determining the steady-state plasma glucose (SSPG) concentration at the end of a 180 min infusion of somatostatin, insulin, and glucose, was also lower (P < .002) after the 8 kg weight loss in the normotensive (243 +/- 23 to 172 +/- 15 mg/dL) and hypertensive subjects (266 +/- 18 to 181 +/- 25 mg/dL). Since the steady-state plasma insulin concentrations were, if anything, slightly lower after weight loss in both groups, the lower post-weight loss SSPG values actually underestimate the improvement of insulin resistance. Thus, weight loss of 8 kg in moderately obese individuals leads to significant decreases in blood pressure and plasma glucose and insulin concentrations in response to an oral glucose challenge and degree of insulin resistance.

    View details for Web of Science ID A1995TD81400003

    View details for PubMedID 8554729

  • RELATIONSHIP BETWEEN INSULIN-MEDIATED GLUCOSE DISPOSAL BY MUSCLE AND ADIPOSE-TISSUE LIPOLYSIS IN HEALTHY-VOLUNTEERS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Pei, D., CHEN, Y. D., Hollenbeck, C. B., Bhargava, R., Reaven, G. M. 1995; 80 (11): 3368-3372

    Abstract

    The present study was performed in 17 nondiabetic subjects and was initiated to determine whether enhanced adipose tissue lipolysis, either basal or catecholamine induced (isoproterenol), and/or resistance to insulin inhibition of isoproterenol-stimulated lipolysis were correlated with resistance to insulin-mediated glucose disposal by muscle. Insulin-mediated glucose disposal was assessed by determining the steady state plasma glucose (SSPG) concentration during the insulin suppression test [180 min infusion of somatostatin (350 micrograms/h), insulin (25 mU/m2min), and glucose (240 mg/m2.min)]. On another occasion, plasma FFA and glycerol concentrations were determined at the end of 3 sequential infusion periods (IP): IP1, somatostatin (350 micrograms/h) plus basal insulin replacement (5 mU/m2.min); IP2, somatostatin (350 micrograms/h), insulin (5 mU/m2.min), and isoproterenol (270 ng/m2.min); and IP3, somatostatin (350 micrograms/h), isoproterenol (270 ng/m2.min), and insulin (10 mU/m2.min). SSPG concentrations correlated with FFA concentrations during all 3 infusion periods after adjustment for age, gender, body mass index, insulin concentration, and ratio of waist to hip girth (IP1:r = 0.61; P < 0.03; IP2: r = 0.70; P < 0.01; IP3: r = 0.65; P < 0.02). Correlations between SSPG and glycerol concentrations were also highly statistically significant (IP1: r = 0.62; P < 0.03; IP2: r = 0.65; P < 0.02; IP3: r = 0.70; P < 0.01). These results demonstrate for the first time that plasma FFA and glycerol concentrations are increased commensurate with the degree of resistance to insulin-mediated glucose disposal at a basal insulin level, in response to isoproterenol stimulation, and after insulin inhibition of isoproterenol-stimulated lipolysis.

    View details for Web of Science ID A1995TD90900047

    View details for PubMedID 7593453

  • CHANGES IN INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY ASSOCIATED WITH METFORMIN TREATMENT OF TYPE-2 DIABETES DIABETES & METABOLISM Santos, R. F., Nomizo, R., WAJHENBERG, B. L., Reaven, G. M., Azhar, S. 1995; 21 (4): 274-280

    Abstract

    This study was performed to define the effect of metformin on glycaemic control and erythrocyte insulin receptor tyrosine kinase activity in patients with non-insulin-dependent (Type 2) diabetes mellitus. A case-control study of the effect of metformin treatment in hyperglycaemic patients with Type 2 diabetes was conducted in outpatients of the Diabetes Clinical Center. The study population consisted of 14 patients with Type 2 diabetes (5 males, 9 females) whose hyperglycaemia was uncontrolled by diet. Patients were treated with metformin 850 mg twice daily for 2 1/2 months. Fasting plasma glucose concentrations decreased from 8.9 to 6.4 mmol/L after 10 weeks of metformin treatment (p < 0.001), in association with significantly lower (p < 0.001) plasma glucose and insulin concentrations in response to an oral glucose load. In addition, both fasting plasma triglyceride and cholesterol concentrations were significantly (p < 0.001) lower after metformin treatment. There was no change in erythrocyte insulin receptor binding associated with metformin treatment, but both basal and insulin-stimulated insulin receptor tyrosine kinase activities of solubilized erythrocyte insulin receptors were significantly higher after 10 weeks of metformin treatment. It is concluded that the increase in insulin-stimulated tyrosine kinase activity contributed to the improvement in glucose insulin and lipoprotein metabolism associated with metformin treatment of Type 2 diabetes.

    View details for Web of Science ID A1995TC30300007

    View details for PubMedID 8529763

  • EFFECT OF METFORMIN ON VARIOUS ASPECTS OF GLUCOSE, INSULIN AND LIPID-METABOLISM IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS WITH VARYING DEGREES OF HYPERGLYCEMIA DIABETES-METABOLISM REVIEWS Reaven, G. M. 1995; 11: S97-S108

    View details for Web of Science ID A1995RW67300013

    View details for PubMedID 8529491

  • ASSOCIATION BETWEEN SALT SENSITIVITY AND INSULIN CONCENTRATIONS IN PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Zavaroni, I., Coruzzi, P., Bonini, L., MOSSINI, G. L., Musiari, L., Gasparini, P., Fantuzzi, M., Reaven, G. M. 1995; 8 (8): 855-858

    Abstract

    This study was performed in 28 patients with mild to moderate hypertension, classified as being either salt sensitive or salt resistant on the basis of the percent decrement in mean arterial blood pressure (MAP) seen 7 days after daily salt intake was decreased from 220 to 30 mmol/L. Ten patients had a percent decrease of MAP > 10% and were defined as being salt sensitive. Salt resistance was defined as a percent decrease in MAP of < 3% and eight patients satisfied this criterion. Both plasma glucose and insulin concentrations following a 75-g oral glucose challenge were significantly higher after the high-salt diet in the salt-sensitive patients. Furthermore, there were correlations of marginal statistical significance between the decrease in MAP after the low-salt diet and the plasma glucose (r = 0.32, P < .10) and insulin (r = 0.38, P < .06) responses to oral glucose. These data are consistent with the view that there is an association between resistance to insulin-mediated glucose disposal and salt sensitivity in patients with high blood pressure.

    View details for Web of Science ID A1995RM14200012

    View details for PubMedID 7576404

  • RESISTANCE TO INSULIN-MEDIATED GLUCOSE-UPTAKE AND HYPERINSULINEMIA IN WOMEN WHO HAD PREECLAMPSIA DURING PREGNANCY AMERICAN JOURNAL OF HYPERTENSION Fuh, M. M., Yin, C. S., Pei, D., Sheu, W. H., Jeng, C. Y., CHEN, Y. D., Reaven, G. M. 1995; 8 (7): 768-771

    Abstract

    Plasma glucose and insulin responses to a 75-g oral glucose load, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations after an infusion of somatostatin, insulin, and glucose, were determined 2 months after delivery in 26 women; 13 who had a normal pregnancy and 13 who developed preeclampsia. The plasma glucose response to oral glucose was not different in the two groups, but the plasma insulin response was significantly greater (P < .02) in those who had been preeclamptic. Although the mean (+/- SE) SSPI concentrations during the infusion study were similar in the two groups (51 +/- 2 v 56 +/- 2 microU/mL), the SSPG concentrations were significantly higher (P < .02) in those who developed preeclampsia (160 +/- 17 v 119 +/- 17 mg/dL). Thus, when studied 2 months after delivery, women who developed preeclampsia were relatively insulin resistant and hyperinsulinemic when compared to those who had an uncomplicated pregnancy.

    View details for Web of Science ID A1995RG33800018

    View details for PubMedID 7546505

  • PATHOPHYSIOLOGY OF INSULIN-RESISTANCE IN HUMAN-DISEASE PHYSIOLOGICAL REVIEWS Reaven, G. M. 1995; 75 (3): 473-486

    Abstract

    The ability of insulin to stimulate glucose uptake varies widely from person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as diseases of Western civilization. Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presented. However, the ability to maintain the degree of compensatory hyperinsulinemia necessary to prevent loss of glucose tolerance in insulin-resistant individuals does not represent an unqualified homeostatic victory. In contrast, evidence is presented supporting the view that the combination of insulin resistance and compensatory hyperinsulinemia predisposes to the development of a cluster of abnormalities, including some degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistance has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disease. Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease.

    View details for Web of Science ID A1995RK90100002

    View details for PubMedID 7624391

  • RELATIONS BETWEEN DELETION POLYMORPHISM OF THE ANGIOTENSIN-CONVERTING ENZYME GENE AND INSULIN-RESISTANCE, GLUCOSE-INTOLERANCE, HYPERINSULINEMIA, AND DYSLIPIDEMIA ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Katsuya, T., Horiuchi, M., CHEN, Y. D., Koike, G., Pratt, R. E., Dzau, V. J., Reaven, G. M. 1995; 15 (6): 779-782

    Abstract

    Recent reports have shown that the frequency of the homozygous deletion genotype (DD) of the angiotensin-converting enzyme (ACE) gene is highly associated with myocardial infarction and cardiomyopathy, particularly in those considered to be at low risk for coronary heart disease (CHD) on the basis of their apoB or LDL cholesterol concentrations. The present study was initiated to extend this inquiry by exploring the possibility that the ACE/DD genotype might be associated with risk factors not evaluated in the initial reports. Consequently, we determined the ACE genotype in 181 subjects, 124 with normal glucose tolerance and 57 with noninsulin-dependent-diabetes mellitus (NIDDM), and compared various aspects of glucose, insulin, and lipoprotein metabolism in the three ACE genotypes. In general, normal subjects with the DD genotype had a lower body mass index, were more insulin sensitive (as assessed by the insulin suppression test), and had lower plasma glucose and insulin responses to oral glucose. In addition, plasma triglyceride and cholesterol concentrations were lowest and HDL cholesterol concentrations highest in the DD group. However, the only statistically significant differences were between the ID and DD groups; the latter had lower values for body mass index, was more insulin sensitive, and had a lower plasma insulin response to oral glucose. Similar but insignificant trends were noted in the patients with NIDDM. The present results show that subjects with the ACE/DD genotype are not at increased risk for CHD because of insulin resistance, relative hyperglycemia and hyperinsulinemia, or a dyslipidemia characterized by a high triglyceride and low HDL cholesterol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995RD14400010

    View details for PubMedID 7773733

  • COMPARISON OF THE HEMODYNAMIC AND METABOLIC EFFECTS OF LOW-DOSE HYDROCHLOROTHIAZIDE AND LISINOPRIL TREATMENT IN OBESE PATIENTS WITH HIGH BLOOD-PRESSURE AMERICAN JOURNAL OF HYPERTENSION Reaven, G. M., Clinkingbeard, C., Jeppesen, J., Maheux, P., Pei, D., Foote, J., Hollenbeck, C. B., CHEN, Y. D. 1995; 8 (5): 461-466

    Abstract

    Patients with high blood pressure tend to be insulin resistant, glucose intolerant, hyperinsulinemic, and dyslipidemic. Since these metabolic defects are accentuated by obesity, we thought it important to compare the effects of 3 months' treatment with either lisinopril (20 mg/day) or low dose hydrochlorothiazide (12.5 mg/day) on blood pressure and glucose, insulin, and lipoprotein metabolism in obese patients with hypertension. There were 14 patients in each group, and they were similar (mean +/- SE) in age (54 +/- 3 v 50 +/- 4 years), gender (nine men/five women), and body mass index (33.4 +/- 0.8 v 33.9 +/- 0.9 kg/m2). Patients treated with lisinopril had a somewhat greater fall in both systolic (18 +/- 3 v 10 +/- 3 mm Hg) and diastolic (12 +/- 2 v 8 +/- 1 mm Hg) blood pressure, but only the change in systolic pressure was statistically significant (P < .05). Plasma glucose, insulin, and triglyceride concentrations were measured at hourly intervals from 8 AM to 4 PM (breakfast at 8 AM and lunch at 12 PM), and there was a modest increase in all three variables following hydrochlorothiazide treatment (P < .05 to P < .09). However, daylong plasma glucose, insulin, and triglyceride concentration did not change with lisinopril treatment. Finally, neither the ability of insulin to mediate glucose disposal nor fasting lipid and lipoprotein concentrations, changed with either treatment. In conclusion blood pressure decreased significantly following treatment with either lisinopril (20 mg/day) or hydrochlorothiazide (12.5 mg/day).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995RA61200004

    View details for PubMedID 7662221

  • ARE INSULIN-RESISTANCE AND/OR COMPENSATORY HYPERINSULINEMIA INVOLVED IN THE ETIOLOGY AND CLINICAL COURSE OF PATIENTS WITH HYPERTENSION Reaven, G. M. STOCKTON PRESS. 1995: S2-S5

    View details for Web of Science ID A1995RD90600002

    View details for PubMedID 7550533

  • Effects of low sodium diet and unilateral nephrectomy on the development of carbohydrate-induced hypertension. Blood pressure Donnelly, R., Ho, H., Reaven, G. M. 1995; 4 (3): 164-169

    Abstract

    Since there appear to be important interactions between mechanisms of salt-sensitive and carbohydrate-sensitive hypertension, the goal of this study was to evaluate the effects of greatly reducing dietary salt intake and removal of one kidney (to increase salt sensitivity) on the hemodynamic and metabolic responses to carbohydrate-enriched diets in three different rat strains. All three strains of laboratory rat developed significant increases in fasting plasma insulin (1-2 fold, p < 0.03) and triglyceride (2-3 fold, p < 0.01) concentrations in response to fructose (or sucrose) enriched diets, irrespective of salt content. Blood pressure increased significantly in response to carbohydrate feeding in both Sprague-Dawley (S-D) and Dahl salt-sensitive rats, but not in Fischer 344 rats, and decreasing salt intake had no effect on the development of carbohydrate-induced hypertension: e.g., delta BP in S-D rats was +20 mmHg after the fructose-0.5% NaCl diet as compared with +19 mmHg after fructose-0.02% NaCl, and delta BP in Dahl salt-sensitive rats was +22 mmHg after fructose-0.02% NaCl. Finally, nephrectomy neither accentuated the degree of hypertension in fructose-fed S-D rats, nor increased blood pressure in fructose-fed Fischer 344 rats. These results emphasize the strain specific characteristics of carbohydrate-induced hypertension in rats, and indicate that the hemodynamic responses of different rat strains to dietary carbohydrate are not modified by either decreasing salt intake or removing one kidney.

    View details for PubMedID 7670650

  • COMPARISON OF THE METABOLIC CHANGES IN RATS WITH HYPERTENSION SECONDARY TO FRUCTOSE FEEDING OR RENAL-ARTERY STENOSIS AMERICAN JOURNAL OF HYPERTENSION DALLAGLIO, E., TOSINI, P., Zavaroni, I., Olivetti, G., Reaven, G. M. 1995; 8 (5): 524-527

    Abstract

    Hypertension was induced in rats by either renal artery stenosis or a fructose-enriched diet, and the consequent changes in plasma glucose, insulin, and triglyceride (TG) concentrations, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a 180-min continuous infusion of glucose and insulin in these two groups of hypertensive rats, were compared to values in a sham-operated group with normal blood pressure. Mean (+/- SEM) blood pressure was significantly higher than the control values (121 +/- 3 mm Hg) at the end of the study in rats with renal artery stenosis (178 +/- 13 mm Hg) and fructose-fed rats (151 +/- 5 mm Hg), whereas left ventricular weight was only significantly (P < .01) higher in rats with renal artery stenosis. Plasma glucose concentration was the same in all three groups, but fructose-fed rats had significantly higher plasma insulin (59 +/- 7 microU/mL) and TG (317 +/- 48 mg/dL) concentration than either sham-operated rats (30 +/- 4 microU/mL and 121 mg/dL) or rats with renal artery stenosis (34 +/- 5 microU/mL and 124 +/- 14 mg/dL). Although SSPI concentrations were similar (approximately 250 microU/mL) in all three groups of rats, SSPG concentrations were significantly higher (P < .01) in the fructose-fed rats (187 +/- 10 mg/dL) than in either sham-operated normotensive rats (120 +/- 6 mg/dL) or hypertensive rats with renal artery stenosis (133 +/- 4 mg/dL). Thus, insulin resistance, hyperinsulinemia, and hypertriglyceridemia developed in rats with fructose-induced hypertension, whereas none of these changes were seen in rats with renal artery stenosis.

    View details for Web of Science ID A1995RA61200014

    View details for PubMedID 7662231

  • POSTPRANDIAL TRIGLYCERIDE AND RETINYL ESTER RESPONSES TO ORAL FAT - EFFECTS OF FRUCTOSE AMERICAN JOURNAL OF CLINICAL NUTRITION Jeppesen, J., CHEN, Y. D., Zhou, M. Y., Schaaf, P., Coulston, A., Reaven, G. M. 1995; 61 (4): 787-791

    Abstract

    It has been shown that addition of fructose to an oral fat load results in higher postprandial concentrations of triglyceride. The present study, performed in 11 healthy volunteers, was initiated to see whether the effect of fructose on fat-induced lipemia also involved changes in postprandial concentrations of triglyceride-rich lipoproteins of intestinal origin. Vitamin A was used to label intestinal lipoproteins, and the retinyl palmitate concentrations were determined in plasma and in the Sf > 400 and Sf 20-400 lipoprotein fractions (Sf denotes the Svedberg flotation index). Addition of fructose (50 g) to a standard (40-g oral) fat load resulted in higher postprandial concentrations of triglyceride and retinyl palmitate in plasma and the Sf > 400 lipoprotein fraction (P < 0.001, analysis of variance), and the higher the fasting plasma triglyceride concentration, the greater the magnitude of the fructose effect (r = 0.83, P < 0.002). These data show that triglyceride-rich lipoproteins of intestinal origin play a role in the fructose-induced accentuation of postprandial lipemia.

    View details for Web of Science ID A1995QQ34200007

    View details for PubMedID 7702020

  • RELATION BETWEEN INSULIN-RESISTANCE, HYPERINSULINEMIA, POSTHEPARIN PLASMA-LIPOPROTEIN LIPASE ACTIVITY, AND POSTPRANDIAL LIPEMIA ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Jeppesen, J., Hollenbeck, C. B., Zhou, M. Y., Coulston, A. M., Jones, C., CHEN, Y. D., Reaven, G. M. 1995; 15 (3): 320-324

    Abstract

    We examined the relation between insulin resistance, plasma glucose and insulin responses to meals, lipoprotein lipase (LPL) activity, and postprandial lipemia in a population of 37 healthy nondiabetic individuals. Plasma glucose and insulin concentrations were determined at frequent intervals from 8 AM through midnight (breakfast at 8 AM and lunch at noon); resistance to insulin-mediated glucose disposal was determined by measuring the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of glucose, insulin, and somatostatin; LPL activity was quantified in postheparin plasma; and postprandial concentrations of triglyceride (TG)-rich lipoproteins were assessed by measuring the TG and retinyl palmitate content in plasma and the Svedberg flotation index (Sf) > 400 and Sf 20 to 400 lipoprotein fractions. Significant simple correlation coefficients were found between various estimates of postprandial lipemia and SSPG (r = .38 to .68), daylong insulin response (r = .37 to .58), daylong glucose response (r = .10 to .39), and LPL activity (r = -.08 to -.58). However, when multiple regression analysis was performed, only SSPG remained independently associated with both postprandial TG and retinyl palmitate concentrations. These data provide evidence that insulin resistance plays an important role in regulating the postprandial concentration of TG-rich lipoproteins, including those of intestinal origin.

    View details for Web of Science ID A1995QL09000004

    View details for PubMedID 7749841

  • MEMBRANE GLYCOPROTEIN PC-1 AND INSULIN-RESISTANCE IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS NATURE Maddux, B. A., Sbraccia, P., Kumakura, S., Sasson, S., Youngren, J., Fisher, A., Spencer, S., Grupe, A., HENZEL, W., Stewart, T. A., Reaven, G. M., Goldfine, I. D. 1995; 373 (6513): 448-451

    Abstract

    Most patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin. Insulin resistance precedes the onset of this disease, suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus, but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity. Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase. Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10, 11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin-dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non-insulin-dependent diabetes mellitus.

    View details for Web of Science ID A1995QE67000062

    View details for PubMedID 7830796

  • TISSUE-DEPENDENT ACTIVATION OF PROTEIN-KINASE-C IN FRUCTOSE-INDUCED INSULIN-RESISTANCE ENDOCRINE Donnelly, R., Chang, H., Azhar, S., Reaven, G. M. 1995; 3 (2): 129-133

    Abstract

    Rats fed a fructose-enriched diet develop increases in blood pressure and resistance to insulin-mediated glucose disposal, but the underlying biochemical alterations have not been clearly defined. Since protein kinase C (PKC) has been implicated in the pathogenesis of insulin resistance, as well as blood pressure (BP) regulation, the present study was initiated to see whether changes in PKC signaling are present in rats with fructose-induced insulin resistance and hypertension. Consequently, liver, muscle, and adipose tissues were collected from fructose (n = 13) and chow (n = 12) fed Sprague-Dawley rats. PKC enzyme activity, and expression of classical PKC isozymes, were measured in cytosol and membrane fractions, and 1, 2-diacylglycerol (DAG), an endogenous stimulator of PKC, was measured by radio-enzymatic assay. Fructose feeding was associated with significant increases in fasting plasma insulin (140%) and triglyceride (400%) levels, and increased BP (20 mmHg). PKC activity was increased in the membrane fraction of adipose tissue (234 ± 38 (SE)vs 85 ± 30 pmol/min/mg protein,P< 0.007), without evidence of increased translocation or activation by DAG. Thus, fructose-induced insulin resistance has no effect on conventional PKC activity and subcellular distribution in liver and muscle, but the 3-fold increase in membraneassociated kinase activity in fat may be relevant to the mechanism of hypertriglyceridemia associated with fructose feeding.

    View details for Web of Science ID A1995QV20700008

    View details for PubMedID 21153149

  • The fourth musketeer--from Alexandre Dumas to Claude Bernard. Diabetologia Reaven, G. M. 1995; 38 (1): 3-13

    Abstract

    Considerations of the pathophysiology of non-insulin dependent diabetes mellitus (NIDDM) usually focus on the respective roles of the so-called triumvirate-beta cell, muscle and liver [1]. Often overlooked in this context is the role of the adipose tissue, and attention is usually addressed to consideration of studies in which isolated adipocytes were used as a surrogate for muscle in studies of insulin action. The goal of this presentation will be to develop a radically different hypothesis, and marshal evidence that it is the loss of normal regulation of adipose tissue that plays the central role in both the hyperglycaemia and the dyslipidaemia that characterizes patients with NIDDM.

    View details for PubMedID 7744226

  • WHY DO LOW-FAT HIGH-CARBOHYDRATE DIETS ACCENTUATE POSTPRANDIAL LIPEMIA IN PATIENT WITH NIDDM DIABETES CARE CHEN, Y. D., Hollenbeck, C. B., Coulston, A. M., Reaven, G. M., Zhou, M. Y. 1995; 18 (1): 10-16

    Abstract

    To understand why low-fat high-carbohydrate (CHO) diets lead to higher fasting and postprandial concentrations of triglyceride (TG)-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM).Patients with NIDDM were placed randomly on diets containing either 55% CHO, 30% fat, and 15% protein or 40% CHO, 45% fat, and 15% protein for 6 weeks, followed by crossover to the other diet. Test meals at the end of each diet period were consumed at 8:00 A.M. and 12:00 P.M. (noon) and contained 20 and 40% of daily calories, respectively. Vitamin A was also given at noon, and TG-rich lipoproteins of intestinal origin were identified by the presence of vitamin A esters. Frequent measurements were made throughout the 24-h study period of plasma glucose, insulin, and TG concentrations. Plasma samples obtained from 12:00 P.M. (noon) until 12 A.M. (midnight) were subjected to ultracentrifugation, and measurements were made of TG and vitamin A ester concentrations in plasma and in both the Svedberg flotation constant (Sf) > 400 (chylomicron) and Sf 20-400 (chylomicron remnant) lipoprotein fractions. In addition, very-low-density lipoprotein (VLDL)-TG turnover rate was estimated by following the decay of [3H]VLDL-TG. Finally, postheparin lipoprotein lipase and hepatic lipase activities were measured at the end of each dietary period.Mean +/- SE hourly concentrations of glucose (8.0 +/- 0.8 vs. 7.5 +/- 0.7 mmol/l), insulin (184 +/- 26 vs. 158 +/- 19 pmol/l), and TG (2.8 +/- 0.2 vs. 2.1 +/- 0.2 mmol/l) were higher (P < 0.05-0.001) after the 55% CHO diet. The 55% CHO diet also led to an increase (P < 0.05-0.01) in the mean +/- SE hourly concentrations of vitamin A esters in plasma (2.3 +/- 0.3 vs. 1.6 +/- 0.1 mumol/l) and in both the chylomicron (2.0 +/- 0.3 vs. 1.4 +/- 0.1 mumol/l) and chylomicron remnant fractions (0.36 +/- 0.04 vs. 0.14 +/- 0.03 mumol/l). In addition, the VLDL-TG production rate was higher (17.2 +/- 1.4 vs. 12.8 +/- 1.0 mg.kg-1.h-1, P < 0.003) and the VLDL-TG fractional catabolic rate lower (0.22 +/- 0.02 to 0.28 +/- 0.02 l/h, P < 0.005) after the 55% CHO diet. Finally, there was an increase in lipoprotein lipase activity (7.0 +/- 0.8 to 8.1 +/- 0.7 mumol free fatty acids released .ml-1.h-1, P < 0.02) in response to the CHO-enriched diet.A low-fat high-CHO diet in patients with NIDDM led to 1) higher day-long plasma glucose, insulin, and TG concentrations; 2) postprandial accumulation of TG-rich lipoproteins of intestinal origin; 3) increased production of VLDL-TG; and 4) increased postheparin lipoprotein lipase activity. These data provide a mechanism for the hypertriglyceridemic effect of CHO-enriched diets in patients with NIDDM and demonstrate that multiple risk factors for coronary heart disease are accentuated when these individuals consume diets recommended to reduce this risk.

    View details for Web of Science ID A1995QG88200002

    View details for PubMedID 7698030

  • EXPRESSION OF THE MAJOR ISOENZYME OF PROTEIN-KINASE-C IN SKELETAL-MUSCLE, NPKC-THETA, VARIES WITH MUSCLE-TYPE AND IN RESPONSE TO FRUCTOSE-INDUCED INSULIN-RESISTANCE ENDOCRINOLOGY Donnelly, R., Reed, M. J., Azhar, S., Reaven, G. M. 1994; 135 (6): 2369-2374

    Abstract

    The ability of insulin to stimulate glucose uptake by skeletal muscle varies as a function of muscle type, but the biochemical mechanisms that regulate insulin-mediated glucose transport under normal conditions and in pathological states of insulin resistance are poorly understood. We evaluated differences in the expression of nPKC theta (the major isoform of protein kinase-C in skeletal muscle) in hind limb muscles of different fiber type composition from normal Sprague-Dawley rats and rats made insulin resistant by feeding a fructose-enriched diet. In total muscle homogenates from normal rats, the amount of nPKC theta per unit total protein quantified by immunoblotting using a specific antipeptide antibody was 2.5 times higher in pure white muscle (tensor fascia latae) compared with red muscle (soleus), with two mixed muscles showing intermediate expression. The development of insulin resistance after a fructose-enriched diet was associated with significant increases in diacylglycerol and nPKC theta mass in the membrane fraction of tensor fascia latae, but fructose feeding had no effect on conventional PKC enzyme activity and immunoreactive protein. Thus, expression of nPKC theta varies as a function of muscle type, and fructose-induced insulin resistance appears to be associated with diacylglycerol-mediated isoenzyme-specific changes in nPKC theta in white muscle.

    View details for Web of Science ID A1994PW23500012

    View details for PubMedID 7988419

  • RELATIONSHIP BETWEEN HEPATIC GLUCOSE-PRODUCTION AND FASTING PLASMA-GLUCOSE CONCENTRATION IN PATIENTS WITH NIDDM DIABETES Jeng, C. Y., Sheu, W. H., Fuh, M. M., CHEN, Y. D., Reaven, G. M. 1994; 43 (12): 1440-1444

    Abstract

    This study was initiated to reevaluate the changes in basal hepatic glucose production (HGP) rate that occur in patients with non-insulin-dependent diabetes mellitus (NIDDM). Measurements were made in 51 volunteers: 18 with normal glucose tolerance and 33 with newly diagnosed NIDDM of varying degrees of severity. To avoid the methodological problems associated with quantifying HGP over short time periods, using non-steady-state isotopic kinetics, radiolabeled glucose was infused for a 12-h period, from 10 P.M. to 10 A.M. with HGP quantified from 9 to 10 A.M.. The results showed that fasting plasma glucose (FPG) concentration and HGP were significantly correlated (r = 0.68, P < 0.001) in patients with NIDDM. However, when the 33 patients with NIDDM were divided into three groups of 11 each on the basis of FPG concentration, it became clear that the relationship between FPG and HGP was complex. Thus, values for HGP in patients with NIDDM and FPG < 180 mg/dl were not higher than in the normal population (1.67 +/- 0.07 vs. 1.69 +/- 0.04 mg.kg-1.min-1, NS). Significant increases (P < 0.01) in HGP above normal were seen in the 11 patients with NIDDM and FPG concentrations between 180 and 250 mg/dl (2.05 +/- 0.07 mg.kg-1.min-1), as well as in those with FPG > 250 mg/dl (2.18 +/- 0.13 mg.kg-1.min-1). Although those with the highest FPG concentrations tended to have the greatest values for HGP, the difference between the latter two groups of patients with NIDDM was not statistically significant. Finally, HGP rates in the 11 patients with FPG concentrations > 250 mg/dl were only 29% higher than values in the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994PV46300009

    View details for PubMedID 7958496

  • ADDITIVE EFFECTS OF OBESITY, HYPERTENSION, AND TYPE-2 DIABETES ON INSULIN-RESISTANCE HYPERTENSION Maheux, P., Jeppesen, J., Sheu, W. H., Hollenbeck, C. B., Clinkingbeard, C., GREENFIELD, M. S., CHEN, Y. D., Reaven, G. M. 1994; 24 (6): 695-698

    Abstract

    Resistance to insulin-mediated glucose disposal has been previously shown to be increased in association with obesity, high blood pressure, and non-insulin-dependent diabetes mellitus. We initiated the present study to quantify the separate effects of hypertension and non-insulin-dependent diabetes mellitus on insulin resistance in both nonobese and obese subjects. To accomplish this, 88 subjects were divided into the following five experimental groups: normal blood pressure, nonobese (n = 17); normal blood pressure, obese (n = 18); high blood pressure, nonobese (n = 18); high blood pressure, obese (n = 19); and high blood pressure, obese, non-insulin-dependent diabetes mellitus (n = 16). Plasma glucose and insulin concentrations were measured before and after a 75-g oral glucose load. Resistance to insulin-mediated glucose disposal was estimated by determining the steady-state plasma insulin and glucose concentrations during the last 30 minutes of a continuous infusion of somatostatin (5 micrograms/min), exogenous insulin (25 mU/m2 per minute), and glucose (240 mg/m2 per minute). Since the steady-state plasma insulin concentrations are similar in all subjects, the higher the steady-state plasma glucose, the more insulin resistant the individual. Nonobese subjects with normal blood pressure had the lowest plasma glucose and insulin responses and steady-state plasma glucose concentrations, and their values were significantly different from the other four groups. Obese or nonobese subjects with high blood pressure had significantly higher plasma glucose responses and steady-state plasma glucose concentrations than did their respective weight-matched control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994PW83700008

    View details for PubMedID 7995625

  • EFFECT OF METFORMIN ON POSTPRANDIAL LIPEMIA IN PATIENTS WITH FAIRLY TO POORLY CONTROLLED NIDDM DIABETES CARE Jeppesen, J., CHEN, Y. D., Zhou, M. Y., Reaven, G. M. 1994; 17 (10): 1093-1099

    Abstract

    To quantify the effect of metformin on the metabolism of triglyceride (TG)-rich lipoprotein of intestinal origin in patients with non-insulin-dependent diabetes mellitus (NIDDM) who had responded to sulfonylurea but still had fasting hyperglycemia.Sixteen patients with NIDDM who had demonstrated a fall in fasting plasma glucose concentration > 2.2 mmol/l in response to glipizide treatment but continued to have fasting plasma glucose concentrations > 8.3 mmol/l were studied. Fasting glucose, GHb, lipid and lipoprotein concentrations were determined, and resistance to insulin-mediated glucose disposal was estimated by measuring the steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of somatostatin, glucose, and insulin. In addition, plasma glucose, insulin, and TG concentrations were measured at frequent intervals from 0800 to 2400, with patients eating breakfast at 0800 and lunch at 1200. Vitamin A was also given at lunch, and the retinyl ester content in plasma and in chylomicron (Svedberg flotation constant [Sf] > 400) and the chylomicron remnant (Sf 20-400) fractions were used to quantify the concentration of postprandial intestinal TG-rich lipoprotein from 1200 to 2400.Fasting plasma glucose concentrations (6.8 +/- 0.4 vs. 10.5 +/- 0.4 mmol/l), GHb levels (7.9 +/- 0.3 vs. 10.8 +/- 0.5%), and day-long plasma glucose concentrations were all significantly lower after metformin treatment (P < 0.001), which was associated with a significant (P < 0.001) fall in SSPG concentration (11.0 +/- 0.9 to 9.6 +/- 0.6 mmol/l). In addition, postprandial concentrations of glucose, insulin, free fatty acids, and TG were lower (P < 0.001) following metformin treatment. Postprandial retinyl ester concentrations were also lower in plasma by 33 +/- 5.7% (P < 0.001) and in both the chylomicron (32 +/- 7.2%, P < 0.001) and chylomicron remnant (26 +/- 7.0%, P < 0.005) fractions.Addition of metformin to sulfonylurea-treated patients with NIDDM with less than optimal glycemic control was associated with improved glycemic control, lower postprandial insulin and TG concentrations, and a decrease in postprandial concentration of TG-rich lipoproteins of intestinal origin. All of these changes might be expected to decrease risk of coronary heart disease.

    View details for Web of Science ID A1994PJ31100001

    View details for PubMedID 7821127

  • Nutritional status modifies insulin-mediated glucose uptake in spontaneously hypertensive rats. Blood pressure PLATO, P. A., Mondon, C. E., Reaven, G. M. 1994; 3 (5): 336-339

    Abstract

    In this study we quantified insulin-mediated glucose uptake in weight-matched (260-330 g) fed (6-8 h fast) and fasted (24 h fast) male rats with spontaneous hypertension (SHR) and control Wistar-Kyoto (WKY) rats. To accomplish this goal, rats were infused continuously for 165 min with glucose and insulin. Blood was taken at frequent intervals from 120-165 min, and the values averaged to determine the steady-state plasma glucose (SSPG) and insulin (SSPI) concentrations. In some studies epinephrine and propranolol were added to the infusate in order to suppress endogenous insulin secretion. Steady-state plasma insulin (SSPI) concentrations were similar in SHR and WKY during the three infusion studies (382-483 pmol/L). However, SSPG was significantly higher in fed SHR as compared to fed WKY during infusions performed with (9.4 +/- 0.8 vs 7.0 +/- 0.4 mmol/L, p < 0.05) or without (8.6 +/- 0.2 vs 7.0 +/- 0.6 mmol/L, p < 0.05) epinephrine and propranolol in the infusate. In contrast, SSPG concentrations (mmol/L) were similar in SHR (6.8 +/- 0.3) and WKY rats (6.5 +/- 0.6) when they were studied after a 24 h fast. These results demonstrates that differences in insulin-mediated glucose removal from plasma between SHR and WKY rats will vary as a function of nutritional status.

    View details for PubMedID 7866599

  • INSULIN-RESISTANCE, COMPENSATORY HYPERINSULINEMIA, AND CORONARY HEART-DISEASE DIABETOLOGIA Reaven, G. M., Laws, A. 1994; 37 (9): 948-952

    View details for Web of Science ID A1994PE39800016

    View details for PubMedID 7806027

  • EFFECT OF GLIPIZIDE TREATMENT ON POSTPRANDIAL LIPEMIA IN PATIENTS WITH NIDDM DIABETOLOGIA Jeppesen, J., Zhou, M. Y., CHEN, Y. D., Reaven, G. M. 1994; 37 (8): 781-787

    Abstract

    The primary goal of the present study was to examine the effects of improved glycaemic control associated with glipizide treatment on postprandial lipaemia in non-insulin-dependent diabetic patients. The metabolism of triglyceride-rich lipoproteins of intestinal origin was assessed by measuring the retinyl palmitate content in plasma and the Svedberg flotation index (Sf) > 400 and Sf 20-400 lipoprotein fractions. Fasting plasma glucose concentrations (14.5 +/- 0.5 vs 9.0 +/- 0.5 mmol/l), glycated haemoglobin levels (13.1 +/- 0.6 vs. 9.7 +/- 0.6%), and daylong plasma glucose concentrations were all significantly lower after glipizide treatment (p < 0.001). The improvement in glycaemic control was associated with increases in insulin-mediated glucose uptake (p < 0.001) and plasma post-heparin lipoprotein and hepatic lipolytic activities (p < 0.02). Both fasting plasma triglyceride (3.09 +/- 0.51 vs 2.37 +/- 0.34 mmol/l), and postprandial triglyceride concentrations (p < 0.05-0.001) were lower following glipizide treatment, associated with a significant fall in retinyl palmitate content in all three lipoprotein fractions (p < 0.02-0.001), with the most substantial decrease seen in the Sf20-400 fraction. These data indicate that glipizide-induced improvement in glycaemic control was associated with changes in the metabolism of triglyceride-rich lipoproteins of intestinal origin that would be anticipated to reduce risk of coronary heart disease in non-insulin-dependent diabetic patients.

    View details for Web of Science ID A1994PA03300008

    View details for PubMedID 7988780

  • EVALUATION OF OCTREOTIDE TO ASSESS INSULIN-MEDIATED GLUCOSE DISPOSAL BY THE INSULIN SUPPRESSION TEST DIABETOLOGIA Pei, D., Jones, C. N., Bhargava, R., CHEN, Y. D., Reaven, G. M. 1994; 37 (8): 843-845

    View details for Web of Science ID A1994PA03300017

    View details for PubMedID 7988789

  • EFFECTS OF GEMFIBROZIL ON TRIGLYCERIDE-METABOLISM IN DAHL SALT-SENSITIVE RATS JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Donnelly, R., PLATO, P. A., Chang, H., Reaven, G. M. 1994; 270 (2): 809-813

    Abstract

    Hypertriglyceridemia is a common feature of patients with increased blood pressure as well as several rodent models of hypertension. The goal of this study was to evaluate the effects of gemfibrozil on established abnormalities of triglyceride (TG) secretion and TG clearance in the Dahl salt-sensitive rat. Consequently, Dahl salt-sensitive rats received 12 days treatment with gemfibrozil (30 mg/kg/day) or vehicle by p.o. gavage and the following measurements were made: 1) fasting plasma TG levels; 2) TG secretion rate after suppression of TG removal with Triton WR 1339; 3) TG removal rate (half-time of disappearance of prelabeled very low density lipoprotein); and 4) lipoprotein lipase (LPL) activity and mRNA in soleus muscle, fat and liver tissues. Gemfibrozil produced a 50% reduction in fasting plasma TG concentrations, with no effect on TG secretion rate (17 +/- 2 vs. 15 +/- 1 mg/100 g b.wt./hr). The half-time of prelabeled very low density lipoprotein-TG removal was significantly lower in drug-treated animals (3.9 +/- 0.3 vs. 6.1 +/- 0.9 min), and this was associated with a tissue-specific increase in LPL activity in soleus muscle (153 +/- 5 vs. 135 +/- 5 U/g, P < .02). Expression of LPL mRNA, relative to beta-actin mRNA, was similar in both groups of rats. Thus, in this rodent model of hypertension and dyslipidemia, gemfibrozil lowers plasma TG levels by 50% with no effect on TG secretion; the hypotriglyceridemic effect is due mainly to an increase in TG removal rate associated with a post-transcriptional increase in LPL activity in skeletal muscle.

    View details for Web of Science ID A1994PD45500053

    View details for PubMedID 8071873

  • METABOLIC RISK-FACTORS FOR ATHEROSCLEROSIS IN HEART-TRANSPLANT RECIPIENTS AMERICAN HEART JOURNAL Kemna, M. S., Valantine, H. A., Hunt, S. A., Schroeder, J. S., CHEN, Y. D., Reaven, G. M. 1994; 128 (1): 68-72

    Abstract

    Development of coronary artery disease (CAD) in the cardiac allograft limits long-term survival after heart transplantation. Previous studies, focusing on lipoprotein metabolism, have paid little attention to changes in glucose and insulin metabolism that increase the risk of CAD in these patients. To address this issue, plasma glucose and insulin responses to an oral glucose load and lipid and lipoprotein concentrations were measured in male normal volunteers (n = 40) and cardiac transplant recipients with pretransplant diagnoses of either idiopathic cardiomyopathy (n = 24) or ischemic heart disease (n = 28), matched for age and body mass index. Patients with a pretransplant diagnosis of ischemic heart disease had higher plasma glucose and insulin concentrations in response to oral glucose as well as higher fasting plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol concentrations than did the control group (p < 0.005 to p < 0.001). In addition, high-density lipoprotein cholesterol concentrations were lower and the ratio of cholesterol to high-density lipoprotein cholesterol higher than control values in those with a pretransplant diagnosis of ischemic heart disease (p < 0.001). Values for almost all variables were intermediate in patients with a pretransplant diagnosis of idiopathic cardiomyopathy and in most instances were significantly different from both. Thus, male cardiac transplant recipients are dyslipidemic, relatively glucose intolerant, and hyperinsulinemic compared to normal volunteers. These changes, observed in patients with a pretransplant diagnosis of either ischemic heart disease or idiopathic cardiomyopathy, emphasize the important role of immunosuppression in the development of metabolic risk factors for CAD in these individuals.

    View details for Web of Science ID A1994NV84000010

    View details for PubMedID 8017286

  • RESISTANCE TO INSULIN-STIMULATED GLUCOSE-UPTAKE AND DYSLIPIDEMIA IN ASIAN INDIANS ARTERIOSCLEROSIS AND THROMBOSIS Laws, A., JEPPESEN, J. L., MAHEUX, P. C., Schaaf, P., CHEN, Y. D., Reaven, G. M. 1994; 14 (6): 917-922

    Abstract

    Persons from the Indian subcontinent have elevated coronary heart disease risk. We measured insulin resistance with the insulin suppression test in 22 Asian Indian men and women and an equal number of control subjects of European ancestry matched for age and body mass index. Asian men and women had increased glucose and insulin responses to oral glucose tolerance tests (P < .05 by ANOVA) and had approximately 60% higher steady-state plasma glucose levels during the insulin suppression test (P < .001 by ANOVA), consistent with insulin resistance. In response to mixed meals, Asian women had higher plasma free fatty acids and glycerol concentrations than women of European ancestry (P < .02 by ANOVA), whereas Asian Indian men had similar free fatty acid and glycerol levels compared with men of European ancestry despite higher plasma insulin levels. Thus, results in both sexes were consistent with resistance to insulin suppression of free fatty acid levels in Asian Indians. Asian Indians of both sexes had higher fasting plasma triglyceride (P < .01) and lower high-density lipoprotein cholesterol (P < .01) concentrations than men and women of European ancestry. Resistance to insulin-stimulated glucose uptake and to insulin suppression of free fatty acid levels in Asian Indians is associated with a number of metabolic abnormalities that are demonstrated risk factors for coronary heart disease, including increased glucose, insulin, and triglyceride concentrations and decreased high-density lipoprotein cholesterol concentrations.

    View details for Web of Science ID A1994NQ53600009

    View details for PubMedID 8199182

  • EFFECTS OF VARYING CARBOHYDRATE CONTENT OF DIET IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Garg, A., Bantle, J. P., Henry, R. R., Coulston, A. M., Griver, K. A., Raatz, S. K., Brinkley, L., CHEN, Y. D., Grundy, S. M., Huet, B. A., Reaven, G. M. 1994; 271 (18): 1421-1428

    Abstract

    To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM).A four-center randomized crossover trial.Outpatient and inpatient evaluation in metabolic units.Forty-two NIDDM patients receiving glipizide therapy.A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks.Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels.The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks.In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable.

    View details for Web of Science ID A1994NJ69300030

    View details for PubMedID 7848401

  • Salt-sensitive and carbohydrate-sensitive rodent hypertension: evidence of strain differences. Blood pressure Reed, M. J., Ho, H., Donnelly, R., Reaven, G. M. 1994; 3 (3): 197-201

    Abstract

    It is well-established that diets enriched either with salt or simple sugars are associated with variable increases in blood pressure, but the interrelationship between carbohydrate- and salt-sensitive hypertension has received comparatively little attention. The effects of varying salt intake on blood pressure responses to a fructose-enriched diet were examined in a variety of common laboratory rat strains. Sprague-Dawley, Fischer 344, and Wistar rats were placed on diets enriched in fructose, salt, or a combination of both for 12 days. Measurements of blood pressure (tail-cuff) and fasting plasma insulin concentrations were recorded before and after dietary intervention. In response to the fructose-enriched diet (normal salt), all strains developed a significant increase in plasma insulin (1-2 fold, p < 0.05). However, only Sprague-Dawley rats showed an increase in blood pressure in response to the fructose-enriched diet (21 mmHg, p < 0.05). A high salt diet increased blood pressure only in Fischer 344 rats (10 mmHg, p < 0.05), but the combination of high fructose and high salt increased blood pressure significantly in both Fischer 344 and Wistar rats (mean of 19 mmHg, p < 0.05). In conclusion, the ability of a fructose-enriched diet to increase blood pressure varies as a function of strain, and can be modulated by changes in salt intake.

    View details for PubMedID 8069409

  • HYPERTRIGLYCERIDEMIC MICE TRANSGENIC FOR THE HUMAN APOLIPOPROTEIN C-III GENE ARE NEITHER INSULIN-RESISTANT NOR HYPERINSULINEMIC JOURNAL OF LIPID RESEARCH Reaven, G. M., Mondon, C. E., CHEN, Y. D., Breslow, J. L. 1994; 35 (5): 820-824

    Abstract

    Plasma glucose and insulin concentrations and in vivo and in vitro estimates of insulin action were compared in hypertriglyceridemic apolipoprotein C-III transgenic mice (mean +/- SE triglyceride concentration = 11.8 +/- 0.9 mmol/l) and their normotriglyceridemic (1.1 +/- 0.1 mmol/l) littermates. There were no differences in the glucose (8.9 +/- 0.2 vs. 9.3 +/- 0.5 mmol/l) or insulin (172 +/- 21 vs. 203 +/- 17 pmol/l) concentrations of the transgenic and control mice, respectively. Steady-state plasma glucose concentrations at the end of a 150-min period of physiological hyperinsulinemia were also similar in transgenic (6.2 +/- 0.5 mmol/l) and control mice (6.7 +/- 0.5 mmol/l). As the steady-state plasma insulin levels were essentially identical in the two groups (approximately 1000 pmol/l), these results show that whole body insulin-mediated glucose disposal was unchanged in the transgenic mice. Finally, values for isoproterenol-stimulated lipolysis, insulin-inhibition of lipolysis, and insulin-stimulated glucose disposal were similar in adipocytes isolated from transgenic and control mice. It can be concluded from these data that insulin resistance does not develop in hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene.

    View details for Web of Science ID A1994NL01700008

    View details for PubMedID 8071604

  • CHANGES IN GLUCOSE, INSULIN, LIPID, LIPOPROTEIN, AND APOPROTEIN CONCENTRATIONS AND INSULIN ACTION IN DOXAZOSIN-TREATED PATIENTS WITH HYPERTENSION - COMPARISON BETWEEN NONDIABETIC INDIVIDUALS AND PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS AMERICAN JOURNAL OF HYPERTENSION Maheux, P., Facchini, F., Jeppesen, J., GREENFIELD, M. S., Clinkingbeard, C., CHEN, Y. D., Reaven, G. M. 1994; 7 (5): 416-424

    Abstract

    Thirty patients with hypertension were enrolled in this study, 13 had non-insulin-dependent diabetes mellitus (NIDDM) and 17 were nondiabetic. Patients were treated with doxazosin for approximately 4 months, and blood pressure fell significantly (P < .001) in both nondiabetics (149/96 to 134/85 mm Hg) and in those with NIDDM (154/96 to 143/84 mm Hg). In the nondiabetic group, doxazosin treatment was associated with significant improvement in insulin-mediated glucose disposal (P < .05) and lower plasma insulin (P < .001), and triglyceride (P < .001) concentrations measured at hourly intervals from 8 AM to 4 PM (breakfast at 8 AM and lunch at noon). In addition, fasting total plasma (P < .001) and VLDL cholesterol (P < .01), and total plasma (P < .05), VLDL (P < .08), LDL (P < .01), HDL (P < .01) triglyceride concentrations were lower following doxazosin treatments in the nondiabetic group, as was the ratio of total to HDL cholesterol (P < .001). Finally, apoprotein B concentrations fell with doxazosin in the nondiabetic group (P < .01). Significant changes seen in the group with NIDDM included a decrease in the ratio of total to HDL cholesterol (P < .001) and a fall in apoprotein B concentration (P < .05). However, values for all other variables did not change significantly with treatment in this group. Thus, doxazosin treatment of nondiabetic subjects with high blood pressure was associated with a series of changes in glucose, insulin, and lipoprotein metabolism that should decrease risk of coronary heart disease (CHD) in these individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994NL62500006

    View details for PubMedID 8060574

  • LIGHT-TO-MODERATE ALCOHOL INTAKE IS ASSOCIATED WITH ENHANCED INSULIN SENSITIVITY DIABETES CARE Facchini, F., CHEN, Y. D., Reaven, G. M. 1994; 17 (2): 115-119

    Abstract

    To test the hypothesis that insulin-mediated glucose uptake is enhanced in light-to-moderate alcohol consumption.This is a case-control study of healthy volunteers, divided into nondrinkers and light-to-moderate drinkers based on their history of alcohol consumption. The study was performed at the General Clinical Research Center at Stanford University Medical Center and involved 40 volunteers, 20 men and 20 women. Measurements were made of the plasma glucose and insulin responses to an oral glucose challenge, fasting plasma lipid and lipoprotein concentrations, and steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations in response to a continuous infusion of somatostatin, insulin, and glucose.Light-to-moderate drinkers (10-30 g/day) had lower integrated plasma glucose (17.8 +/- 0.8 vs. 19.8 +/- 0.9 mM/h, P < 0.02) and insulin (600 +/- 65 vs. 1,075 +/- 160 pM/h, P < 0.01) responses to the glucose challenge and higher fasting plasma high-density lipoprotein (HDL) cholesterol concentrations (1.46 +/- 0.08 vs. 1.25 +/- 0.08, P < 0.02). Despite similar SSPI concentrations of approximately 300 pM, SSPG concentrations were lower (P < 0.01) in light-to-moderate drinkers (6.7 +/- 0.8 vs. 10.7 +/- 1.2 mM). Results were independent of age, body mass index, ratio of waist-to-hip girth, and estimates of level of habitual physical activity.Light-to-moderate alcohol consumption in healthy men and women is associated with enhanced insulin-mediated glucose uptake, lower plasma glucose and insulin concentrations in response to oral glucose, and a higher HDL-cholesterol concentration. The changes in glucose and insulin metabolism may contribute to the lower risk of coronary heart disease described in light-to-moderate drinkers.

    View details for Web of Science ID A1994MT06200002

    View details for PubMedID 7907975

  • EFFECT OF PRAVASTATIN TREATMENT ON GLUCOSE, INSULIN, AND LIPOPROTEIN METABOLISM IN PATIENTS WITH HYPERCHOLESTEROLEMIA AMERICAN HEART JOURNAL Sheu, W. H., Shieh, S. M., SHEN, D. D., Fuh, M. M., Jeng, C. Y., CHEN, Y. D., Reaven, G. M. 1994; 127 (2): 331-336

    Abstract

    Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.

    View details for Web of Science ID A1994MV48300012

    View details for PubMedID 8296701

  • Syndrome X: 6 years later. Journal of internal medicine. Supplement Reaven, G. M. 1994; 736: 13-22

    Abstract

    Resistance to insulin-stimulated glucose uptake is a common phenomenon, occurring in approximately 25% of the population at large, and is associated with a number of conditions known to be risk factors for coronary heart disease (CHD). These include hyperinsulinaemia, abnormal glucose tolerance, non-insulin-dependent diabetes mellitus, increased plasma triglyceride and decreased high-density-lipoprotein cholesterol concentrations, smaller, denser low-density-lipoprotein particles, hypertension, and abnormalities of fibrinolysis. These abnormalities frequently occur in a cluster within individuals. Understanding the basis of these changes, as well as the interrelationships between them, will contribute substantially to future studies of the causes of CHD, and ultimately form the basis for the clinical management of insulin-resistant individuals.

    View details for PubMedID 7986303

  • VERBAL-LEARNING AND OR MEMORY IMPROVES WITH GLYCEMIC CONTROL IN OLDER SUBJECTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF THE AMERICAN GERIATRICS SOCIETY GRADMAN, T. J., Laws, A., Thompson, L. W., Reaven, G. M. 1993; 41 (12): 1305-1312

    Abstract

    To determine whether cognitive function improves with improved glycemic control in older subjects with non-insulin-dependent diabetes (NIDDM). We hypothesized that with improved glycemic control: 1) learning and memory, 2) attention, and 3) complex perceptual-motor function would improve, but that 4) simple perceptual-motor function would not.Non-randomized control trial.Aging Study Unit, Department of Veterans Affairs Medical Center.Thirty subjects with NIDDM; 17 on oral hypoglycemic agents; 13 untreated at study entry. Thirteen normal controls.Subjects on oral hypoglycemic agents were taken off medications. After 1 month, they and previously untreated subjects began treatment with glipizide. Dose was titrated up weekly until fasting plasma glucose was less than 7.8 mmol/L or maximal dose (40 mg/day). Controls received no medication.Fasting plasma glucose (FPG), glycated hemoglobin, and measures of cognitive function in four general categories: 1) learning and memory, 2) ability to sustain attention, 3) complex perceptual-motor function, and 4) simple perceptual-motor function. All were evaluated in subjects with NIDDM at baseline (T1), after 1-month washout (T2), and after 2 (T3) and 4 months (T4) of optimal glycemic control or maximal dose. Controls were evaluated at the same intervals.FPG and glycated hemoglobin rose in previously treated subjects from T1 to T2 (9.4 +/- SEM 0.4 to 14.7 +/- 0.7 mmol/L and 10.9 +/- 0.7% to 12.2 +/- 0.6%, respectively) but were unchanged in previously untreated subjects (11.3 +/- 0.6 to 11.8 +/- 0.9 mmol/L and 10.9 +/- 0.7% to 11.7 +/- 0.7%). With glipizide treatment, there was a decrease in FPG level at T3 (9.4 +/- 0.5 mmol/L in previously treated, 6.9 +/- 0.4 mmol/L in previously untreated), which persisted at T4. Glycated hemoglobin fell similarly. FPG and glycated hemoglobin were unchanged in controls. As hypothesized, learning and memory improved over time with treatment in both groups of subjects but was unchanged in controls (P < 0.05). Detailed analysis indicated that the improvement occurred primarily in the learning of verbal material. Contrary to hypothesis, attention and complex perceptual-motor function did not show improvement. As expected, simple perceptual-motor function did not show any improvement with treatment.The results are consistent with previous findings that poor glycemic control in older subjects with NIDDM is associated with decreased cognitive functioning, and suggest that verbal learning and memory may improve with improved glycemic control.

    View details for Web of Science ID A1993MK55900004

    View details for PubMedID 8227912

  • METABOLIC AND BEHAVIORAL COVARIATES OF HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL AND TRIGLYCERIDE CONCENTRATIONS IN POSTMENOPAUSAL WOMEN JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Laws, A., King, A. C., Haskell, W. L., Reaven, G. M. 1993; 41 (12): 1289-1294

    Abstract

    To determine predictors of high-density lipoprotein cholesterol (HDL) and triglyceride (TG) concentrations in postmenopausal women.Cross-sectional study.Clinical research facility.One hundred twenty-seven healthy, relatively sedentary, postmenopausal women not on estrogen replacement, mean age 57 years.Alcohol intake, cigarette smoking, aerobic fitness (VO2max), body mass index (BMI), percent body fat, waist-hip ratio, lipids and lipoproteins, fasting plasma glucose (FPG), and insulin (FPI) concentrations.In univariate analyses, HDL was significantly (P < 0.05) inversely related to BMI, waist-hip ratio, smoking, FPG, and FPI, and directly related to VO2max and alcohol intake. Triglycerides were related directly to BMI, waist-hip ratio, percent body fat, FPG, and FPI, and inversely to VO2max. In stepwise multiple regressions, BMI, waist-hip ratio, alcohol, smoking, and FPG were significantly associated with HDL (R2 for the model = 0.43). Addition of TG to these models reduced relations of BMI and waist-hip ratio, but not the other variables, to insignificance. For triglycerides, waist-hip ratio, alcohol, smoking, FPG, and FPI were significant predictors (R2 = 0.33). VO2max and percent body fat did not contribute to any model.Obesity, abdominal obesity, smoking, alcohol intake, and measures of carbohydrate metabolism predict HDL and triglyceride concentrations in postmenopausal women.

    View details for Web of Science ID A1993MK55900001

    View details for PubMedID 8227909

  • EVIDENCE FOR LINKAGE OF THE APOLIPOPROTEIN-A-II LOCUS TO PLASMA APOLIPOPROTEIN-A-II AND FREE FATTY-ACID LEVELS IN MICE AND HUMANS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Warden, C. H., Daluiski, A., Bu, X. D., PURCELLHUYNH, D. A., DEMEESTER, C., Shieh, B. H., Puppione, D. L., Gray, R. M., Reaven, G. M., CHEN, Y. D., Rotter, J. I., Lusis, A. J. 1993; 90 (22): 10886-10890

    Abstract

    Although it has been hypothesized that the synteny between mouse and human genes provides an approach to the localization of genes that determine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipoprotein A-II (apoAII) and free fatty acid (FFA) levels. ApoAII is the second most abundant protein of high density lipoprotein particles, but its function remains largely unknown. We now show that, in a backcross between strains Mus spretus and C57BL/6J, apoAII levels correlate with plasma FFA concentrations on both chow (P < 0.0001) and high-fat (P < 0.0003) diets and that apoAII levels are linked to the apoAII gene (P < 0.0002). To test whether variations of the apoAII gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease. The segregation of the apoAII gene was followed by using an informative simple sequence repeat in the second intron of the gene and two nearby genetic markers. Robust sib-pair linkage analysis was performed on members of these families using the SAGE linkage programs. The results suggest linkage between the human apoAII gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with plasma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linkage with a gene controlling FFA levels (P = 0.003). Evidence for nonrandom segregation was seen with markers as far as 6-12 centimorgans from the apoAII structural locus. These data provide evidence, in two species, that the apoAII gene is linked to a gene that controls plasma apoAII levels and that apoAII influences, by an unknown mechanism, plasma FFA levels. The results illustrate the utility of animal studies for analysis of complex traits.

    View details for Web of Science ID A1993MH32200098

    View details for PubMedID 8248186

  • Role of insulin resistance in the pathophysiology of non-insulin dependent diabetes mellitus. Diabetes/metabolism reviews Reaven, G. M. 1993; 9: 5S-12S

    View details for PubMedID 8299489

  • INSULIN-RESISTANCE AND RISK-FACTORS FOR CORONARY HEART-DISEASE BAILLIERES CLINICAL ENDOCRINOLOGY AND METABOLISM Laws, A., Reaven, G. M. 1993; 7 (4): 1063-1078

    Abstract

    In this presentation an effort has been made to review the impact of resistance to insulin-mediated glucose uptake and/or hyperinsulinaemia on various metabolic end-points and clinical syndromes. Insulin resistance is present in the great majority of patients with states of glucose intolerance, but frank decompensation of glucose homoeostasis does not occur if individuals can maintain a state of compensatory hyperinsulinaemia. Although compensatory hyperinsulinaemia may prevent the development of NIDDM in insulin-resistant individuals, there is substantial evidence that insulin resistance and/or hyperinsulinaemia is associated with higher plasma concentrations of triglyceride, uric acid and plasminogen activator inhibitor 1 and with lower HDL cholesterol concentrations. Obesity, decreased physical activity and possibly cigarette smoking accentuate the degree of insulin resistance and its manifestations, and a genetic basis is also involved. Resistance to insulin-mediated glucose uptake and/or hyperinsulinaemia have been shown to be associated with high blood pressure, microvascular angina and CHD. Thus, resistance to insulin-mediated glucose uptake is a common phenomenon, which makes a major contribution to the aetiology and clinical course of common and serious diseases. Based on the above considerations, it is difficult to over-emphasize the health-related implication of a defect in insulin-mediated glucose uptake.

    View details for Web of Science ID A1993MF26900010

    View details for PubMedID 8304913

  • INSULIN-RESISTANCE AND INSULIN-SECRETION ARE DETERMINANTS OF ORAL GLUCOSE-TOLERANCE IN NORMAL INDIVIDUALS DIABETES Reaven, G. M., Brand, R. J., CHEN, Y. D., Mathur, A. K., Goldfine, I. 1993; 42 (9): 1324-1332

    Abstract

    Plasma glucose values after oral glucose challenge vary widely in nondiabetic subjects. We have now evaluated the role of insulin resistance in determining the plasma glucose response to oral glucose in 74 volunteer subjects with normal glucose tolerance. In these subjects, we determined the plasma glucose and insulin responses over a 3-h period to a 75-g oral glucose challenge, and the steady-state plasma glucose concentration during a continuous infusion of somatostatin, glucose, and insulin (a quantitative measure of insulin resistance). The plasma glucose response was defined as the incremental increase in plasma glucose concentration above the fasting value for 3 h after the oral glucose challenge. Multiple regression analysis was used to define the relationship between the dependent variable (plasma glucose response) and various predictors of this response. These analyses indicated that both the steady-state plasma glucose and the incremental insulin response during the first 30 min after the glucose load were significant predictors of the plasma glucose response. In those individuals in whom insulin action was impaired and the 30-min plasma insulin response was decreased, plasma glucose values reached higher levels. When standardized regression coefficients were determined, the incremental glucose response was directly correlated with steady-state plasma glucose (r = 0.700, P < 0.001) and inversely with the insulin response during the first 30 min (r = 0.268, P = 0.023). Furthermore, the correlation between steady-state plasma glucose and glucose response was significantly greater (P < 0.005) than that between the glucose response and 30-min insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993LU54200015

    View details for PubMedID 8349044

  • RELATION OF PLASMA TRIGLYCERIDE AND APO-B LEVELS TO INSULIN-MEDIATED SUPPRESSION OF NONESTERIFIED FATTY-ACIDS - POSSIBLE EXPLANATION FOR SEX-DIFFERENCES IN LIPOPROTEIN PATTERN ARTERIOSCLEROSIS AND THROMBOSIS McKeigue, P. M., Laws, A., Chen, Y. D., Marmot, M. G., Reaven, G. M. 1993; 13 (8): 1187-1192

    Abstract

    To test whether a sex difference in insulin-mediated suppression of nonesterified fatty acids (NEFAs) could account for sex differences in plasma triglyceride levels, we studied 632 normoglycemic men and women of European and South Asian descent aged 40 to 69 years. Mean fasting NEFA levels were 19% higher in women than in men. Between fasting and 2 hours after a 75-g oral glucose load, NEFA levels fell by 69% in women and 55% in men, so that mean NEFA levels at 2 hours after loading were 19% lower in women than in men. Plasma triglyceride and apolipoprotein B levels were correlated with 2-hour NEFA levels in each sex and ethnic group, and these associations were independent of glucose, insulin, and central obesity. These results are consistent with experimental studies of the effects of insulin and NEFAs on hepatic production of triglycerides and apolipoprotein B. Suppression of NEFA levels in response to insulin is greater in women than in men, and this may account for some of the sex differences in lipoprotein pattern and coronary heart disease risk.

    View details for Web of Science ID A1993LQ68400007

    View details for PubMedID 8343493

  • WHY DOES INSULIN-RESISTANCE DEVELOP DURING MATURATION JOURNALS OF GERONTOLOGY Reed, M. J., Reaven, G. M., Mondon, C. E., Azhar, S. 1993; 48 (4): B139-B144

    Abstract

    We compared skeletal muscle glucose uptake between young and mature rats. Hindlimb perfusions at insulin concentrations of 0, 100, 250, or 10,000 microU/mL were performed on male Sprague-Dawley rats at 5 weeks or 4 months of age. Basal glucose uptake, and glucose uptake at all insulin concentrations were significantly lower in the 4-month-old mature rats (p < .05). This difference was most pronounced at maximally stimulating insulin concentrations. Skeletal muscle insulin receptor binding, autophosphorylation, and tyrosine kinase activity did not differ between young and mature rats. Surprisingly, GLUT-4 glucose transporter content was significantly higher in several muscles of the mature rats (p < .05). Therefore, the decline in insulin-stimulated glucose uptake in hindlimbs of mature rats cannot be explained by decreased activity of these steps in the glucose transport system.

    View details for Web of Science ID A1993LL26100020

    View details for PubMedID 8315217

  • PLASMA LACTATE CONCENTRATION IN OBESITY AND TYPE-2 DIABETES DIABETES & METABOLISM CHEN, Y. D., VARASTEH, B. B., Reaven, G. M. 1993; 19 (4): 348-354

    Abstract

    The purpose of this study was three-fold: 1) to define the effects of obesity and Type 2 diabetes on plasma lactate concentrations; 2) to relate changes in plasma lactate concentration to plasma glucose and insulin concentrations; and 3) to evaluate the effect of differences in blood sample processing on plasma lactate determination in a disparate population group. To accomplish this, fasting plasma lactate concentrations were determined in 30 volunteers (10 non-obese individuals with normal glucose tolerance, 10 obese individuals with Type 2 diabetes) on blood drawn, processed, and maintained in a variety of ways. Results demonstrated that fasting plasma lactate measurements were least confounded when blood was drawn without the subject "hand pumping" following venous occlusion, the samples maintained on ice at 4 degrees C until precipitated with perchloric acid, and kept as this temperature until lactate concentration was determined. Under these conditions, plasma lactate concentration was lowest in the non-obese group with normal glucose tolerance (0.81 +/- 0.07 mmol/L), highest in the obese subjects with Type 2 diabetes (1.46 +/- 0.14 mmol/L), and intermediate in obese individuals with normal glucose tolerance (1.17 +/- 0.13 mmol/L). All three groups were significantly different from each other. In addition plasma lactate concentrations were associated with both fasting plasma glucose and glycated haemoglobin concentrations.

    View details for Web of Science ID A1993ML49300004

    View details for PubMedID 8293860

  • INSULIN-RESISTANCE AND HYPERINSULINEMIA IN INDIVIDUALS WITH SMALL, DENSE, LOW-DENSITY-LIPOPROTEIN PARTICLES JOURNAL OF CLINICAL INVESTIGATION Reaven, G. M., CHEN, Y. D., Jeppesen, J., Maheux, P., Krauss, R. M. 1993; 92 (1): 141-146

    Abstract

    Subjects characterized by a predominance of small LDL particles (pattern B) have changes in plasma triglyceride (TG) and HDL-cholesterol concentrations consistent with the presence of resistance to insulin-mediated glucose uptake. To pursue this issue, plasma glucose and insulin responses to oral glucose, insulin-mediated glucose disposal, and lipoprotein concentrations were measured in subjects categorized on the basis of LDL peak diameter measured by gradient gel electrophoresis. Subjects with pattern B had higher (P < 0.05-0.001) total integrated plasma glucose (20.7 +/- 1.0 mmol/liter.h) and insulin (1,743 +/- 293 pmol/liter.h) responses to oral glucose compared with glucose (16.3 +/- 0.4 and 19.2 +/- 0.8 mmol/liter.h) and insulin (856 +/- 60 and 1,222 +/- 168 pmol/liter.h) responses in those with either pattern A or an intermediate pattern. Pattern B individuals were shown to be more insulin resistant on the basis of higher steady state plasma glucose concentrations (SSPG, 10.4 +/- 1.0, P < 0.002, vs. 7.5 +/- 0.7 and 6.0 +/- 0.4 mmol/liter) after a constant infusion of somatostatin, glucose, and insulin than those with either the intermediate or pattern A subclass. Pattern B subjects also had higher concentrations of (P < 0.001) TG (1.98 +/- 0.15 vs. 1.33 +/- 0.17 and 0.77 +/- 0.05 mmol/liter) and lower (P < 0.01-0.001) HDL cholesterol (1.12 +/- 0.06 vs. 1.34 +/- 0.05 vs. 1.45 +/- 0.05 mmol/liter) than those with either the intermediate or pattern A. Finally, significant (P < 0.001) correlation coefficients existed between LDL diameter and SSPG (r = -0.44); glucose (r = -0.41) and insulin (r = -0.38) responses; TG (r = -0.65) and HDL-cholesterol (r = 0.42) concentrations; and systolic (r = -0.34) and diastolic (r = -0.34) blood pressure. Thus, pattern B subjects are insulin resistant, have higher glucose, insulin, and TG, lower HDL-cholesterol levels, and higher blood pressure than those with pattern A or intermediate.

    View details for Web of Science ID A1993LL77300019

    View details for PubMedID 8325978

  • Clinical review 43: Treatment of hypertension: focus on prevention of coronary heart disease. journal of clinical endocrinology and metabolism Reaven, G. M. 1993; 76 (3): 537-540

    View details for PubMedID 8445007

  • MECHANISM OF HYPERTRIGLYCERIDEMIA IN DAHL RATS HYPERTENSION Mondon, C. E., PLATO, P. A., DALLAGLIO, E., Sztalryd, C., Reaven, G. 1993; 21 (3): 373-379

    Abstract

    Plasma triglyceride concentrations were shown to be higher in hypertensive (153 +/- 2 mm Hg) male Dahl salt-sensitive rats than in control Sprague-Dawley rats (122 +/- 2 mm Hg). These differences in triglyceride concentrations were seen when blood was drawn at 9 AM from unfasted animals (229 +/- 27 versus 111 +/- 8 mg/dL), at 1 PM after a 4-hour fast (186 +/- 13 versus 88 +/- 4 mg/dL), or at 9 AM after a 13-hour fast (151 +/- 6 versus 90 +/- 6 mg/dL), all p < 0.001. Total triglyceride secretion was also compared in groups of rats by determining the increment in plasma triglyceride concentration for 2 hours after blocking triglyceride removal from plasma by injecting Triton. Studies performed at 1 PM and 9 AM, after the 4- and 13-hour fast, demonstrated that total triglyceride secretion was greater (p < 0.05) in Dahl rats only when studied at 1 PM. Direct estimates of hepatic triglyceride secretion at 1 PM also demonstrated a significant (p < 0.02) increase in secretion rate by perfused livers from Dahl rats, due in part to their increased liver size. In addition, removal of prelabeled very low density lipoprotein-triglyceride in the intact rat was significantly (p < 0.05) decreased in Dahl rats. Lipoprotein lipase activity measured in skeletal muscle, heart, and adipose tissue was also significantly decreased at 9 AM and 1 PM (after 0 and 4 hours of fasting) in tissue from Dahl rats. These data confirm that Dahl rats have higher plasma triglyceride concentrations than Sprague-Dawley rats. Since both total and hepatic triglyceride secretion were somewhat greater in Dahl rats, in association with a decrease in both removal of very low density lipoprotein from plasma and decreased muscle and adipose tissue lipoprotein lipase activity, it seems likely that hypertriglyceridemia in Dahl rats results from a combination of increased triglyceride secretion and decreased triglyceride removal.

    View details for Web of Science ID A1993KQ78900017

    View details for PubMedID 8478046

  • EFFECT OF VARIATIONS IN DIETARY-FAT AND CARBOHYDRATE INTAKE ON POSTPRANDIAL LIPEMIA IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM CHEN, Y. D., Swami, S., Skowronski, R., Coulston, A. M., Reaven, G. M. 1993; 76 (2): 347-351

    Abstract

    The effect of dietary composition on concentrations of postprandial lipoproteins was studied in eight sulfonylurea-treated patients with noninsulin dependent diabetes mellitus. Two diets were consumed by each patient for 2 weeks in random order, one contained (as percent of total calories) 15% protein, 40% fat, and 45% carbohydrate (CHO), whereas the other consisted of 15% protein, 25% fat, and 60% CHO. At the end of each dietary period, patients were given Vitamin A (60,000 U/m2) with their noon meal, and the concentration of triglyceride (TG) and retinyl esters in plasma and two lipoprotein fractions (Sf > 400 and Sf 20-400) determined over the next 12 h. The results indicated that both postprandial TG and retinyl ester concentrations were higher in plasma (Sf > 400, and Sf 20-400 lipoproteins), when patients ate the 25% fat/60% CHO diet. Thus, replacing saturated fat with CHO accentuates the magnitude of postprandial lipemia. Since TG-rich lipoproteins may be atherogenic, appropriate dietary advice for patients with type 2 diabetes may deserve reappraisal.

    View details for Web of Science ID A1993KM44500016

    View details for PubMedID 8432777

  • DIFFERENCES IN POSTPRANDIAL LIPEMIA BETWEEN PATIENTS WITH NORMAL GLUCOSE-TOLERANCE AND NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM CHEN, Y. D., Swami, S., Skowronski, R., Coulston, A., Reaven, G. M. 1993; 76 (1): 172-177

    Abstract

    In this paper we have compared the postprandial increase in triglyceride (TG) rich lipoproteins of intestinal origin in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) and 10 subjects with normal glucose tolerance. The two groups were matched for age, sex distribution, body mass index, and plasma TG concentration. Breakfast was consumed at 0800 h and lunch at 1200 h, at which time vitamin A was also administered. Blood was sampled frequently from 1200 h to 2400 h, and measurements made of glucose, insulin, and TG concentrations. Furthermore, the retinyl palmitate (RP) content of plasma, the Sf > 400 lipoprotein fraction, and the Sf 20-400 lipoprotein fraction was also determined, and differences compared by two-way analysis of variance. Fasting and postprandial (from 1200 h to 2400 h) TG concentrations in the plasma and the two lipoprotein fractions were not significantly different in normal subjects and patients with NIDDM. In addition, the postprandial RP concentration of the two groups was not different in the chylomicron containing Sf > 400 lipoprotein fraction. However, the postprandial Sf 20-400 RP concentration was significantly higher (P < 0.001) in patients with NIDDM, estimated as hourly values over time, peak value, or total integrated response area. Significant correlation coefficients (r = 0.60-0.75, P < 0.08 < 0.02) were seen in patients with NIDDM between the total integrated insulin response and both the TG and RP responses in the Sf > 400 and Sf 20-400 fractions. In addition, fasting high density lipoprotein-cholesterol concentration in patients with NIDDM was significantly correlated with the postprandial TG response in the Sf > 400 (r = -0.64, P < 0.05) and the Sf 20-400 (r = -0.68, P < 0.05) lipoprotein fractions. In summary, the postprandial RP concentration in the Sf 20-400 lipoprotein fraction was higher than normal in patients with NIDDM. In addition, associations have been defined in patients with NIDDM between postprandial insulin response, fasting TG and high density lipoprotein-cholesterol concentrations, and magnitude of postprandial increase in TG-rich lipoproteins of intestinal origin.

    View details for Web of Science ID A1993LB52400033

    View details for PubMedID 8421086

  • ROLE OF INSULIN RESISTANCE IN HUMAN-DISEASE (SYNDROME-X) - AN EXPANDED DEFINITION ANNUAL REVIEW OF MEDICINE Reaven, G. M. 1993; 44: 121-131

    Abstract

    Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.

    View details for Web of Science ID A1993KW47800011

    View details for PubMedID 8476236

  • Are triglycerides important as a risk factor for coronary disease? Heart disease and stroke : a journal for primary care physicians Reaven, G. M. 1993; 2 (1): 44-48

    View details for PubMedID 8149087

  • PLASMA-INSULIN, C-PEPTIDE, AND PROINSULIN CONCENTRATIONS IN OBESE AND NONOBESE INDIVIDUALS WITH VARYING DEGREES OF GLUCOSE-TOLERANCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Reaven, G. M., CHEN, Y. D., Hollenbeck, C. B., Sheu, W. H., Ostrega, D., Polonsky, K. S. 1993; 76 (1): 44-48

    Abstract

    Conventional immunoassays to quantify insulin concentration do not differentiate between insulin and proinsulin. Thus, previous conclusions as to the relationship between the development of hyperglycemia in patients with noninsulin-dependent diabetes mellitus (NIDDM) and pancreatic insulin secretory function may have been confounded by not being able to determine the contribution made by plasma proinsulin to the putative measurements of plasma insulin concentration in these patients. The current study was initiated to address this issue by making specific measurements of plasma insulin, proinsulin, and C-peptide concentrations in 42 individuals: 14 with normal glucose tolerance, 12 with impaired glucose tolerance (IGT), and 16 with NIDDM. The study population was further subdivided into a nonobese (body mass index, < 30 kg/m2) and an obese (body mass index, > 30 kg/m2) group. Mixed meals were given at 0800, 1200, and 1800 h, and blood was removed at 0800 h (before the meal) and at hourly intervals from then until 1600 h. Plasma glucose concentrations throughout the sampling period were slightly, but significantly (P < 0.01), greater in patients with IGT than in normal individuals. Patients with NIDDM had markedly elevated glycemic excursions, greater than either of the other two groups (P < 0.002). Both plasma immunoreactive insulin and C-peptide concentrations from 0800-1600 h were higher (P < 0.002-0.001) in patients with either IGT or NIDDM than in the group with normal glucose tolerance. Although day-long plasma immunoreactive insulin and C-peptide concentrations were higher, on the average, in patients with IGT compared to those with NIDDM, the difference was not statistically significant. Plasma proinsulin concentrations were highest in patients with NIDDM (P < 0.002), lower in those with normal glucose tolerance (P < 0.002), and intermediate in patients with IGT. When the calculated "true" insulin concentration was determined by taking the proinsulin content into consideration, patients with IGT had the highest day-long levels, with the lowest values found in the control population (P < 0.002). Although absolute values varied as a function of obesity, the generalizations outlined above were found in both weight groups. These results show that ambient plasma proinsulin concentrations increase as glucose tolerance declines. However, true plasma insulin concentrations in response to mixed meals remain highest in patients with IGT, lowest in normal individuals, and intermediate in patients with NIDDM. Thus, previous conclusions that absolute day-long plasma insulin concentrations are not lower than normal in patients with NIDDM do not appear to result from an inability to differentiate true insulin from proinsulin.

    View details for Web of Science ID A1993LB52400008

    View details for PubMedID 8421101

  • LACTATE PRODUCTION AND PYRUVATE-DEHYDROGENASE ACTIVITY IN FAT AND SKELETAL-MUSCLE FROM DIABETIC RATS DIABETES Mondon, C. E., Jones, I. R., Azhar, S., Hollenbeck, C. B., Reaven, G. M. 1992; 41 (12): 1547-1554

    Abstract

    This study was initiated to explore the possibility that an increase in the supply of gluconeogenic precursors contributes to the overproduction of glucose by the liver in NIDDM patients. To address this issue, a form of experimental NIDDM was produced in rats by injecting a low dose (38 mg/kg) of STZ and comparing lactate and alanine production and PDH activity in skeletal muscle and isolated adipocytes from normal and diabetic rats. Skeletal muscle lactate production was measured by using a hindlimb perfusion technique and was significantly greater (P < 0.01) in the diabetic rats compared with two groups of control rats: one perfused at normal glucose levels and the other perfused at glucose concentrations comparable with those observed in diabetic rats. Alanine production by hindlimb from diabetic rats was 46% greater than hindlimbs from control rats perfused at normal glucose levels (P < 0.01) but was not significantly greater than control rats perfused at diabetic glucose levels. The percentage of glucose converted to lactate by muscle from both control groups was 4-5%, significantly lower than the 18% conversion rate observed in diabetic animals (P < 0.001). An increase in the ratio of lactate produced/glucose transport by isolated adipocytes from diabetic rats also was observed when measured in both the basal state (0.65 +/- 0.12 vs. 0.15 +/- 0.03, P < 0.01) and in the presence of maximal amounts of insulin (0.15 +/- 0.02 vs. 0.04 +/- 0.01, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992KA59300007

    View details for PubMedID 1446795

  • GLUCOSE, INSULIN, AND LIPID-METABOLISM IN DOXAZOSIN-TREATED PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Shieh, S. M., Sheu, W. H., Shen, D. C., Fuh, M. M., CHEN, Y. D., Reaven, G. M. 1992; 5 (11): 827-831

    Abstract

    The metabolic changes associated with doxazosin treatment of hypertension were evaluated in ten patients with mild hypertension (mean +/- SEM = 150 +/- 3/100 +/- 1 mm Hg) and a plasma triglyceride (TG) concentration > 1.50 mmol/L. The blood pressure was lower after 4 to 6 months of doxazosin treatment (mean +/- SEM = 134 +/- 4/87 +/- 1 mm Hg), which was also associated with a significantly lower plasma insulin response to a 75 g oral glucose load, and lower plasma TG and cholesterol concentrations. In addition, insulin-mediated glucose uptake was significantly greater after doxazosin treatment. These data suggest that doxazosin treatment of patients with mild hypertension is associated with changes in insulin and lipid metabolism that should decrease the risk of coronary heart disease.

    View details for Web of Science ID A1992JX96600009

    View details for PubMedID 1457085

  • INSULIN RESISTANCE, HYPERINSULINEMIA, AND DYSLIPIDEMIA IN NONOBESE INDIVIDUALS WITH A FAMILY HISTORY OF HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Facchini, F., CHEN, Y. D., Clinkingbeard, C., Jeppesen, J., Reaven, G. M. 1992; 5 (10): 694-699

    Abstract

    Various facets of glucose, insulin, and lipid metabolism were compared in 76 normal volunteers--38 with and 38 without a family history of hypertension. The two groups were comparable in terms of age, gender distribution, and degree of obesity (both generalized and abdominal). Although the plasma glucose response to oral glucose was similar in both groups, glucose-stimulated insulin concentrations were significantly greater in volunteers with a family history of hypertension (P < .001). Furthermore, the steady state plasma glucose concentration during a constant infusion of glucose, insulin and somatostatin was significantly greater in subjects with a family history of hypertension (8.1 +/- 0.6 v 6.2 +/- 0.6 mmol/L, P < .001). Since the steady-state plasma insulin levels during the infusion were similar, these results indicate that normotensive individuals with a family history of hypertension are relatively insulin resistant. Finally, plasma very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol were higher in those with a family history of hypertension, as was the ratio of total to high density lipoprotein cholesterol. Thus, normotensive individuals with a family history of high blood pressure are insulin resistant, hyperinsulinemic and dyslipidemic when compared to a matched group of healthy volunteers without a family history of hypertension.

    View details for Web of Science ID A1992JU21900006

    View details for PubMedID 1418831

  • GLUCOSE, INSULIN AND LIPID-METABOLISM IN DOXAZOSIN TREATED PATIENTS WITH HYPERTENSION Shieh, S. M., Sheu, W. H., SHEN, D. D., Fuh, M. M., CHEN, Y. D., Reaven, G. M. LIPPINCOTT WILLIAMS & WILKINS. 1992: 542-542
  • DEMONSTRATION OF A RELATIONSHIP BETWEEN WHITE BLOOD-CELL COUNT, INSULIN RESISTANCE, AND SEVERAL RISK-FACTORS FOR CORONARY HEART-DISEASE IN WOMEN JOURNAL OF INTERNAL MEDICINE Facchini, F., Hollenbeck, C. B., Chen, Y. N., CHEN, Y. D., Reaven, G. M. 1992; 232 (3): 267-272

    Abstract

    In order to evaluate the relationship between peripheral white blood cell (WBC) count, insulin-mediated glucose uptake, and several risk factors for coronary heart disease (CHD), WBC, plasma glucose and insulin responses to a 75-g oral glucose challenge, fasting plasma cholesterol, high-density-lipoprotein (HDL)-cholesterol, and triglyceride concentration, and systolic and diastolic blood pressure were determined in 63 consecutive female volunteers with normal glucose tolerance. The results demonstrated the presence of statistically significant correlation coefficients between WBC count and both insulin-mediated glucose disposal (r = 0.50, P less than 0.001) and insulin response to oral glucose (r = 0.50, P less than 0.001). Furthermore, WBC count correlated with plasma glucose response to oral glucose (r = 0.48, P less than 0.001), fasting plasma triglyceride (r = 0.37, P less than 0.005) and HDL-cholesterol concentrations (r = -0.38, P less than 0.005), and systolic (r = 0.22, P less than 0.1) and diastolic (r = 0.27, P less than 0.05) blood pressure. However, the only two variables significantly correlated with WBC count in multivariate regression analysis were insulin resistance (r = 0.49, P less than 0.01) and insulin response (r = 0.35, P less than 0.05). These data indicate that WBC count is significantly correlated with changes in carbohydrate and lipoprotein metabolism and blood pressure that increase the risk of CHD. However, it appears that these relationships are secondary to resistance to insulin-mediated glucose uptake and hyperinsulinaemia.

    View details for Web of Science ID A1992JQ88200011

    View details for PubMedID 1402624

  • EFFECT OF NICOTINIC-ACID ON PLASMA-GLUCOSE CONCENTRATION IN NORMAL INDIVIDUALS HORMONE AND METABOLIC RESEARCH Landau, C., CHEN, Y. D., Skowronski, R., Hollenbeck, C. B., Jaspan, J. B., Reaven, G. M. 1992; 24 (9): 424-428

    Abstract

    In order to assess the ability of nicotinic acid to decrease plasma glucose concentration, normal individuals were given continuous four hour infusions of either nicotinic acid (NA), somatostatin (SRIF), NA + SRIF, or 0.9% NaCl (Saline). Plasma non-esterified fatty acid (NEFA) concentration decreased to about one-fourth of the basal value in response to either NA or NA + SRIF, associated with statistically significant decreases in plasma glucose concentration. The ability of NA and NA + SRIF to decrease plasma glucose concentration was seen despite the fact that plasma insulin concentrations also fell significantly during both infusions. Although plasma glucose concentration fell significantly in response to both NA and NA + SRIF, the effect of NA + SRIF was approximately twice as great as that seen with NA alone. The augmented hypoglycaemic effect of NA + SRIF as compared to NA alone was associated with a concomitant fall in plasma glucagon concentration. In contrast, plasma glucose concentration did not change following Saline, and was actually higher than baseline after the infusion of SRIF alone. These results provide evidence that NA can lower plasma glucose concentration in normal volunteers, and suggests that this is mediated by the NA-associated decrease in plasma NEFA concentration.

    View details for Web of Science ID A1992JN84100006

    View details for PubMedID 1358776

  • IMPROVEMENT IN METABOLIC RISK-FACTORS FOR CORONARY HEART-DISEASE ASSOCIATED WITH CILAZAPRIL TREATMENT AMERICAN JOURNAL OF HYPERTENSION Shieh, S. M., Sheu, W. H., SHEN, D. D., Fuh, M. M., Jeng, C. Y., Jeng, J. R., CHEN, Y. D., Reaven, G. M. 1992; 5 (8): 506-510

    Abstract

    Patients with hypertension tend to be glucose intolerant, hyperinsulinemic, and dyslipedemic. Since all of these changes increase risk of coronary heart disease (CHD), it is important to know what effect antihypertensive treatment has on these variables. The current open-labelled, uncontrolled study was initiated in order to extend our understanding of these issues. This study was performed in 19 patients with hypertension who were started on an angiotensin converting enzyme (ACE)-inhibitor, cilazapril, with hydrochlorothiazide (HC) added if needed to control blood pressure. Plasma glucose and insulin responses to oral glucose and lipid concentrations were measured before, 26, and 52 weeks after starting treatment. Patients treated with either cilazapril (n = 9) or cilazapril+HC (n = 10) did not differ in terms of original (mean +/- SEM) blood pressure (159 +/- 5/101 +/- 1 v 156 +/- 4/103 +/- 2 mm Hg), age (53 +/- 2 v 54 +/- 2 years), sex distribution (5M:4F v 7M:3F), or body mass index (24.4 +/- 0.5 v 24.2 +/- 0.9 kg/m2). Blood pressure was also similar after 26 (137 +/- 4/88 +/- 1 v 133 +/- 3/90 +/- 1 mm Hg) and 52 (137 +/- 4/87 +/- 1 v 134 +/- 4/89 +/- 2 mm Hg) weeks of treatment. Plasma glucose and insulin responses decreased by 8 +/- 3% (P less than .05) and 25 +/- 9% (P less than .002), respectively, in cilazapril-treated patients, but did not change in those treated with cilazapril plus HC.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992JF70600003

    View details for PubMedID 1388960

  • INSULIN RESISTANCE AND ABNORMAL ELECTROCARDIOGRAMS IN PATIENTS WITH HIGH BLOOD-PRESSURE AMERICAN JOURNAL OF HYPERTENSION Sheu, W. H., Jeng, C. Y., Shieh, S. M., Fuh, M. M., SHEN, D. D., CHEN, Y. D., Reaven, G. M. 1992; 5 (7): 444-448

    Abstract

    Plasma glucose and insulin responses to an oral glucose challenge and fasting plasma lipid and lipoprotein concentration were compared in 25 normal individuals and 53 patients with high blood pressure. Patients with hypertension were further subdivided into two groups--normal electrocardiogram (EKG) (n = 24) or abnormal EKG (n = 29)--using the Minnesota code criteria. Patients with hypertension and an abnormal EKG had significantly higher plasma glucose and insulin concentrations following oral glucose than did the control population. Furthermore, plasma triglyceride (TG) concentration was higher and high density lipoprotein cholesterol concentration lower then normal in hypertensive patients with an abnormal EKG, and the ratio of total to HDL cholesterol was higher in this subgroup. Values for patients with high blood pressure and a normal EKG were intermediate. Insulin-mediated glucose uptake was also measured in a subset of patients with hypertension and either a normal (n = 18) or abnormal (n = 17) EKG. When these two subgroups were compared, those with high blood pressure and an abnormal EKG were significantly more insulin resistant than patients with hypertension and a normal EKG. In addition, they also had higher plasma glucose and insulin responses to oral glucose, higher fasting plasma triglyceride and cholesterol concentrations, and an increase in the ratio of total to HDL cholesterol. Thus, patients with high blood pressure have abnormalities of glucose, insulin, and lipid metabolism when compared to a nonhypertensive control group, and the magnitude of these metabolic defects is significantly greater in patients with high blood pressure who have EKG evidence of coronary heart disease.

    View details for Web of Science ID A1992JB22300004

    View details for PubMedID 1637516

  • INSULIN RESISTANCE AND CIGARETTE-SMOKING LANCET Facchini, F. S., Hollenbeck, C. B., Jeppesen, J., CHEN, Y. D., Reaven, G. M. 1992; 339 (8802): 1128-1130

    Abstract

    Cigarette smoking is associated with increases in plasma triglycerides and decreases in plasma high density-lipoprotein-cholesterol concentration. These changes not only increase risk of coronary heart disease but also are secondary to resistance to insulin-stimulated glucose uptake or hyperinsulinaemia. To see whether there is a relation between cigarette smoking and insulin-mediated glucose uptake we measured plasma lipid and lipoprotein concentrations, plasma glucose and insulin response to an oral glucose challenge, and insulin-mediated glucose uptake in 40 matched healthy volunteers (20 non-smokers, 20 smokers). Smokers had significantly higher mean (SEM) very-low-density-lipoprotein triglycerides (0.66 [0.10] vs 0.39 [0.03] mmol/l, p less than 0.02) and cholesterol (0.45 [0.06] vs 0.23 [0.04] mmol/l, p less than 0.005) concentrations and lower high-density-lipoprotein cholesterol concentrations (1.16 [0.05] vs 1.51 [0.08] mmol/l, p less than 0.001). Although plasma glucose concentrations in response to the oral glucose load were similar in the two groups, plasma insulin response of the smokers was significantly higher (p less than 0.001). Finally, smokers had higher steady-state plasma glucose concentrations in response to a continuous infusion of glucose, insulin, and somatostatin (8.4 [0.2] vs 5.0 [0.3] mmol/l, p less than 0.001), despite similar steady-state plasma insulin concentrations. The findings show that chronic cigarette smokers are insulin resistant, hyperinsulinaemic, and dyslipidaemic compared with a matched group of non-smokers, and may help to explain why smoking increases risk of coronary heart disease.

    View details for Web of Science ID A1992HT23600002

    View details for PubMedID 1349365

  • THE ROLE OF INSULIN RESISTANCE AND HYPERINSULINEMIA IN CORONARY HEART-DISEASE Reaven, G. M. W B SAUNDERS CO. 1992: 16-19

    Abstract

    Patients with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are more resistant to insulin-stimulated glucose uptake than are individuals with normal glucose tolerance. Evidence has also been published showing that first-degree relatives of patients with NIDDM are insulin resistant when compared with a matched group of relatives of subjects with normal glucose tolerance. In addition, the ability of insulin to stimulate glucose uptake varies approximately fourfold in individuals with normal glucose tolerance, and insulin resistance of a degree comparable to that seen in patients with IGT or with Type II diabetes is present in a significant portion of the normal population. Given a defect in insulin-stimulated glucose uptake, glucose tolerance can only be maintained if insulin-resistant individuals continue to secrete greater than normal amounts of insulin. As a corollary, glucose homeostasis will decompensate when the insulin secretory response begins to decrease, and the greater the decline in insulin secretion, the larger the increase in plasma glucose concentration. Resistance to insulin-stimulated glucose uptake and compensatory hyperinsulinemia seems to represent the basic defect in patients with NIDDM, with failure of beta-cell function and subsequent development of fasting hyperglycemia only occurring later. This general formulation has received considerable support from longitudinal studies of the natural history of NIDDM. The fact that an increase in ambient insulin concentration can prevent gross decompensation of glucose tolerance in an insulin-resistant individual does not mean that this compensatory response is benign.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992HU84000005

    View details for PubMedID 1574008

  • COMBINED METFORMIN-SULFONYLUREA TREATMENT OF PATIENTS WITH NONINSULIN-DEPENDENT DIABETES IN FAIR TO POOR GLYCEMIC CONTROL JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Reaven, G. M., Johnston, P., Hollenbeck, C. B., Skowronski, R., Zhang, J. C., Goldfine, I. D., CHEN, Y. D. 1992; 74 (5): 1020-1026

    Abstract

    The effect of metformin treatment was studied in 13 patients with noninsulin-dependent diabetes mellitus (NIDDM), whose fasting plasma glucose concentration was greater than 10 mmol/L with maximal sulfonylurea doses. Patients were studied before and 3 months after receiving 2.5 g/day metformin. The fasting plasma glucose concentration (12.4 +/- 0.8 vs. 8.8 +/- 0.7 mmol/L), mean hourly postprandial plasma glucose concentration from 0800-1600 h (14.0 +/- 1 vs. 9.4 +/- 0.9 mmol/L), and glycosylated hemoglobin level (12.3 +/- 0.6% vs. 9.0 +/- 0.6%) were all significantly (P less than 0.005-0.001) lower after the administration of metformin. The improvement in glycemic control was associated with a 24% increase (P less than 0.05) in insulin-stimulated glucose uptake during glucose clamp studies and a 16% decrease in basal hepatic glucose production (P less than 0.05). Mean hourly concentrations of plasma insulin (411 +/- 73 vs. 364 +/- 73 pmol/L) and FFA concentrations (440 +/- 31 vs. 390 +/- 40 mumol/L) were also lower after 3 months of metformin treatment. However, neither insulin binding nor insulin internalization by isolated monocytes changed in response to metformin. Finally, plasma triglyceride, very low density lipoprotein triglyceride, and very low density lipoprotein cholesterol were significantly decreased (P less than 0.01-0.001), and high density lipoprotein cholesterol was significantly increased (P less than 0.001) after metformin treatment. Thus, the addition of metformin to sulfonylurea-treated patients with NIDDM not in good glycemic control significantly lowered fasting and postprandial plasma glucose concentrations, presumably due to the combination of enhanced glucose uptake and decreased hepatic glucose production. Since the dyslipidemia present in these patients also improved, the results suggest that metformin may be of significant clinical utility in patients with NIDDM not well controlled with sulfonylurea compounds.

    View details for Web of Science ID A1992HQ47200012

    View details for PubMedID 1569149

  • RENAL VASCULAR HYPERTENSION DOES NOT LEAD TO HYPERINSULINEMIA IN SPRAGUE-DAWLEY RATS AMERICAN JOURNAL OF HYPERTENSION Reaven, G. M., Ho, H. 1992; 5 (5): 314-317

    Abstract

    The effect of renal vascular hypertension on blood pressure and plasma glucose, insulin, and triglyceride concentration was studied in Sprague-Dawley rats. Three weeks after the induction of renal artery sterosis, mean (+/- SEM) blood pressure was significantly greater (153 +/- 3 v 117 +/- 2 mm Hg, P less than .001) compared with that in sham-operated rats. However, the two groups were similar in terms of plasma glucose (140 +/- 3 v 140 +/- 2 mg/dL), insulin (27 +/- 3 v 23 +/- 2 microU/mL), and triglyceride (89 +/- 8 v 95 +/- 6 mg/dL) concentrations. Furthermore, blood pressure increased to a similar degree in the two groups of rats (22 +/- 4 v 24 +/- 2 mm Hg), as did plasma insulin (47 +/- 5 v 44 +/- 4 microU/mL) and triglyceride (407 +/- 50 v 381 +/- 46 mg/dL) concentrations, after 2 weeks of a high-fructose diet. These data indicate that experimental induction of renal vascular hypertension in normal rats was not associated with an increase in either plasma insulin or triglyceride concentration. Furthermore, the response of rats with renal vascular hypertension to a high-fructose diet was similar to that of the sham-operated group. These data support the view that hypertension, per se, does not lead to hyperinsulinemia and hypertriglyceridemia in normal rats.

    View details for Web of Science ID A1992HR67900009

    View details for PubMedID 1581013

  • INSULIN RESISTANCE AND ABNORMAL ELECTROCARDIOGRAMS IN PATIENTS WITH HIGH BLOOD-PRESSURE Fuh, M. M., Sheu, W. H., Shen, D. C., Shieh, S. M., CHEN, Y. D., Reaven, G. M. SLACK INC. 1992: A44-A44
  • Syndrome X. Blood pressure. Supplement Reaven, G. M. 1992; 4: 13-16

    View details for PubMedID 1345329

  • EVIDENCE FOR AN INDEPENDENT RELATIONSHIP BETWEEN INSULIN RESISTANCE AND FASTING PLASMA HDL-CHOLESTEROL, TRIGLYCERIDE AND INSULIN CONCENTRATIONS JOURNAL OF INTERNAL MEDICINE Laws, A., Reaven, G. M. 1992; 231 (1): 25-30

    Abstract

    Elevated plasma insulin and triglyceride (TG) and decreased high-density-lipoprotein (HDL)-cholesterol concentrations have been shown to be risk factors for coronary heart disease (CHD). It has been suggested that these metabolic abnormalities are all secondary to resistance to insulin-stimulated glucose uptake. To examine this in more detail, we divided 18 non-diabetic, moderately overweight, sedentary men aged 25-50 years into three groups on the basis of their steady-state plasma glucose levels (SSPG): a low group, (n = 7; SSPG less than 8.3 mmol l-1), a middle group, (n = 6; SSPG 8.3-11.1 mmol l-1), and a high group (n = 5; SSPG greater than 11.1 mmol l-1). The high group had significantly higher fasting (P less than 0.05) and post-oral glucose challenge (P less than 0.01) insulin concentrations, higher fasting TG (P less than 0.05) and lower fasting HDL-cholesterol (P less than 0.05) concentrations than the other two groups. However, there were no statistically significant differences between the groups with regard to body mass index, waist-to-hip ratio or physical endurance capacity as determined by maximal oxygen consumption during a treadmill test. The data suggest that insulin resistance has an effect on the modulation of plasma insulin, TG and HDL-cholesterol concentrations, independent of generalized, abdominal or physical endurance capacity.

    View details for Web of Science ID A1992HA16700006

    View details for PubMedID 1732395

  • EFFECT OF ACUTE VARIATIONS IN DIETARY-FAT AND CARBOHYDRATE INTAKE ON RETINYL ESTER CONTENT OF INTESTINALLY DERIVED LIPOPROTEINS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM CHEN, Y. D., Skowronski, R., Coulston, A. M., Pietarinen, J., Hollenbeck, C. B., Reaven, G. M. 1992; 74 (1): 28-32

    Abstract

    Vitamin A was administered to eight patients with noninsulin-dependent diabetes mellitus in conjunction with the two different test meals containing (as percentage of total calories) either 15% protein, 60% carbohydrate (CHO), and 25% fat or 15% protein, 40% CHO, and 45% fat. The vitamin A and test meals were given at noon (4 h after a standard breakfast), and blood was obtained hourly from noon to midnight for measurement of plasma glucose, insulin, triglyceride (TG), and cholesterol concentrations; concentrations of TG and cholesterol in Sverdberg floatation (Sf) unit above 400 and Sf 20-400 lipoproteins; retinyl ester concentration in plasma; and both Sf more than 400 and Sf 20-400 lipoproteins. The postprandial TG response in plasma, Sf more than 400 lipoproteins, and Sf 20-400 lipoproteins from noon to midnight was only slightly higher than values seen after consumption of the 60% CHO diet, which contained much less fat (25% vs. 45%) and the retinyl ester concentration was actually higher in both lipoprotein fractions after the diet containing the smallest amount of fat (60% CHO). Furthermore, the cholesterol concentration in the plasma and two lipoprotein fractions was identical after the two diets, despite the great difference in fat content. These data indicate that the acute ingestion of high CHO (60%), low fat (25%) diets by patients with noninsulin-dependent diabetes mellitus led to little or no decrease in postprandial plasma or lipoprotein TG or cholesterol concentrations and an actual increase in concentration of potentially atherogenic small chylomicron and/or chylomicron remnants.

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