Bio

Clinical Focus


  • Endocrinology / Diabetes
  • Endocrinology

Academic Appointments


Professional Education


  • Residency:University of Michigan Hospital (6/1959) MI
  • Internship:University of Chicago Hospitals (6/1954) IL
  • Fellowship:Stanford University School of Medicine (6/1960) CA
  • Medical Education:University of Chicago Hospitals (6/1953) IL

Research & Scholarship

Clinical Trials


  • 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.

    View full details

Teaching

Postdoctoral Advisees


Publications

Journal Articles


  • Habitual shortened sleep and insulin resistance: An independent relationship in obese individuals. Metabolism 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 PubMedID 23849514

  • 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 PubMedID 23809477

  • 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 PubMedID 23885045

  • Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism 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) ?mol/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 PubMedID 23151437

  • 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?

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

    View details for Web of Science ID 000315167200052

    View details for PubMedID 22481243

  • Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome? Nutrition, metabolism, and cardiovascular diseases : NMCD Liu, A., Reaven, G. M. 2013

    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 PubMedID 23352957

  • 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. 2013

    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 PubMedID 23420066

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 ?-cells in the pathogenesis and treatment of patients with type 2 diabetes (2DM): (i) Homeostatic Model Assessment (HOMA)-?, 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) ?I/?G, 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 ?-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 ?-cell in the natural history of 2DM.

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

    View details for PubMedID 20923533

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

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

    View details for PubMedID 11452209

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

    View details for PubMedID 8538710

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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.

    View details for Web of Science ID A1992HD94900007

    View details for PubMedID 1727825

  • RELATIONSHIP BETWEEN RESISTANCE TO INSULIN-MEDIATED GLUCOSE-UPTAKE, URINARY URIC-ACID CLEARANCE, AND PLASMA URIC-ACID CONCENTRATION JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Facchini, F., CHEN, Y. D., Hollenbeck, C. B., Reaven, G. M. 1991; 266 (21): 3008-3011

    Abstract

    To define the relationship, if any, between insulin-mediated glucose disposal and serum uric acid.Cross-sectional study of healthy volunteers.General Clinical Research Center, Stanford (Calif) University Medical Center.Thirty-six presumably healthy individuals, nondiabetic, without a history of gout.Obesity (overall and regional), plasma glucose and insulin responses to a 75-g oral glucose load, fasting uric acid concentrations, plasma triglyceride and high-density lipoprotein-cholesterol concentrations, systolic and diastolic blood pressure, insulin-mediated glucose disposal, and urinary uric acid clearance.Magnitude of insulin resistance and serum uric acid concentration were significantly related (r = .69; P less than .001), and the relationship persisted when differences in age, sex, overall obesity, and abdominal obesity were taken into account (r = .57; P less than .001). Insulin resistance was also inversely related to urinary uric acid clearance (r = -.49; P less than .002), and, in addition, urinary uric acid clearance was inversely related to serum uric acid concentration (r = -.61; P less than .001).Urinary uric acid clearance appears to decrease in proportion to increases in insulin resistance in normal volunteers, leading to an increase in serum uric acid concentration. Thus, it appears that modulation of serum uric concentration by insulin resistance is exerted at the level of the kidney.

    View details for Web of Science ID A1991GR77500033

    View details for PubMedID 1820474

  • ABNORMALITIES OF CARBOHYDRATE AND LIPID-METABOLISM IN DAHL RATS HYPERTENSION Reaven, G. M., Twersky, J., Chang, H. 1991; 18 (5): 630-635

    Abstract

    Plasma glucose, insulin, and triglyceride concentration, blood pressure, and insulin action on isolated adipocytes were determined in weight-matched Sprague-Dawley, Dahl salt-resistant, and Dahl salt-sensitive rats. Blood pressure and plasma glucose concentrations were not significantly different in the three groups. However, Dahl salt-sensitive rats had significantly higher plasma insulin (39 +/- 2 microunits/ml) and triglyceride (213 +/- 11 mg/dl) concentrations than did Sprague-Dawley rats (27 +/- 2 microunits/ml and 101 +/- 6 mg/dl, respectively). Values for insulin (34 +/- 4 microunits/ml) and triglyceride (159 +/- 11 mg/dl) were intermediate in Dahl salt-resistant rats. In contrast, maximal insulin-stimulated glucose transport was significantly lower in adipocytes isolated from Dahl salt-sensitive as compared with Sprague-Dawley rats (400 +/- 16 versus 523 +/- 14 fl/cell/sec), with Dahl salt-resistant rats again having intermediate values. However, the ability of insulin to maximally inhibit catecholamine-stimulated lipolysis was similar in all three groups, averaging approximately 20% of the activity present in the absence of insulin. All of these differences were seen when the rats were eating conventional chow and did not change in Dahl rats after 2 weeks of an 8% NaCl diet. On the other hand, the predicted rise in blood pressure took place in Dahl salt-sensitive rats, increasing from 147 +/- 4 to 181 +/- 6 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991GN92200009

    View details for PubMedID 1937666

  • RELATION OF FASTING PLASMA-INSULIN CONCENTRATION TO HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL AND TRIGLYCERIDE CONCENTRATIONS IN MEN ARTERIOSCLEROSIS AND THROMBOSIS Laws, A., King, A. C., Haskell, W. L., Reaven, G. M. 1991; 11 (6): 1636-1642

    Abstract

    Low plasma high density lipoprotein (HDL) cholesterol concentration is a risk factor for coronary heart disease (CHD) and is frequently associated with high triglyceride concentration. Both of these abnormalities have been related to insulin resistance as estimated by plasma insulin concentrations and to measures of obesity, regional adiposity, and physical fitness. To determine which of these variables (fasting plasma insulin, obesity as measured by body mass index [BMI], or regional adiposity as measured by waist to hip ratio [WHR]) best identifies men with low HDL cholesterol and high triglyceride concentrations, we divided 83 men, aged 50-65 years, who were free of CHD or diabetes, into tertiles based on BMI, WHR, or fasting plasma insulin concentration. Only for plasma insulin tertiles were there statistically significant differences in HDL cholesterol (tertile 1, mean +/- SEM, 1.34 +/- 0.08 mmol/l; 2, 1.16 +/- 0.05 mmol/l; 3, 1.10 +/- 0.06 mmol/l; p less than 0.03) and triglyceride (tertile 1, 1.05 +/- 0.08 mmol/l; 2, 1.48 +/- 0.12 mmol/l; 3, 1.82 +/- 0.17 mmol/l; p less than 0.005) concentrations. In forward stepwise regressions with HDL cholesterol and triglyceride as dependent variables, fasting insulin concentration but not BMI, WHR, or maximal oxygen uptake (VO2max), a measure of physical fitness, predicted HDL cholesterol (R2 = 0.07, p less than 0.02) and triglyceride (R2 = 0.20, p less than 0.001) concentrations. The data suggest that plasma insulin concentration is an important predictor of HDL cholesterol and triglyceride concentrations independent of BMI, WHR, or VO2max.

    View details for Web of Science ID A1991GQ63000002

    View details for PubMedID 1931867

  • DIFFERENCES IN INSULIN ACTION AS A FUNCTION OF ORIGINAL ANATOMICAL SITE OF NEWLY DIFFERENTIATED ADIPOCYTES OBTAINED IN PRIMARY CULTURE JOURNAL OF CLINICAL INVESTIGATION Sztalryd, C., Azhar, S., Reaven, G. M. 1991; 88 (5): 1629-1635

    Abstract

    Stromal vascular cells were isolated from adipose tissue obtained from three different anatomical locations: epididymal (EPI), retroperitoneal (RP), and dorsal subcutaneous (SC), and allowed to differentiate in primary tissue culture. Cell number, protein concentration, glycerophosphate dehydrogenase, and lipoprotein lipase activity were similar in cells obtained from the EPI, RP, and SC regions, as were total insulin binding and the affinity of insulin for its receptor. However, both maximal insulin receptor tyrosine kinase activity and insulin-stimulated phosphorylation of the insulin receptor were significantly lower (P less than 0.05) in cells cultured from the SC region. In addition, newly differentiated adipocytes from the SC region were less sensitive to the ability of insulin to stimulate glucose uptake, and maximal insulin-stimulated glucose uptake by these cells was also significantly lower (P less than 0.05) when compared to cells obtained from the two other regions. Since these studies were performed on adipocyte precursor cells, allowed to differentiate to a similar degree in primary culture, the observed differences in insulin receptor phosphorylating activity, as well as the ability of insulin to stimulate glucose uptake appear to be intrinsic to adipose tissue from the three sites.

    View details for Web of Science ID A1991GN72700026

    View details for PubMedID 1658046

  • EFFECTS OF METFORMIN ON GLUCOSE, INSULIN AND LIPID-METABOLISM IN PATIENTS WITH MILD HYPERTRIGLYCERIDEMIA AND NON-INSULIN-DEPENDENT DIABETES BY GLUCOSE-TOLERANCE TEST CRITERIA DIABETES & METABOLISM Hollenbeck, C. B., Johnston, P., VARASTEH, B. B., CHEN, Y. D., Reaven, G. M. 1991; 17 (5): 483-489

    Abstract

    The effect of metformin treatment was studied in nine patients with mild (fasting plasma glucose concentration less than 7.5 mmol.l-1) non-insulin-dependent diabetes mellitus (NIDDM) and fasting plasma triglyceride (TG) concentration greater than 2.0 mmol.l-1. Individuals were studied before and three months after receiving 2.5 g/day of metformin. Mean hourly plasma glucose concentration from 8 AM to 4 PM (7.5 +/- 0.5 vs 6.5 +/- 0.4 mmol.l-1, p less than 0.001), as well as glycosylated hemoglobin levels (7.0 +/- 0.5 vs 6.2 +/- 0.2%, p less than 0.02) were significantly lower following metformin treatment. The improvement in glycaemic control was not associated with an improvement in insulin stimulated glucose disposal as measured by the glucose clamp technique. Mean hourly day-long concentrations of plasma insulin (519 +/- 81 vs 364 +/- 64 pmol.l-1, p less than 0.001), FFA (502 +/- 45 vs 460 +/- 35 mu mol.l-1, p less than 0.01), and triglyceride (3.60 +/- 0.33 vs 3.02 +/- 0.31 mmol.l-1, p less than 0.001) concentrations were significantly lower following three months of metformin treatment. Finally, fasting plasma TG concentration, very low density lipoprotein (VLDL)-TG, and VLDL-cholesterol concentrations were significantly decreased, while high density lipoprotein (HDL)-cholesterol concentration was significantly increased following metformin therapy. Thus, metformin administration to individuals with NIDDM, who did not have significant fasting hyperglycaemia, led to a decrease in plasma glucose, insulin, FFA, and TG concentration, and an increase in plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991GQ60700008

    View details for PubMedID 1752350

  • INTESTINALLY-DERIVED LIPOPROTEINS - METABOLISM AND CLINICAL-SIGNIFICANCE DIABETES-METABOLISM REVIEWS CHEN, Y. D., Reaven, G. M. 1991; 7 (3): 191-208

    View details for Web of Science ID A1991HM88400007

    View details for PubMedID 1817004

  • AGE-ASSOCIATED DIFFERENCES IN BETA ADRENERGIC-STIMULATED LIPOLYSIS IN ADIPOCYTES FROM SPRAGUE-DAWLEY AND FISCHER-344 RATS JOURNALS OF GERONTOLOGY Twersky, J., Hoffman, B. B., Reaven, G. M. 1991; 46 (4): B125-B129

    Abstract

    We compared the ability of adipocytes isolated from the epididymal fat pads of Sprague-Dawley and Fischer 344 rats of different ages and weights to release glycerol in response to beta-adrenergic stimulation. Twelve-month-old Sprague-Dawley rats weighed approximately three times more than did 2-month-old rats of the same strain (761 +/- 61 g vs 223 +/- 8 g, p less than .001). Basal glycerol release was increased in the adipocytes of the 12-month-old rats (128 +/- 8 nmol/10(5) cells/L compared to the 2-month-old rats 51 +/- 3 nmol/10(5) cells/L). However, the ability of isoproterenol to stimulate glycerol release above basal was markedly decreased in the older and fatter Sprague-Dawley rats (178 +/- 15 nmol/10(5) cells/L vs 482 +/- 20 nmol/10(5) cells/L, p less than .001), and significant correlation coefficients between isoproterenol-stimulated glycerol release and both total body (r = .76, p less than .001) and fat pad (r = .83, p less than .001) weight were seen in Sprague-Dawley rats. Total body weights of 2-month (188 +/- 16 g), 12-month (393 +/- 15 g), and 27-month-old (402 +/- 36 g) Fischer 344 rats were less disparate. Isoproterenol-stimulated glycerol release was similar in the three groups of Fischer 344 rats, and there was no correlation between either total body or fat pad weight and lipolysis in these rats.

    View details for Web of Science ID A1991FW03300016

    View details for PubMedID 2071826

  • SUGAR-INDUCED HYPERTENSION IN SPRAGUE-DAWLEY RATS AMERICAN JOURNAL OF HYPERTENSION Reaven, G. M., Ho, H. 1991; 4 (7): 610-614

    Abstract

    Male Sprague-Dawley rats were fed either conventional rat chow, or a diet in which vegetable starch was replaced with either glucose or sucrose for two weeks. At the end of this period, measurements were made of weight, blood pressure, and plasma glucose, insulin, and triglyceride concentrations. The average weight gain over the dietary period was approximately 75 g, and did not vary between the three groups. Mean (+/- SEM) blood pressure remained stable in the rats fed conventional chow (124 +/- 2 to 127 +/- 3 mm Hg), but increased significantly in rats fed the glucose-enriched diet (122 +/- 1 to 134 +/- 2 mm Hg, P less than .02, compared to chow-fed rats). The increase in blood pressure was even greater in rats fed the sucrose-enriched diet (122 +/- 2 to 144 +/- 2), and was significantly greater (P less than .005) than in rats fed either conventional chow or the glucose-enriched diet. Plasma glucose concentrations did not change in any of the groups, but plasma insulin concentration approximately doubled in rats fed either the glucose-enriched or sucrose-enriched diets. Finally, plasma triglyceride concentrations also were significantly higher (P less than .002) in both glucose-fed and sucrose-fed rats than in the control group. However, the increase was greatest in the sucrose-fed rats, and was significantly higher than in rats fed the glucose-enriched diet (P less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991FW77000008

    View details for PubMedID 1873016

  • Abnormalities of carbohydrate and lipoprotein metabolism in patients with hypertension. Relationship to obesity. Annals of epidemiology Reaven, G. M. 1991; 1 (4): 305-311

    Abstract

    Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and both hyperinsulinemic and hypertriglyceridemic when compared to matched control groups with normal blood pressure. All of these abnormalities would be accentuated in obese individuals. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in rat models of hypertension, including rats with spontaneous hypertension and Sprague-Dawley rats fed a fructose-enriched diet, and the defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Furthermore, experimental interventions that prevent insulin resistance and/or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Since endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease, it is likely that they contribute to the increased prevalence of ischemic heart disease in patients with high blood pressure. The fact that past antihypertensive treatment has not focused on these metabolic abnormalities, and, indeed, may have exacerbated them, could help explain why it has been difficult to show that lowering blood pressure decreases risk of coronary artery disease. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and the clinical course of hypertension.

    View details for PubMedID 1669512

  • REGULATION OF NONESTERIFIED FATTY-ACID AND GLYCEROL CONCENTRATION BY INSULIN IN NORMAL INDIVIDUALS AND PATIENTS WITH TYPE-2 DIABETES DIABETIC MEDICINE Skowronski, R., Hollenbeck, C. B., VARASTEH, B. B., CHEN, Y. D., Reaven, G. M. 1991; 8 (4): 330-333

    Abstract

    Plasma glycerol and non-esterified fatty acid (NEFA) concentrations were determined in the basal state and in response to physiological hyperinsulinaemia in 30 non-obese individuals, 15 with Type 2 diabetes and 15 with normal glucose tolerance. Patients with Type 2 diabetes had higher basal concentrations of both glycerol (81 +/- 7 (+/- SE) vs 61 +/- 7 mumol l-1, p less than 0.05) and NEFA (842 +/- 40 vs 630 +/- 46 mumol l-1, p less than 0.002). Plasma NEFA and glycerol concentrations fell in both groups when steady-state plasma insulin concentrations were raised to approximately 450 pmol l-1 by an infusion of exogenous insulin, but plasma concentrations of glycerol (28 +/- 3 vs 13 +/- 3 mumol l-1, p less than 0.002) and NEFA (186 +/- 15 vs 109 +/- 14 mumol l-1, p less than 0.001) were still higher in patients with Type 2 diabetes. Percentage decrease in glycerol from basal levels in response to insulin was significantly less in patients with Type 2 diabetes than in control subjects (64 +/- 3 vs 80 +/- 3%, p less than 0.005); percentage decrease in plasma NEFA concentration was similar in the two groups (78 +/- 3 vs 80 +/- 4%). These results suggest that both plasma glycerol and NEFA concentrations are higher than normal in patients with Type 2 diabetes when measured at the same insulin concentration, both under basal conditions and in response to physiological hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991FL44500004

    View details for PubMedID 1677322

  • Resistance to insulin-stimulated glucose uptake and hyperinsulinemia: role in non-insulin-dependent diabetes, high blood pressure, dyslipidemia and coronary heart disease. Diabète & métabolisme Reaven, G. M. 1991; 17 (1): 78-86

    Abstract

    Patients with impaired glucose tolerance (IGT) and Type 2 diabetes have been shown to be more resistant to insulin-stimulated glucose uptake than individuals with normal glucose tolerance. Evidence has also been published showing that first degree relatives of patients with Type 2 diabetes are insulin resistant when compared to a matched group of relatives of subjects with normal glucose tolerance. In addition, it has recently been shown that the ability of insulin to stimulate glucose uptake varies approximately four-fold in individuals with normal glucose tolerance, and insulin resistance of a degree comparable to that seen in patients with IGT or with Type 2 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 fall, and the greater the decline in insulin secretion, the larger the rise in plasma glucose concentration. The net result of these changes is that plasma glucose and insulin response will be positively correlated within a population composed of glucose tolerant individuals and patients with IGT or Type 2 diabetes in the absence of significant fasting hyperglycemia. On the other hand, the relationship between plasma insulin and glucose concentration will be negatively correlated in patients with Type 2 diabetes and varying degrees of fasting hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for PubMedID 1936488

  • LOW-DOSE STREPTOZOTOCIN-INDUCED DIABETES IN THE SPONTANEOUSLY HYPERTENSIVE RAT METABOLISM-CLINICAL AND EXPERIMENTAL Reaven, G. M., Ho, H. 1991; 40 (4): 335-337

    Abstract

    Streptozotocin (STZ, 35 mg/kg body weight) was injected into spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and plasma glucose and triglyceride concentrations measured 10 days later. Neither mean (+/- SEM) plasma glucose (130 +/- 3 v 136 +/- 3 mg/dL) nor triglyceride (93 +/- 6 v 108 +/- 7 mg/dL) concentrations increased in WKY rats. In contrast, both plasma glucose (141 +/- 3 v 262 +/- 36) and triglyceride (121 +/- 8 v 196 +/- 7 mg/dL) concentrations increased significantly (P less than .01) following administration of STZ in SHR. Furthermore, when SHR previously injected with STZ were fed a diet enriched in fructose, they had a further increase (P less than .01) in both plasma glucose (343 +/- 38 mg/dL) and triglyceride (774 +/- 57 mg/dL) concentrations. Plasma triglyceride concentration also increased significantly (P less than .05) when STZ-injected WKY rats ingested the fructose-enriched diet, but plasma glucose levels still remained within the normal range (152 +/- 5 mg/dL). These results indicate that SHR were more sensitive to the effects of a decrease in pancreatic beta-cell function (STZ) and an increase in insulin resistance (fructose feeding) than WKY rats.

    View details for Web of Science ID A1991FE22600001

    View details for PubMedID 2011074

  • INSULIN RESISTANCE AND COMPENSATORY HYPERINSULINEMIA - ROLE IN HYPERTENSION, DYSLIPIDEMIA, AND CORONARY HEART-DISEASE AMERICAN HEART JOURNAL Reaven, G. M. 1991; 121 (4): 1283-1288

    Abstract

    Resistance to insulin-stimulated glucose uptake and hyperinsulinemia may play a central role in the cause and clinical course of patients with non-insulin-dependent diabetes mellitus, high blood pressure, abnormalities of lipoprotein metabolism, and coronary heart disease. This article summarizes the evidence in support of this general hypothesis.

    View details for Web of Science ID A1991FF21600004

    View details for PubMedID 2008857

  • HIGH-DENSITY-LIPOPROTEIN TURNOVER IN PATIENTS WITH HYPERTENSION HYPERTENSION CHEN, Y. D., Sheu, W. H., Swislocki, A. L., Reaven, G. M. 1991; 17 (3): 386-393

    Abstract

    Although hyperinsulinemia and decreased high density lipoprotein cholesterol concentration can occur in patients with hypertension, there is no information available concerning the dynamic state of high density lipoprotein metabolism. To address this issue, we quantified high density lipoprotein turnover in 12 patients with mild hypertension and 11 matched subjects with normal blood pressure. Patients with high blood pressure had lower high density lipoprotein cholesterol concentrations. Fractional catabolic rates of 125I-apolipoprotein AI (apoAI)/high density lipoprotein were faster in patients with hypertension (0.36 +/- 0.02 versus 0.26 +/- 0.02 l/day, p less than 0.001). Total synthetic rates of apoAI were also significantly greater in patients with high blood pressure (17.4 +/- 1.1 versus 13.2 +/- 0.6 mg/kg/day, p less than 0.001). Although significant correlation was observed between blood pressure and fractional catabolic rate of 125I-apoAI/high density lipoprotein in the experimental population (r = 0.52, p less than 0.01), no relation was found when patients with normal blood pressure or hypertension were considered separately. However, a highly significant positive correlation was found between 125I-apoAI/high density lipoprotein fractional catabolic rate and insulin concentration in the entire population (r = 0.72, p less than 0.001). In conclusion, the patients with mild hypertension studied were hyperinsulinemic, had a faster fractional catabolic rate of 125I-apoAI/high density lipoprotein, and a lower high density lipoprotein-cholesterol concentration. It is suggested that the changes seen in high density lipoprotein-cholesterol concentration and 125I-apoAI/high density lipoprotein fractional catabolic rates were secondary to the hyperinsulinemia and not due to the high blood pressure per se.

    View details for Web of Science ID A1991FA88200018

    View details for PubMedID 1900259

  • INSULIN RESISTANCE, HYPERINSULINEMIA, HYPERTRIGLYCERIDEMIA, AND HYPERTENSION - PARALLELS BETWEEN HUMAN-DISEASE AND RODENT MODELS DIABETES CARE Reaven, G. M. 1991; 14 (3): 195-202

    Abstract

    There is considerable evidence that abnormalities of glucose, insulin, and lipoprotein metabolism occur more frequently in untreated hypertensive patients than in normotensive control subjects. More recently, it has also become apparent that similar metabolic abnormalities occur in rodent models of hypertension. One purpose of this article is to review the experimental data that have led to the above generalizations. The second goal is to address the significance of these findings, which is certainly not clear. For example, it could be argued that the relationship between high blood pressure and the associated metabolic defects is incidental. On the other hand, there is evidence that the changes in glucose, insulin, and lipoprotein metabolism may play a role in the etiology and/or clinical course of patients with high blood pressure. Although it is impossible at this point to definitively choose between these possibilities, an effort is made to marshal the evidence in support of the latter alternative.

    View details for Web of Science ID A1991EZ64800002

    View details for PubMedID 2044435

  • COMPARISON OF THE EFFECTS OF ATENOLOL AND NIFEDIPINE ON GLUCOSE, INSULIN, AND LIPID-METABOLISM IN PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Sheu, W. H., Swislocki, A. L., Hoffman, B., CHEN, Y. D., Reaven, G. M. 1991; 4 (3): 199-205

    Abstract

    Various aspects of carbohydrate and lipid metabolism have been studied in two groups of patients with mild hypertension before and after four months of treatment with either nifedipine (n = 12) or atenolol (n = 12). Mean (+/- SEM) blood pressure fell to the same degree following treatment with either nifedipine (147 +/- 3/98 +/- 2 to 134 +/- 2/85 +/- 2 mm Hg) or atenolol (149 +/- 3/99 +/- 2 to 135 +/- 2/86 +/- 3 mm Hg). Circulating plasma glucose, insulin, and triglyceride concentrations were measured at hourly intervals from 8:00 AM to 4:00 PM, before and after breakfast (8:00 AM), and at lunch time (noon). The response to treatment was different in the two groups. Specifically, plasma glucose concentration were unchanged and insulin concentrations were higher in association with atenolol treatment. In contrast, nifedipine-treated patients had similar plasma insulin, but lower plasma glucose and triglyceride concentrations after four months of therapy. The changes in day-long plasma glucose and insulin responses suggested that resistance to insulin-stimulated glucose uptake had increased in association with atenolol treatment and decreased following nifedipine. This conclusion was supported in that measurement of insulin-stimulated glucose disposal showed a decrease in atenolol-treated patients and an increase in nifedipine-treated patients. Finally, plasma lipoprotein cholesterol concentrations did not change following atenolol therapy, whereas plasma high density lipoprotein cholesterol increased in association with nifedipine administration. These data show that changes in carbohydrate and lipid metabolism observed with treatment of mild hypertension can vary significantly as a function of the drug used, despite similar beneficial effects on blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991FC49300001

    View details for PubMedID 2043298

  • Insulin resistance, hyperinsulinemia, and hypertriglyceridemia in the etiology and clinical course of hypertension. American journal of medicine Reaven, G. M. 1991; 90 (2A): 7S-12S

    Abstract

    Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and are more hyperinsulinemic and hypertriglyceridemic than matched groups of patients with normal blood pressure. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in spontaneous hypertensive rats and in Sprague-Dawley rats fed a fructose-enriched diet. The defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Experimental interventions that prevent insulin resistance or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Since endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease (CAD), it is likely that they contribute to the increased prevalence of CAD in hypertensive patients. Antihypertensive treatment may have exacerbated these metabolic abnormalities, which could help explain why it has been difficult to show that lowering blood pressure decreases the risk of CAD. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and clinical course of hypertension.

    View details for PubMedID 1994722

  • HYPERTRIGLYCERIDEMIA IN DAHL RATS - EFFECT OF SODIUM-INTAKE AND GENDER HORMONE AND METABOLIC RESEARCH Reaven, G. M., Twersky, J., Ho, H., Chang, H. 1991; 23 (1): 44-45

    View details for Web of Science ID A1991EY13500011

    View details for PubMedID 2016079

  • CHANGES IN CARBOHYDRATE-METABOLISM IN ASSOCIATION WITH GLIPIZIDE TREATMENT OF TYPE-2 DIABETES DIABETIC MEDICINE Jeng, C. Y., Hollenbeck, C. B., Wu, M. S., Foley, J. E., CHEN, Y. D., Reaven, G. M. 1991; 8 (1): 32-39

    Abstract

    Nineteen patients with Type 2 diabetes were treated with glipizide for 2.5-6 months, and measurements made of metabolic variables before and after glipizide treatment. For purposes of analysis, the glipizide associated decrease in fasting plasma glucose concentration was used to divide patients into 'good' responders (decrease of 4.0 mmol l-1 or more, n = 9) or 'fair' responders (decrease of 3.0 mmol l-1 or less, n = 10). Good responders had a significantly greater fall in their mean (+/- SE) hourly plasma glucose (6.3 +/- 0.6 vs 2.7 +/- 0.3 mmol l-1, p less than 0.001) and NEFA (164 +/- 40 vs 60 +/- 37 mumol l-1, p less than 0.05) concentrations from 0800 to 1600 h in response to meals (0800 and 1200 h) than did the fair responders. However, the increase in hourly plasma insulin concentration following glipizide treatment was the same in the good (323 +/- 103 to 413 +/- 124 pmol l-1) and fair (276 +/- 42 to 345 +/- 43 pmol l-1) responders.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1991ET26600007

    View details for PubMedID 1826242

  • CHARACTERIZATION OF INSULIN-RECEPTOR KINASE-ACTIVITY AND AUTOPHOSPHORYLATION IN DIFFERENT SKELETAL-MUSCLE TYPES AMERICAN JOURNAL OF PHYSIOLOGY Azhar, S., BUTTE, J. C., Santos, R. F., Mondon, C. E., Reaven, G. M. 1991; 260 (1): E1-E7

    Abstract

    We have examined insulin binding, autophosphorylation, and tyrosine kinase activity in detergent-solubilized and wheat germ agglutinin-purified insulin receptor preparations from four rat muscles of different fiber composition (i.e., tensor fascia latae, soleus, vastus intermedius, and plantaris). Insulin binding activity was similar in three of the four muscles but lower in tensor fascia latae. No significant differences were noted in the affinity of insulin for its receptor from various muscle types. Insulin receptor tyrosine kinase activity measured in the absence (basal) and presence of insulin (0.3-300 nM) was comparable in all muscle types (normalized to the amount of insulin bound). Insulin sensitivity, measured as the dose of insulin required for half-maximal activation of kinase activity, was also similar in all muscle types. Likewise, incubation of receptor preparations with [gamma-32P]ATP, Mn2+, and insulin (0.25-100 nM) resulted in a dose-dependent autophosphorylation of the beta-subunit (relative molecular weight approximately 95 kDa) with similar kinetics in all muscle types. In conclusion, these results show that the functional behavior of the insulin receptor autophosphorylation-kinase system (in vitro) is not changed by alterations in muscle fiber composition, indicating that differences in insulin sensitivity between different skeletal muscle types is probably not due to modulation of the insulin receptor phosphorylation system.

    View details for Web of Science ID A1991EU06500024

    View details for PubMedID 1846272

  • ACUTE CHANGES IN PLASMA NONESTERIFIED FATTY-ACID CONCENTRATION DO NOT CHANGE HEPATIC GLUCOSE-PRODUCTION IN PEOPLE WITH TYPE-2 DIABETES DIABETIC MEDICINE Johnston, P., Hollenbeck, C., SHEU, W., CHEN, Y. D., Reaven, G. M. 1990; 7 (10): 871-875

    Abstract

    The effect of changes in plasma non-esterified fatty acid concentration (NEFA) on plasma glucose concentration, hepatic glucose production (Ra), and glucose disposal (Rd) rates was determined in 14 patients with Type 2 diabetes. Seven patients had relatively mild fasting hyperglycaemia (less than 10.0 mmol l-1), whereas the remaining seven had relatively severe fasting hyperglycaemia (greater than 14.0 mmol l-1). Each patient was infused from 2000 to 0800 h with 3-3H-glucose on two occasions, with or without neutral fat emulsion and heparin (mild hyperglycaemia group), or with or without nicotinic acid (severe hyperglycaemia group). Plasma NEFA concentration increased from 0.33 +/- 0.06 (+/- SE) to 4.78 +/- 0.42 mmol l-1 in response to the lipid and heparin infusion, but plasma glucose concentration (7.8 +/- 0.7 vs 7.4 +/- 0.8 mmol l-1), Ra (0.44 +/- 0.02 vs 0.46 +/- 0.02 mmol m-2 min-1), and Rd (0.42 +/- 0.02 vs 0.46 +/- 0.02 mmol m-2 min-1) were unchanged. Nicotinic acid decreased plasma NEFA concentration from 0.54 +/- 0.15 to 0.23 +/- 0.08 mmol l-1, but plasma glucose (15.0 +/- 1.0 vs 15.5 +/- 1.4 mmol l-1), Ra (0.74 +/- 0.07 vs 0.68 +/- 0.07 mmol m-2 min-1), and Rd (0.73 +/- 0.07 vs 0.68 +/- 0.07 mmol m-2 min-1) were unchanged. The results indicate that acute changes in plasma NEFA concentration did not lead to any change in overnight glucose production or disposal rates.

    View details for Web of Science ID A1990EM34900005

    View details for PubMedID 2149683

  • EFFECTS OF INSULIN ON CARBOHYDRATE AND PROTEIN-METABOLISM IN VOLUNTARY RUNNING RATS AMERICAN JOURNAL OF PHYSIOLOGY Rodnick, K. J., Reaven, G. M., Azhar, S., Goodman, M. N., Mondon, C. E. 1990; 259 (5): E706-E714

    Abstract

    The goal of this study was to assess the effects of voluntary running activity in rats on various aspects of carbohydrate and protein metabolism. After 6 wk of exercise training, rats (ET) were rested for 24 h and their hindquarters, along with those from sedentary control (SC) and dietary control (DC) rats, were perfused with 0, 60, 250, or 6,000 microU/ml insulin. At 0 insulin, glucose clearance was similar for all groups, and it was increased with added insulin. However, the insulin effect was 20-40% greater for ET rats at all insulin concentrations (P less than 0.05). Muscle glycogen deposition also increased with added insulin but showed muscle-specific differences. Specifically, glycogen content of the plantaris muscle was significantly higher in ET compared with SC or DC rats, whereas this pattern was reversed in soleus muscle. In plantaris muscle, insulin stimulated glucose 6-phosphate (G-6-P)-independent (-G-6-P) glycogen synthase activity only in SC and DC rats and increased its affinity for G-6-P at 250 microU/ml in all groups. In contrast, the -G-6-P synthase activity was not increased in soleus muscle and was actually decreased in all groups at 6,000 microU/ml. Tyrosine release was suppressed by insulin in all groups, but this effect was significantly greater at insulin levels of 60 microU/ml (P less than 0.02) in hindquarters from ET rats compared with SC and DC rats. Neither insulin nor exercise training decreased 3-methylhistidine release from perfused hindquarters.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990EJ48100033

    View details for PubMedID 2122739

  • EFFECT OF CENTRAL OBESITY ON REGULATION OF CARBOHYDRATE-METABOLISM IN OBESE PATIENTS WITH VARYING DEGREES OF GLUCOSE-TOLERANCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Golay, A., Chen, N., CHEN, Y. D., Hollenbeck, C., Reaven, G. M. 1990; 71 (5): 1299-1304

    Abstract

    It has been proposed that central obesity, by virtue of the enhanced lipolytic activity of abdominal adipose tissue, leads to higher plasma FFA concentrations, which, in turn, decrease both hepatic removal of insulin and insulin-stimulated glucose uptake by peripheral tissues. In short, the predicted consequences of abdominal obesity are elevations in circulating FFA and insulin levels as well as insulin resistance. The goal of this study was to evaluate the relationships predicted by the overall hypothesis; this study was carried out in 31 obese females, defined as having normal glucose tolerance (n = 12), impaired glucose tolerance (n = 8), or noninsulin-dependent diabetes mellitus (n = 11). Abdominal obesity was estimated by determining the ratio of waist to hip girth, fasting and postprandial plasma FFA and insulin concentrations were measured at hourly intervals from 0800-1600 h, and insulin-stimulated glucose disposal was quantified by the euglycemic hyperinsulinemic clamp technique. The first step in the postulated sequence of events to be tested was that the greater the WHR, the higher the total integrated plasma FFA response. The correlation coefficient between these two variables was 0.29, indicating that the results did not support the prediction. Furthermore, we could not demonstrate any relationship between the magnitude of the plasma FFA and insulin responses (r = 0.20; P = NS). However, there was a modest inverse relationship between height of circulating plasma insulin concentration and a decrease in insulin-stimulated glucose uptake (r = -0.43; P less than 0.03) in the group as a whole. On the other hand, when the three groups were analyzed individually, a significant inverse relationship was only seen in the control group (r = -0.67), and a direct relationship was actually seen in patients with impaired glucose tolerance (r = 0.88). Furthermore, when the mean responses for the variables in each of the three groups were compared, it was apparent that the postulated relationships between abdominal obesity, plasma FFA concentration, and insulin secretion and action were not present. Thus, the data presented do not support the hypothesis that differences in the degree of central obesity play an important role in regulation of plasma concentrations of either FFA or insulin or in modulation of insulin-stimulated glucose uptake in the patients we studied.

    View details for Web of Science ID A1990EF13200038

    View details for PubMedID 2229287

  • EFFECT OF PRAZOSIN TREATMENT ON HDL KINETICS IN PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Sheu, W. H., Swislocki, A. L., Hoffman, B. B., Reaven, G. M., CHEN, Y. D. 1990; 3 (10): 761-768

    Abstract

    The effect of prazosin treatment on blood pressure, plasma HDL-cholesterol concentration, and apoprotein-AI/HDL (apoAI/HDL) kinetics was studied in 11 patients with mild hypertension. Blood pressure (mean +/- SEM) fell from 143 +/- 1/96 +/- 1 to 134 +/- 1/86 +/- 1 mm Hg after 4 to 5 months of prazosin treatment (P less than .001), associated with an increase in plasma HDL-cholesterol concentration from 38 +/- 2 to 46 +/- 2 mg/dL (P less than .001). Both the fractional catabolic rate (FCR) and total synthetic rate of apoAI/HDL, which were higher than previous reported values for normal individuals, decreased from 0.36 +/- 0.02 to 0.30 +/- 0.02 L/day and 17.4 +/- 1.1 to 13.8 +/- 1.1 mg/kg/min, respectively. These changes were statistically significant, and the post-treatment values for both variables were now within the normal range. When the decay curve was further analyzed by nonlinear curve fitting, it was shown that the return to normal of the FCR of apoAI/HDL in patients treated with prazosin was accounted for by the decrease of the decay constants of the second [p(2)] and third [p(3)] components of the 125I-AI/HDL disappearance curve. In conclusion, abnormalities in HDL concentration and HDL kinetics exist in patients with very mild hypertension. These defects were significantly improved with prazosin treatment, and this may render the compound of particular clinical benefit in the treatment of patients with mild hypertension.

    View details for Web of Science ID A1990ED20500005

    View details for PubMedID 2121164

  • EFFECT OF ACARBOSE ON CARBOHYDRATE AND LIPID-METABOLISM IN NIDDM PATIENTS POORLY CONTROLLED BY SULFONYLUREAS DIABETES CARE Reaven, G. M., LARDINOIS, C. K., GREENFIELD, M. S., Schwartz, H. C., Vreman, H. J. 1990; 13: 32-36

    Abstract

    The ability of acarbose to lower plasma glucose concentration was studied in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were poorly controlled by diet plus sulfonylurea drugs. Patients were studied before and 3 mo after the addition of acarbose to their treatment program, and a significant improvement in glycemic control was noted. Although the decrease in fasting plasma glucose concentration was modest (12.0 +/- 0.8 to 10.8 +/- 0.3 mM), average postprandial plasma glucose concentration decreased by 3.4 mM. When acarbose therapy was discontinued in 5 patients, plasma glucose levels rapidly returned toward pretreatment levels. In addition to the improvement in glycemia, acarbose treatment also led to a significant reduction in HbA1c (7.4 +/- 0.2 to 6.4 +/- 0.2%, P less than 0.01) and triglyceride (2.4 +/- 0.1 to 2.1 +/- 0.1 mM, P less than 0.01) concentrations. Neither the plasma insulin response to meals nor insulin-stimulated glucose uptake improved with acarbose therapy, consistent with the view that acarbose improves glycemic control by delaying glucose absorption. Considerable individual variation was noted in the response to acarbose, and the results in 4 patients were dramatic, with striking reductions in both fasting and postprandial glucose concentrations. The addition of acarbose to patients with NIDDM not well controlled by sulfonylureas appears to have significant clinical benefit.

    View details for Web of Science ID A1990DR37200006

    View details for PubMedID 2209341

  • EFFECTS OF A FRUCTOSE-ENRICHED DIET ON PLASMA-INSULIN AND TRIGLYCERIDE CONCENTRATION IN SHR AND WKY RATS HORMONE AND METABOLIC RESEARCH Reaven, G. M., Ho, H., Hoffman, B. B. 1990; 22 (7): 363-365

    Abstract

    Significant increases (P less than 0.001) in plasma insulin and triglyceride concentrations and in blood pressure were seen when SHR and WKY rats ate a fructose-enriched diet for 14 days. However, all of the changes were significantly accentuated (P less than 0.02-0.001) in SHR rats. Specifically the increment in plasma insulin concentration following the fructose-enriched diet was 42 +/- 4 microU/ml in SHR as compared to 25 +/- 4 microU/ml in WKY rats (P less than 0.001). Plasma triglyceride concentrations also increased to a greater degree in response to fructose in SHR rats (260 +/- 24 vs. 136 +/- 20 mg/dl, P less than 0.001). Finally, the fructose-induced increase in blood pressure of 29 +/- 4 mm of Hg in SHR rats was greater (P less than 0.02) than that seen in WKY rats (19 +/- 2 mm of Hg). There was no change in plasma glucose concentration in response to the fructose diet. WKY rats gained more weight than did the SHR rats. Thus, although plasma triglyceride and insulin concentration and blood pressure increased when either WKY or SHR rats consumed a fructose enriched diet, the magnitude of these changes was greater in SHR rats.

    View details for Web of Science ID A1990DP87800001

    View details for PubMedID 2205554

  • EFFECT OF DIFFERENCE IN GLUCOSE-INFUSION RATE ON QUANTIFICATION OF HEPATIC GLUCOSE-PRODUCTION JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sheu, W. H., Hollenbeck, C. B., Wu, M. S., Jaspan, J. B., CHEN, Y. D., Reaven, G. M. 1990; 70 (5): 1354-1360

    Abstract

    This study was carried out to determine whether hepatic glucose production (HGP) could be suppressed in normal subjects by infusing different amounts of glucose, in the absence of significant changes in steady state plasma glucose (SSPG) or insulin (SSPI) concentrations. Consequently, subjects were infused with somatostatin (215 nmol/h), insulin (28.7 pmol/m2.min), and amounts of glucose varying from 0-200 mumol/m2.min in the absence or presence of glucagon (5.2 pmol/m2.min). SSPI concentrations were constant (60-70 pmol/L) during these studies, and values for the total glucose appearance rate (glucose infusion rate plus HGP) and SSPG did not vary significantly as a function of the rate of exogenous glucose infusion. However, values for HGP fell in response to increases in glucose infusion rate and could be suppressed to approximately 50% of the original value despite the fact that SSPG, SSPI, and glucose appearance rate did not change significantly. These data indicate that HGP can be regulated by varying the rate of exogenous glucose infusion during glucose clamp studies.

    View details for Web of Science ID A1990DC73800021

    View details for PubMedID 1970829

  • EFFECT OF CHRONIC-RENAL-FAILURE ON HIGH-DENSITY-LIPOPROTEIN KINETICS KIDNEY INTERNATIONAL Fuh, M. M., Lee, C. M., Jeng, C. Y., Shen, D. C., Shieh, S. M., Reaven, G. M., CHEN, Y. D. 1990; 37 (5): 1295-1300

    Abstract

    Plasma lipid and lipoprotein concentration and high density lipoprotein (HDL) kinetics were determined in control subjects and patients with chronic renal failure (CRF). Results demonstrated that plasma triglyceride (TG) concentration was significantly higher (P less than 0.001) in patients with CRF, associated with a significant increase in plasma VLDL-cholesterol (P less than 0.002) and a significant decrease (P less than 0.05) in plasma HDL-cholesterol concentration. The rate of removal of 125I-apoAI/HDL from plasma was slower (P less than 0.001) in the patients with CRF, resulting in an increase in the residence time of 125I-apoAI/HDL (P less than 0.001) and a decrease in the fractional catabolic rate (P less than 0.001). Since plasma apoAI concentration was lower in patients with CRF, total apoAI/HDL synthetic rate was also significantly (P less than 0.05) decreased. These data provide support for the view that low plasma HDL-cholesterol concentrations in patients with CRF are related to decreases in the synthetic rate of apoAI/HDL.

    View details for Web of Science ID A1990DA26900012

    View details for PubMedID 2111860

  • GLUCOREGULATION AND HORMONAL RESPONSES TO MAXIMAL EXERCISE IN NON-INSULIN-DEPENDENT DIABETES JOURNAL OF APPLIED PHYSIOLOGY Kjaer, M., Hollenbeck, C. B., FREYHEWITT, B., Galbo, H., Haskell, W., Reaven, G. M. 1990; 68 (5): 2067-2074

    Abstract

    Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990DG20500044

    View details for PubMedID 2193907

  • DOES GLUCAGON INCREASE PLASMA-FREE FATTY-ACID CONCENTRATION IN HUMANS WITH NORMAL GLUCOSE-TOLERANCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Wu, M. S., Jeng, C. Y., Hollenbeck, C. B., CHEN, Y. D., JASPAN, J., Reaven, G. M. 1990; 70 (2): 410-416

    Abstract

    To evaluate the effect of glucagon on regulation of plasma FFA concentration, continuous iv infusions of either somatostatin (S) or somatostatin (S) plus glucagon (G) were administered to 18 individuals with normal glucose tolerance. In 9 of these individuals there was no insulin replacement, whereas in the other 9 individuals enough insulin was infused to restore the insulin concentration to the basal level. Measurements were made of plasma glucose, insulin, G, and FFA concentrations as well as hepatic glucose production (Ra). The results indicated that plasma FFA concentrations were significantly lower when G was infused (S greater than S + G) regardless of whether insulin was infused. However, similar elevations of the plasma G concentration did lead to higher values of Ra and plasma glucose, although the basal concentration of plasma insulin decreased the increases in Ra and plasma glucose caused by G. The ability of a similar amount of insulin to lower plasma FFA concentrations was greater in magnitude than the decrease in Ra. These data indicate that G does not increase plasma FFA concentrations in normal individual, and that insulin plays a role of greater magnitude in suppression of plasma FFA concentrations than in inhibition of Ra.

    View details for Web of Science ID A1990CL67600020

    View details for PubMedID 1967614

  • DIFFERENCES IN INSULIN-INDUCED GLUCOSE-UPTAKE AND ENZYME-ACTIVITY IN RUNNING RATS JOURNAL OF APPLIED PHYSIOLOGY Rodnick, K. J., Mondon, C. E., Haskell, W. L., Azhar, S., Reaven, G. M. 1990; 68 (2): 513-519

    Abstract

    To evaluate the relationship between enhanced insulin action and level of exercise training, in vivo glucose uptake was assessed in the absence of added insulin and during insulin-stimulated conditions for three activity levels of voluntarily trained rats (low 2-5 km/day, medium 6-9 km/day, high 11-16 km/day). After rats rested for 24 h and fasted overnight, glucose uptake was estimated by comparing steady-state serum glucose (SSSG) levels at low insulin (SSSI) concentrations achieved during an insulin suppression test. In the absence of added insulin, SSSI averaged approximately 20 microU/ml and glucose uptake was similar for high runners and younger weight-matched controls. However, with insulin added to sustain SSSI at approximately 35 microU/ml, SSSG was significantly reduced in all runners (P less than 0.02), with the lowest value attained in high runners. Fasting serum triglycerides were also reduced in all runners (P less than 0.05), with the lowest values seen in medium and high runners. The concentration of glycogen in liver and select skeletal muscles at the start of the study was not different between trained and control rats, suggesting that enhanced insulin-stimulated glucose uptake was not the result of lower glycogen levels. In addition, glycogen synthase and succinate dehydrogenase activities in biceps femoris muscle were only elevated for high runners, but glycogen synthase activity was not enhanced in plantaris muscle and was decreased in soleus muscle. These findings indicate that enhanced insulin-stimulated glucose uptake and reduced serum triglyceride concentrations induced in exercise-trained rats at varying activity levels are dissociated from changes in glycogen synthase and oxidative enzyme activity for skeletal muscle.

    View details for Web of Science ID A1990CQ88000012

    View details for PubMedID 2108119

  • EFFECT OF METFORMIN ON CARBOHYDRATE AND LIPOPROTEIN METABOLISM IN NIDDM PATIENTS DIABETES CARE Wu, M. S., Johnston, P., Sheu, W. H., Hollenbeck, C. B., Jeng, C. Y., Goldfine, I. D., CHEN, Y. D., Reaven, G. M. 1990; 13 (1): 1-8

    Abstract

    The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after approximately 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was less than 25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P less than 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.

    View details for Web of Science ID A1990CG58200001

    View details for PubMedID 2404714

  • RELATIONSHIP BETWEEN HYPERGLYCEMIA AND COGNITIVE FUNCTION IN OLDER NIDDM PATIENTS DIABETES CARE Reaven, G. M., Thompson, L. W., NAHUM, D., HASKINS, E. 1990; 13 (1): 16-21

    Abstract

    The nature and extent of cognitive impairment was examined in 29 healthy elderly subjects (mean age 69.8 yr) with non-insulin-dependent diabetes mellitus (NIDDM) and 30 demographically similar nondiabetic community volunteers (mean age 68 yr). Measures of verbal learning, abstract reasoning, and complex psychomotor functioning were performed more poorly by diabetic than nondiabetic subjects. Conversely, there were no between-group differences in performance on tasks involving pure motor speed and simple verbal abilities. Within the diabetic group, individuals with poorer metabolic control performed more poorly on tasks involving learning, reasoning, and complex psychomotor performance, although this relationship was not evident for simple verbal or motor tasks. These data indicate that older people with NIDDM who are functioning well and perceive themselves as in good health are likely to manifest greater deficits than healthy elderly people in processing complex verbal or nonverbal material. Possible explanatory mechanisms are discussed, and directions for future research are explored.

    View details for Web of Science ID A1990CG58200003

    View details for PubMedID 2298111

  • DIETARY-MANAGEMENT OF NURSING-HOME RESIDENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS AMERICAN JOURNAL OF CLINICAL NUTRITION Coulston, A. M., Mandelbaum, D., Reaven, G. M. 1990; 51 (1): 67-71

    Abstract

    Eighteen residents with non-insulin-dependent diabetes mellitus (NIDDM) from two skilled nursing facilities were monitored for glycemic control on diabetic and regular diets provided by the institution. Weekly fasting plasma glucose and 1-d dietary intake were followed for 16 wk: 4 wk on diabetic diets before and after an 8-wk regular-diet period. All residents were in good glycemic control (fasting plasma glucose 7.0 +/- 0.6 mmol/L) at entry into the study. During the regular-diet period, fasting plasma glucose increased an average of 0.6 mmol/L for all residents. Caloric intake increased during the regular-diet period although body weight did not change significantly. In both study periods nutrient intake of the residents met or exceeded the Recommended Dietary Allowances for the age group. These results indicate that the short-term substitution of regular for diabetic diets did not result in gross deterioration of glycemic control in patients with NIDDM confined to chronic-care facilities.

    View details for Web of Science ID A1990CJ82400011

    View details for PubMedID 2404398

  • Hypertension as a disease of carbohydrate and lipoprotein metabolism. American journal of medicine Reaven, G. M., Hoffman, B. B. 1989; 87 (6A): 2S-6S

    Abstract

    Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and both hyperinsulinemic and hypertriglyceridemic when compared with matched control groups with normal blood pressure. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in rat models of hypertension, including spontaneously hypertensive rats and Sprague-Dawley rats fed a fructose-enriched diet, and the defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Furthermore, experimental interventions that prevent insulin resistance and/or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Finally, endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease, and may contribute to the increased prevalence of ischemic heart disease in patients with high blood pressure. The fact that past antihypertensive treatment has not focused on these metabolic abnormalities, and, indeed, may have exacerbated them, could help explain why it has been difficult to show that lowering blood pressure decreases risk of coronary artery disease. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and the clinical course of hypertension.

    View details for PubMedID 2688409

  • ABNORMAL INSULIN METABOLISM BY SPECIFIC ORGANS FROM RATS WITH SPONTANEOUS HYPERTENSION AMERICAN JOURNAL OF PHYSIOLOGY Mondon, C. E., Reaven, G. M., Azhar, S., Lee, C. M., Rabkin, R. 1989; 257 (4): E491-E498

    Abstract

    Spontaneously hypertensive rats (SHR) have been shown to be both insulin resistant and hyperinsulinemic after oral glucose administration or infusion of exogenous insulin during an insulin suppression test. To determine if this hyperinsulinemia may be due to decreased removal of insulin, the metabolic clearance (k) of insulin was measured in isolated perfused liver, kidney, and hindlimb skeletal muscle from SHR and Wistar-Kyoto (WKY) control rats. The data indicate that the k for insulin removal by liver was similar in SHR and WKY rats, averaging 287 +/- 18 and 271 +/- 10 microliters.min-1.g-1 liver, respectively. In contrast, the k for insulin removal by hindlimbs from SHR was decreased 37% (P less than 0.001) compared with WKY rats (8.6 +/- 0.5 vs. 13.7 +/- 0.7 microliters.min-1.g-1 muscle), and this decrease was not accompanied by decreased binding of insulin to its receptor in plantaris muscle. Although the removal of insulin by glomerular filtration was similar in SHR and WKY rats (653 +/- 64 microliters/min vs. 665 +/- 90 microliters.min-1.kidney-1), total insulin removal by kidney was significantly lower (P less than 0.05) in SHR (710 +/- 78 microliters/min) compared with WKY rats (962 +/- 67 microliters/min), due to decreased peritubular clearance of insulin in SHR (56 +/- 73 vs. 297 +/- 59 microliters/min, P less than 0.05). These findings suggest that the decreased clearance of insulin in SHR rats was possibly not due to impaired hepatic removal of insulin but rather to decreased removal by skeletal muscle and kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989CC64500037

    View details for PubMedID 2679128

  • RESISTANCE TO INSULIN-STIMULATED GLUCOSE-UPTAKE IN ADIPOCYTES ISOLATED FROM SPONTANEOUSLY HYPERTENSIVE RATS DIABETES Reaven, G. M., Chang, H., Hoffman, B. B., Azhar, S. 1989; 38 (9): 1155-1160

    Abstract

    The ability of insulin to stimulate glucose uptake and inhibit catecholamine-induced lipolysis was measured in adipocytes of similar size isolated from SHR and WKY rats. The results indicate that glucose transport was decreased in adipocytes from SHR rats; both basal (19 +/- 2 vs. 32 +/- 2 fmol.cell-1.s-1, P less than .001) and maximal (207 +/- 30 vs. 373 +/- 20 fmol.cell-1.s-1, P less than .01) insulin-stimulated glucose transport were lower in SHR than in WKY rats. In addition, the EC50 of insulin-stimulated glucose uptake was higher (921 +/- 82 vs. 557 +/- 69 pM insulin, P less than .05) in adipocytes from SHR rats than from WKY rats. The ability of phenylisopropyladenosine (PIA) to modulate basal and maximal insulin-stimulated glucose uptake was compared in adipocytes from SHR and WKY rats. These results also demonstrated that glucose uptake was decreased in adipocytes from SHR rats and that PIA similarly enhanced both basal and maximal insulin-stimulated glucose uptake in adipocytes from both groups. Although maximal isoproterenol-stimulated lipolysis was decreased in adipocytes from SHR rats, the ability of insulin to inhibit catecholamine-stimulated lipolysis was at least as great in adipocytes from SHR as from WKY rats. Despite the decrease in insulin-stimulated glucose transport in isolated adipocytes from SHR rats, total number of insulin receptors, their affinity for insulin, and the ability of insulin to stimulate receptor-associated tyrosine kinase activity were similar in adipocytes from SHR and WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989AN36100013

    View details for PubMedID 2670644

  • EFFECT OF AGE ON GLUCOSE-TOLERANCE AND GLUCOSE-UPTAKE IN HEALTHY-INDIVIDUALS JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Reaven, G. M., Chen, N., Hollenbeck, C., CHEN, Y. D. 1989; 37 (8): 735-740

    Abstract

    Plasma glucose and insulin responses and basal and insulin-stimulated glucose uptake were determined in 24 non-obese, healthy, physically active individuals, divided into two groups on the basis of age. The mean (+/- SEM) age of the younger group was 33 +/- 3 years, in contrast to an age of 64 +/- 2 years for the older group. Plasma glucose concentrations were significantly higher (two-way ANOVA, P less than .001) for three hours after a 75 g oral glucose challenge in the older group, as was the plasma insulin response (two-way ANOVA, P less than .001). Furthermore, there was a significant correlation between age and total plasma glucose (r = 0.63, P less than .001) and insulin (r = 0.44, P less than .01) during the glucose tolerance test. However, the magnitude of the decrease in glucose tolerance with age was relatively modest. For example, total plasma glucose response was only 11% higher in the older group, and the plasma glucose concentration 120 minutes after the oral glucose load only increased approximately 2 mg/dL per decade. Glucose uptake during euglycemic clamp studies was also reduced in the older group, and this was true if the clamps were performed at plasma insulin concentration of approximately 10 microU/mL (P less than .05) or 60 microU/mL (P less than .10). However the differences were relatively modest in magnitude, ie, 10-25%. The fact that the increase in glucose uptake when plasma insulin was raised six-fold was similar in both groups suggests that insulin sensitivity does not decline with age.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989AJ47000009

    View details for PubMedID 2666485

  • SOMATOSTATIN INHIBITION OF FRUCTOSE-INDUCED HYPERTENSION HYPERTENSION Reaven, G. M., Ho, H., Hoffmann, B. B. 1989; 14 (2): 117-120

    Abstract

    The role of insulin resistance and hyperinsulinemia in the etiology of fructose-induced hypertension was studied in male Sprague-Dawley rats. Rats consumed a fructose-enriched diet (containing 66% of total calories as fructose) for 11 days and were infused continuously during the last 7 days with either a somatostatin analogue or vehicle. At the end of this period, rats receiving the somatostatin analogue had a lower plasma insulin concentration (52 +/- 4 vs. 70 +/- 6 microunits/ml, p less than 0.01) and a lower blood pressure (133 +/- 2 vs. 150 +/- 2 mm Hg) than did the rats infused with the control solution. In addition, the increase in plasma triglyceride concentration in response to the fructose-enriched diet was significantly attenuated (p less than 0.001) in the rats infused with somatostatin. These data provide further support that the increase in blood pressure that occurs when normal rats are fed a high fructose diet is dependent on the ability of this intervention to cause insulin resistance and hyperinsulinemia.

    View details for Web of Science ID A1989AK48000001

    View details for PubMedID 2569446

  • INSULIN RESISTANCE AND HYPERTRIGLYCERIDEMIA IN NONDIABETIC RELATIVES OF PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Laws, A., Stefanick, M. L., Reaven, G. M. 1989; 69 (2): 343-347

    Abstract

    Plasma glucose, FFA, and insulin responses to an oral glucose challenge, plasma lipid and lipoprotein concentrations, and the ability of insulin to stimulate glucose disposal were measured in 35 nondiabetic sedentary and overweight subjects. The subjects were divided into 2 groups on the basis of the presence (n = 19) or absence (n = 16) of a history of a first degree relative with noninsulin-dependent diabetes. The 2 groups were similar in age, body mass index, waist to hip ratio, and maximal aerobic capacity. The results demonstrated that the ability of insulin to stimulate disposal of a glucose load was significantly reduced in the subjects with a positive family history of noninsulin-dependent diabetes. In addition, these individuals had significantly higher plasma triglyceride and very low density lipoprotein cholesterol concentrations. Since all environmental factors known to modify insulin action and very low density lipoprotein metabolism were equal in the 2 groups, these data suggest that the metabolic differences noted are likely to be genetic in origin.

    View details for Web of Science ID A1989AF97500020

    View details for PubMedID 2666429

  • INSULIN RESISTANCE, GLUCOSE-INTOLERANCE AND HYPERINSULINEMIA IN PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF HYPERTENSION Swislocki, A. L., Hoffman, B. B., Reaven, G. M. 1989; 2 (6): 419-423

    Abstract

    Plasma glucose and insulin responses to an oral glucose challenge and insulin-stimulated glucose uptake were measured in 47 age-, weight-, and sex-matched lean white men (16 with normal blood pressure, 14 with untreated hypertension, nine treated with a thiazide diuretic only, and eight treated with combined diuretic and beta-adrenergic antagonist drugs). Following a 75-g glucose dose, plasma glucose and insulin were measured for a three-hour period. In separate studies, insulin-stimulated glucose uptake was estimated by measuring the steady-state plasma glucose (SSPG) and insulin (SSPI) concentrations achieved during the last 30 minutes of a 180-minute continuous infusion of somatostatin, insulin, and glucose (insulin suppression test). Under these conditions endogenous insulin secretion was suppressed, and differences in SSPG concentration allowed comparisons of the ability of exogenous insulin to stimulate disposal of an identical glucose load in different individuals. The results indicated that men with untreated hypertension had significantly elevated plasma glucose (P less than .001) and insulin concentrations (P less than .001) after an oral challenge compared to normal volunteers. Mean SSPG concentrations were also higher (P less than .05) than normal in patients with untreated hypertension.2+ Furthermore, plasma glucose and insulin concentrations after the oral glucose challenge and SSPG concentration during the insulin suppression test were higher in treated than in treated patients than in untreated patients with hypertension. These results confirm earlier observations that untreated patients with hypertension are insulin resistant, hyperglycemic, and hyperinsulinemic compared to a well-matched normotensive control group, and suggest that conventional treatment programs for lowering blood pressure many exaggerated these metabolic defects.

    View details for Web of Science ID A1989AD20000001

    View details for PubMedID 2667570

  • HOW DOES GLIBENCLAMIDE LOWER PLASMA-GLUCOSE CONCENTRATION IN PATIENTS WITH TYPE-2 DIABETES DIABETIC MEDICINE Jeng, C. Y., Hollenbeck, C. B., Wu, M. S., CHEN, Y. D., Reaven, G. M. 1989; 6 (4): 303-308

    Abstract

    Twelve patients with Type 2 diabetes and uncontrolled hyperglycaemia, never before treated with anti-diabetic drugs, were studied before and after several months of glibenclamide therapy. Fasting plasma glucose fell significantly (p less than 0.01) from 12.5 +/- 1.1 (mean +/- SE) to 8.3 +/- 0.4 mmol l-1 with glibenclamide therapy, as did glycosylated haemoglobin (from 12.0 +/- 0.9 to 8.4 +/- 0.7%). The improvement in blood glucose control was accompanied by an increase in postprandial plasma insulin concentration measured hourly from 0800 to 1600 h (p less than 0.001). Over the same period, plasma NEFA and lactate levels were significantly (p less than 0.001) lower after treatment with glibenclamide. Mean (+/- SE) insulin-mediated glucose metabolic clearance rate was evaluated during glucose clamp studies, and was significantly higher (p less than 0.001) after glibenclamide therapy at steady-state insulin levels of approximately 10 mU l-1 (53 +/- 3 vs 38 +/- 2 ml-2 min-1) and approximately 70 mU l-1 (78 +/- 9 vs 55 +/- 6 ml m-2 min-1). Hepatic glucose production was also lower following glibenclamide treatment at both the lower (56 +/- 5 vs 68 +/- 5 mg m-2 min-1) and higher 22 +/- 4 vs 32 +/- 6 mg m-2 min-1) insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989U499700004

    View details for PubMedID 2524334

  • CELLULAR TOLERANCE TO ADENOSINE RECEPTOR-MEDIATED INHIBITION OF LIPOLYSIS - ALTERED ADENSOINE 3',5'-MONOPHOSPHATE METABOLISM AND PROTEIN-KINASE ACTIVATION ENDOCRINOLOGY Hoffman, B. B., Prokocimer, P., Thomas, J. M., Vagelos, R., Chang, H., Reaven, G. M. 1989; 124 (5): 2434-2442

    Abstract

    Prolonged exposure of many types of cells to drugs or hormones that inhibit the activity of the enzyme adenylate cyclase, such as narcotics and alpha 2-adrenergic agonists, leads to enhanced accumulation of cAMP upon removal of the inhibitory drug. We have found previously that chronic infusion of the adenosine A1 receptor agonist phenylisopropyladenosine (PIA), an inhibitor of adenylate cyclase, into rats leads to enhanced isoproterenol-stimulated cAMP accumulation in adipocytes isolated from these animals. The enhanced cAMP accumulation was associated with an impaired ability of PIA to inhibit lipolysis in these cells. In the present study we have investigated the mechanism of the enhanced cAMP accumulation in adipocytes from PIA-infused rats and the relationship of these changes to the impaired antilipolytic action of the drug. The enhanced isoproterenol-stimulated cAMP accumulation in adipocytes prepared from PIA-infused rats was due to both an increased rate of cAMP synthesis and a decreased rate of cAMP metabolism at high concentrations of cAMP without a change in phosphodiesterase activity. There was heterologous desensitization of the ability of PIA, prostaglandin E1, and nicotinic acid to inhibit cAMP accumulation in the adipocytes from PIA-infused rats; there was an increase in the EC50 of each of these agonists, although maximal inhibition of cAMP accumulation was similar. The relationship between the activation of cAMP-dependent kinase and extent of lipolysis was similar in the two groups of cells. We demonstrated that the explanation for the impaired ability of PIA to decrease the rate of isoproterenol (10(-7) M)-stimulated lipolysis in the cells from the PIA-infused rats was due to the markedly increased concentrations of cAMP in these cells, which led to sufficient activation of the kinase to maintain a high rate of lipolysis even in the presence of PIA. In addition, we found that the changes induced by the PIA infusion were largely reversible over a 2-day period after discontinuing the PIA infusion. These results demonstrate that adipocytes from PIA-infused rats provide an interesting model to investigate the mechanisms of tolerance to inhibitory drugs.

    View details for Web of Science ID A1989U353100054

    View details for PubMedID 2539980

  • EFFECTS OF EXERCISE TRAINING ON THE RELATIONSHIP BETWEEN INSULIN BINDING AND INSULIN-STIMULATED TYROSINE KINASE-ACTIVITY IN RAT SKELETAL-MUSCLE METABOLISM-CLINICAL AND EXPERIMENTAL Santos, R. F., Mondon, C. E., Reaven, G. M., Azhar, S. 1989; 38 (4): 376-386

    Abstract

    The effect of exercise training on insulin binding and insulin receptor tyrosine kinase activity was studied using detergent solubilized wheat germ agglutinin (WGA)-agarose purified receptor preparations from rat biceps femoris (BF) and tensor fascia lata (TFL) muscles. Insulin receptor activity, as assessed by A14 [125I] insulin binding, was significantly elevated in BF of exercise-trained rats when compared with similar preparations from a sedentary control group. This increase in binding activity was due to change in Bmax not KD. In contrast, neither the Bmax nor the KD of insulin binding to TFL changed with exercise training. The structure of insulin receptors isolated from BF or TFL was unaltered by exercise training as determined by affinity labeling (alpha-subunit, molecular weight (mol wt) approximately 131 kilodaltons [kDa]) and electrophoretic mobility of the alpha- and beta-subunit. Furthermore, basal tyrosine kinase activity was not affected by exercise training in extracts from either BF or TFL. However, the insulin dependent increase in maximal tyrosine kinase activity (Vmax) of the BF, but not TFL, was enhanced by exercise training. Specifically, insulin stimulated phosphorylation of both the beta-subunit of the insulin receptor (auto phosphorylation) and of a synthetic peptide (exogenous phosphorylation) were increased over control values in BF from exercise-trained rats, whereas both measurements of tyrosine kinase activity of TFL from the two experimental groups were similar. In contrast, both insulin-stimulated autophosphorylation and tyrosine kinase activity were significantly decreased in BF of exercise-trained rats when normalized to insulin binding activity. This disassociation was only seen in BF from exercise-trained rats, and was not true of TFL. These data indicate that exercise training can lead to increases in insulin receptor number and tyrosine kinase activity, as well as modifying the relationship between these two variables. The changes noted are not observed in all exercising muscles, and their development seems to depend upon the fiber composition. These results emphasize the complex relationship that exists in the regulation of insulin action at the level of its receptor.

    View details for Web of Science ID A1989U017000016

    View details for PubMedID 2542721

  • IMPAIRED INSULIN-MEDIATED INHIBITION OF LIPOLYSIS AND GLUCOSE-TRANSPORT WITH AGING HORMONE AND METABOLIC RESEARCH Reaven, G. M., Chang, H., Hoffman, B. B. 1989; 21 (4): 168-171

    Abstract

    Regulation of hormone action with aging has been extensively studied; adipocytes provide an interesting model for some of these questions. We have compared the ability of insulin to stimulate glucose uptake and suppress lipolysis in adipocytes isolated from two month and twelve month-old rats. The ability of insulin to stimulate maximal glucose transport was decreased in adipocytes from the older rats (P less than 0.001); as well, insulin's EC50 was also higher (P less than 0.01) in these cells. Furthermore, these defects were present when insulin-stimulated glucose transport was measured in the presence or absence of adenosine deaminase which metabolizes endogenously released adenosine. Endogenously released adenosine is a stimulator of glucose transport and an inhibitor of lipolysis. Maximal suppression of isoproterenol-induced lipolysis by insulin was similar when adipocytes isolated from the two age groups were incubated in the absence of adenosine deaminase. However, maximal insulin-mediated suppression of lipolysis was found to be significantly decreased (P less than 0.001) in adipocytes isolated from older rats when the experiments were done in the presence of adenosine deaminase; also, insulin's EC50 was increased in these cells under these conditions (P less than 0.001). These results emphasize the importance of the adenosine receptor in modulating the response of isolated adipocytes to insulin, particularly for lipolysis, and document the presence of age-associated defects in insulin regulation of both glucose transport and lipolysis.

    View details for Web of Science ID A1989U585600002

    View details for PubMedID 2666294

  • THE COMBINED USE OF INSULIN AND SULFONYLUREA THERAPY IN PATIENTS WITH NON-INSULIN DEPENDENT DIABETES-MELLITUS HORMONE AND METABOLIC RESEARCH Reaven, G. M., FRAZE, E., Chen, N. Y., Hollenbeck, C., CHEN, Y. D. 1989; 21 (3): 132-136

    Abstract

    This study was initiated in order to evaluate the clinical efficacy of glipizide treatment in 18 patients with non-insulin dependent diabetes mellitus in poor glycemic control with insulin. Insulin dose was kept constant, and various facets of carbohydrate and lipid metabolism were evaluated before and from 4-6 months after the addition of glipizide. The results indicated that fasting and post-prandial glucose concentration were significantly (P less than 0.001) reduced following glipizide treatment, associated with a commensurate fall in glycosylated hemoglobin concentration. The average fall in fasting plasma glucose concentration in the total patient group approximated 60 mg/dl, and the mean decrement in 8 of the 18 patients who had a fall of more than 70 mg/dl in fasting glucose was 93 mg/dl. These results demonstrate that the addition of glipizide to the treatment program of patients with non-insulin dependent diabetes mellitus poorly controlled on insulin can lead to substantial clinical benefit.

    View details for Web of Science ID A1989U144700007

    View details for PubMedID 2663691

  • VARIATIONS IN RUNNING ACTIVITY AND ENZYMATIC ADAPTATIONS IN VOLUNTARY RUNNING RATS JOURNAL OF APPLIED PHYSIOLOGY Rodnick, K. J., Reaven, G. M., Haskell, W. L., Sims, C. R., Mondon, C. E. 1989; 66 (3): 1250-1257

    Abstract

    The running behavior and biochemical markers of oxidative and glycolytic activities associated with voluntary running activity were studied in male Sprague-Dawley rats after 6 wk of training in exercise wheel cages. Twenty-four-hour recordings of running activity were used to quantify the number of individual running bouts, their duration and running speed, and the distance run per day. We then established three categories of voluntary running activity based on the mean distance run per day during the last 3 wk of training: low-activity runners averaged 2-5 km/day, medium runners 6-9 km/day, and high runners greater than 11 km/day. Each group demonstrated an intermittent, nocturnal running pattern, at relatively high intensities, with a similar mean running speed for all groups (avg approximately 45 m/min). Differences in total distance run per day were the result of variations in both the number and duration of individual running bouts. Specifically, high runners (n = 7) had 206 +/- 30 individual running bouts per 24 h, each lasting 87 +/- 7 s; medium runners (n = 7) 221 +/- 22 running bouts, lasting 47 +/- 5 s; and low runners (n = 7) 113 +/- 7 bouts, each lasting 40 +/- 7 s. Voluntary running depressed the rate of body weight gain compared with sedentary control rats, despite an increased food and water intake for all runners. Furthermore, drinking activity was temporally associated with running periods.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989T698800032

    View details for PubMedID 2540143

  • PERSISTENCE OF HYPERTRIGLYCERIDEMIC EFFECT OF LOW-FAT HIGH-CARBOHYDRATE DIETS IN NIDDM PATIENTS DIABETES CARE Coulston, A. M., Hollenbeck, C. B., Swislocki, A. L., Reaven, G. M. 1989; 12 (2): 94-101

    Abstract

    Although low-fat high-carbohydrate diets are recommended for patients with non-insulin-dependent diabetes mellitus (NIDDM) in an effort to reduce the risk of coronary artery disease (CAD), the results of short-term studies have shown that these diets can lead to changes in carbohydrate and lipid metabolism associated with an increased risk of CAD. This study has extended these earlier observations by determining the metabolic effects of such diets over a longer period in these patients. The comparison diets contained either 40 or 60% of the total calories as carbohydrates, with reciprocal changes in fat content from 40 to 20% consumed in random order for 6 wk in a crossover experimental design. The ratio of polyunsaturated to saturated fat and the total cholesterol intake were held constant in the two diets. Plasma glucose and insulin concentrations were significantly (P less than .001) elevated throughout the day when patients consumed the 60% carbohydrate diet, and 24-h urinary glucose excretion more than doubled (0.8 vs. 1.8 mol/24 h). Fasting plasma total and very-low-density lipoprotein (VLDL) triglyceride (TG) concentrations increased by 30% (P less than .001) after 1 wk on the 60% carbohydrate diet, and the magnitude of carbohydrate-induced hypertriglyceridemia persisted unchanged throughout the 6-wk study period. Total plasma cholesterol concentrations were similar after both diets. However, VLDL cholesterol (VLDL-chol) was significantly increased, whereas both low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) chol concentrations were significantly decreased after consumption of the 60% carbohydrate diet. Consequently, neither total-chol-to-HDL-chol nor LDL-chol-to-HDL-chol ratios changed.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989T057000003

    View details for PubMedID 2539286

  • EFFECT OF PRAZOSIN TREATMENT ON CARBOHYDRATE AND LIPOPROTEIN METABOLISM IN PATIENTS WITH HYPERTENSION AMERICAN JOURNAL OF MEDICINE Swislocki, A. L., Hoffman, B. B., Sheu, W. H., CHEN, Y. D., Reaven, G. M. 1989; 86 (1B): 14-18

    Abstract

    This study evaluated the effect of prazosin in controlled mild hypertension and evaluated select metabolic changes that occurred with prazosin monotherapy. Various aspects of glucose, insulin, and lipid metabolism were studied before and after approximately 10 weeks of prazosin treatment in 12 patients with mild hypertension. Prazosin was well tolerated and induced a significant decrease (p less than 0.001) in both systolic and diastolic blood pressures, without any change in body weight. Plasma concentrations of glucose, free fatty acid, and lactate, which were measured hourly from 8 A.M. to 4 P.M. following meals consumed at 8 A.M. and noon, did not change with prazosin treatment. However, the plasma insulin response from 8 A.M. to 4 P.M. decreased significantly (p less than 0.001) following prazosin treatment. In addition, fasting plasma triglyceride and cholesterol concentrations were significantly lower (p less than 0.05) in prazosin-treated persons, as were postprandial triglyceride concentrations (p less than 0.001). Lower total plasma triglyceride and cholesterol concentrations were accounted for by decreases in very low-density lipoprotein cholesterol and triglyceride and low-density lipoprotein cholesterol and triglyceride, whereas both high-density lipoprotein triglyceride and high-density lipoprotein cholesterol concentrations increased following prazosin treatment. Finally, although both apolipoprotein A1 and apolipoprotein B concentrations decreased in association with prazosin treatment, the decrease in apolipoprotein B was much greater in magnitude, leading to an increase in the ratio of apolipoprotein A1 to apolipoprotein B. In this study, treatment of mild hypertension with prazosin led to lower blood pressures and changes in insulin and lipoprotein metabolism that are important in this patient population.

    View details for Web of Science ID A1989T105000004

    View details for PubMedID 2643861

  • RELATIONSHIP BETWEEN GLUCOSE-TOLERANCE, INSULIN-SECRETION, AND INSULIN ACTION IN NON-OBESE INDIVIDUALS WITH VARYING DEGREES OF GLUCOSE-TOLERANCE DIABETOLOGIA Reaven, G. M., Hollenbeck, C. B., CHEN, Y. D. 1989; 32 (1): 52-55

    Abstract

    Plasma glucose and insulin concentration following a 75 g oral glucose challenge and glucose uptake during a hyperinsulinaemic glucose clamp study were determined in 50 non-obese individuals. The study population was divided into five groups on the basis of their glucose tolerance: normal, impaired glucose tolerance, Type 2 (non-insulin-dependent) diabetes mellitus with fasting plasma glucose of less than 8 mmol/l, between 8-15 mmol/l, and more than 15 mmol/l. The plasma insulin response was significantly greater (p less than 0.001) than normal in those with either impaired glucose tolerance or Type 2 diabetes and a fasting plasma glucose concentration less than 8 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989T282000009

    View details for PubMedID 2651188

  • EFFECTS OF SUCROSE ON CARBOHYDRATE AND LIPID-METABOLISM IN NIDDM PATIENTS DIABETES CARE Hollenbeck, C. B., Coulston, A. M., Reaven, G. M. 1989; 12 (1): 62-66

    Abstract

    Recently, there has been increasing interest toward the liberalization of sucrose in the diets of individuals with non-insulin-dependent diabetes mellitus (NIDDM). However, there is evidence from several well-controlled prospective studies demonstrating that the consumption of moderate amounts of sucrose may result in hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and reduced high-density lipoprotein cholesterol concentrations. The fact that not all studies demonstrate these deleterious effects does not negate the positive data. The magnitude of the deleterious effects will probably vary with individual patients, baseline status, and amount of sucrose. Because these metabolic abnormalities are most disturbed in diabetes and are associated with increased risk of coronary artery disease, it would seem reasonable to continue to advise patients with NIDDM to limit sucrose consumption, at least until available data would allow us to predict in which individuals and at what level of sucrose consumption these adverse metabolic effects would not be present.

    View details for Web of Science ID A1989R641400021

    View details for PubMedID 2653750

  • Banting lecture 1988. Role of insulin resistance in human disease. Diabetes Reaven, G. M. 1988; 37 (12): 1595-1607

    Abstract

    Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for PubMedID 3056758

  • ROLE OF ABNORMAL FREE FATTY-ACID METABOLISM IN THE DEVELOPMENT OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS AMERICAN JOURNAL OF MEDICINE Reaven, G. M., CHEN, Y. D. 1988; 85 (5A): 106-112

    View details for Web of Science ID A1988R234600012

    View details for PubMedID 3057887

  • EFFECT OF TIME ON MEASUREMENT OF HEPATIC GLUCOSE-PRODUCTION JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM CHEN, Y. D., Swislocki, A. L., Jeng, C. Y., Juang, J. H., Reaven, G. M. 1988; 67 (5): 1084-1088

    Abstract

    Basal hepatic glucose production (HGP) was determined in obese and nonobese normal subjects and patients with noninsulin-dependent diabetes mellitus (NIDDM) using [3-3H]glucose and the nonsteady state equations of Steele. When HGP was estimated at hourly intervals from 0800-1300 h, it became evident that calculated values for HGP fell for the first 2-4 h until a plateau was reached, and this decline was quite precipitous during the first 2 h in patients with NIDDM. Furthermore, when the same patient with NIDDM was studied on two occasions, similar values for HGP were not uniformly obtained unless measurements were made at least 4 h after [3-3H] glucose administration. Since it has been the convention to use the nonsteady state equations of Steele to calculate HGP in patients with NIDDM 2 h after [3-3H] glucose administration, it is almost certain that published values for HGP in patients with NIDDM are falsely high. Based upon the data presented, we suggest that HGP using [3-3H]glucose and the nonsteady state Steele equations be measured for at least a 4-h period in patients with NIDDM in order to increase the validity of the calculated value.

    View details for Web of Science ID A1988Q768000033

    View details for PubMedID 3182959

  • ROLE OF INSULIN IN REGULATION OF LIPOPROTEIN METABOLISM IN DIABETES DIABETES-METABOLISM REVIEWS Reaven, G. M., CHEN, Y. D. 1988; 4 (7): 639-652

    View details for Web of Science ID A1988Q839400002

    View details for PubMedID 3069396

  • EFFECT OF ENPROSTIL ON PLASMA-GLUCOSE, INSULIN AND LIPID-METABOLISM IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS HORMONE AND METABOLIC RESEARCH Reaven, G. M., Swislocki, A. L., Jeng, C. Y., Hollenbeck, C. B., Schwartz, K., CHEN, Y. D. 1988; 20 (10): 633-636

    Abstract

    Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.

    View details for Web of Science ID A1988Q796600008

    View details for PubMedID 3146538

  • EVIDENCE FOR AGE-RELATED-CHANGES IN PYRIDINE-NUCLEOTIDE CONTENT OF ISOLATED RAT ISLETS HORMONE AND METABOLIC RESEARCH Azhar, S., HO, H. Y., Reaven, E., Reaven, G. M. 1988; 20 (9): 559-561

    Abstract

    The purpose of this study was to document the effect of age on alpha-glycerophosphate activity and pyridine nucleotide concentration in pancreatic islets isolated from rats. In order to do this, islets were isolated from pancreases of 2 and 12 month-old rats, and measurements made of alpha-glycerophosphate activity and of NAD+ and NADH, determinations were made following incubation at both basal (5.6 mM) and elevated glucose concentrations (28 mM). The results indicated that islet alpha-glycerophosphate dehydrogenase activity was decreased (P less than 0.001) by approximately 50% in the older rats. This was associated with an increase in mean (+/- SEM) basal NADH content (pmol/microgram DNA) in 12 month-old (4.48 +/- 0.31) as compared to 2 month-old rats (2.73 +/- 0.49). Although mean (+/- SEM) basal NAD+ levels (pmol/microgram DNA) were the same in 2 and 12 month-old rats (29.4 +/- 2.5 and 30.8 +/- 2.8, respectively), NAD+ content following incubation at elevated levels of glucose declined (absolutely and relatively) to a significantly greater degree in the younger rats. The incremental rise in islet NADH concentration following incubation at the elevated glucose concentration was similar in the two groups, but the relative increase was only approximately half as great in islets from 12 month-old rats. These data indicate that the age-related decline in the activity of alpha-glycerophosphate dehydrogenase, the enzyme regulating the glycerophosphate shuttle system in 12 month-old rats, is associated with alterations in islet pyridine nucleotide composition.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988Q576000005

    View details for PubMedID 3058568

  • AMINO-TERMINAL PEPTIDE OF GROWTH-HORMONE ENHANCES INSULIN ACTION IN NORMAL RATS ENDOCRINOLOGY Mondon, C. E., Reaven, G. M., Ling, N., Lewis, U. J., Frigeri, L. G. 1988; 123 (2): 827-833

    Abstract

    Earlier studies demonstrated that the 20K-dalton variant of human GH (hGH), which differs from hGH by deletion of the amino acid residues 32-46, has decreased insulin-like activity. The current study assessed whether a peptide representing this deleted region could enhance insulin-stimulated glucose uptake in the intact rat and if this effect was localized in liver and/or muscle. Peptides hGH-(32-46) and rat GH-(32-45) were used in these studies. Assessment of the action of a peptide was done by determining its effect on the steady state serum glucose (SSSG) concentration during an insulin suppression test. Glucose was infused alone and with two rates of infusion of insulin. The data indicated that neither of the GH peptides affected SSSG in the absence of exogenously administered insulin or at low (40 microU/ml) serum levels of insulin, but when serum insulin was increased to 77 microU/ml, a significant (P less than 0.05) decrease in SSSG was produced by the peptides. In subsequent studies isolated liver and hind limb skeletal muscle were perfused with a solution of hGH-(32-46). Basal glucose release from the liver was suppressed by both hGH-(32-46) and insulin alone, and this decrease was not enhanced by combining insulin with hGH-(32-46). Glucose uptake by skeletal muscle, expressed as a metabolic clearance constant (k), was enhanced by infusion of insulin and further increased with added peptide. Basal uptake was 6.67 microliter/min.g muscle; uptake was 8.17 microliter/min.g (P less than 0.01) after addition of 128 microU/ml insulin. This increased still farther to 9.24 microliter/min.g (P less than 0.05) when peptide was administered with insulin. These findings suggest that GH peptides independently suppress glucose outflow from the liver and potentiate insulin action by facilitating glucose uptake by peripheral tissues.

    View details for Web of Science ID A1988P507100021

    View details for PubMedID 3135175

  • ATTENUATION OF FRUCTOSE-INDUCED HYPERTENSION IN RATS BY EXERCISE TRAINING HYPERTENSION Reaven, G. M., Ho, H., Hoffman, B. B. 1988; 12 (2): 129-132

    Abstract

    This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988P816100007

    View details for PubMedID 3410522

  • MEASUREMENT OF PLASMA-GLUCOSE, FREE FATTY-ACID, LACTATE, AND INSULIN FOR 24-H IN PATIENTS WITH NIDDM DIABETES Reaven, G. M., Hollenbeck, C., Jeng, C. Y., Wu, M. S., CHEN, Y. D. 1988; 37 (8): 1020-1024

    Abstract

    Fasting and postprandial plasma glucose, free fatty acid (FFA), lactate, and insulin concentrations were measured at hourly intervals for 24 h in 27 nonobese individuals-9 with normal glucose tolerance, 9 with mild non-insulin-dependent diabetes mellitus (NIDDM, fasting plasma glucose less than 175 mg/dl), and 9 with severe NIDDM (fasting plasma glucose greater than 250 mg/dl). In addition, hepatic glucose production (HGP) was measured from midnight to 0800 in normal individuals and patients with severe NIDDM. Plasma glucose concentration was highest in patients with severe NIDDM, lowest in those with normal glucose tolerance, and intermediate in those with mild NIDDM (two-way ANOVA, P less than .001). Variations in plasma FFA and lactate levels of the three groups were qualitatively similar, with lowest concentrations seen in normal individuals, intermediate levels in the group with mild NIDDM, and the highest concentration in those with severe NIDDM (two-way ANOVA, P less than .001). Of particular interest was the observation that plasma FFA concentrations were dramatically elevated from midnight to 0800 in patients with severe NIDDM. The 24-h insulin response was significantly increased in patients with mild NIDDM, with comparable values seen in the other two groups. Values for HGP fell progressively throughout the night in normal individuals and patients with severe NIDDM, despite a concomitant decline in plasma glucose and insulin levels. Although the magnitude of the fall in HGP was greater in NIDDM, the absolute value was significantly (P less than .001) greater than normal throughout the period of observation.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988P437000004

    View details for PubMedID 3292322

  • RELATIONSHIP BETWEEN PLASMA-GLUCOSE AND INSULIN CONCENTRATION, GLUCOSE-PRODUCTION, AND GLUCOSE DISPOSAL IN NORMAL SUBJECTS AND PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES JOURNAL OF CLINICAL INVESTIGATION CHEN, Y. D., Jeng, C. Y., Hollenbeck, C. B., Wu, M. S., Reaven, G. M. 1988; 82 (1): 21-25

    Abstract

    The changes in hepatic glucose production (Ra), tissue glucose disposal (Rd), and plasma glucose and insulin concentration that took place over a 16-h period from 10 to 2 p.m. were documented in 14 individuals; 8 with non-insulin-dependent diabetes mellitus (NIDDM) and 6 with normal glucose tolerance. Values for Ra were higher than normal in patients with NIDDM at 10 p.m. (4.73 +/- 0.41 vs. 3.51 +/- 0.36 mg/kg per min, P less than 0.001), but fell at a much faster rate throughout the night than that seen in normal subjects. As a consequence, the difference between Ra in normal individuals and patients with NIDDM progressively narrowed, and by 2 p.m., had ceased to exist (1.75 +/- 0.61 vs. 1.67 +/- 0.47 mg/kg per min, P = NS). Plasma glucose concentration also declined in patients with NIDDM over the same period of time, but they remained quite hyperglycemic, and the value of 245 +/- 27 mg/dl at 2 p.m. was about three times greater than in normal individuals. Plasma insulin concentrations also fell progressively from 10 to 2 p.m., and were similar in both groups throughout most of the 16-h study period. Thus, the progressive decline in Ra in patients with NIDDM occurred despite concomitant falls in both plasma glucose and insulin concentration. Glucose disposal rates also fell progressively in both groups, but the magnitude of the fall was greater in patients with NIDDM. Consequently, Rd in patients with NIDDM was higher at 10 p.m. (3.97 +/- 0.48 vs. 3.25 +/- 0.13 mg/kg per min, P less than 0.001) and lower the following day at 2 p.m. (1.64 +/- 0.21 vs. 1.97 +/- 0.35 mg/kg per min, P less than 0.01). These results indicate that a greatly expanded pool size can exist in patients with NIDDM at a time when values for Ra are identical to those in normal subjects studied under comparable conditions, which suggests that fasting hyperglycemia in NIDDM is not simply a function of an increase in Ra.

    View details for Web of Science ID A1988P227600005

    View details for PubMedID 3292584

  • EVIDENCE OF ABNORMALITIES OF INSULIN METABOLISM IN RATS WITH SPONTANEOUS HYPERTENSION METABOLISM-CLINICAL AND EXPERIMENTAL Mondon, C. E., Reaven, G. M. 1988; 37 (4): 303-305

    Abstract

    Various aspects of insulin metabolism were compared in rats with spontaneous hypertension (SHR) and a suitable control group of similar sized Kyota Wistar (WKY) rats. The results indicated that the total integrated serum insulin response to an oral glucose challenge was significantly greater in the SHR rats, despite the fact that the total integrated serum glucose responses were similar in the two groups. This indirect evidence of resistance to insulin-stimulated glucose disposal was supported by the observation that the ability of similar serum concentrations of exogenous insulin to stimulate glucose disposal was reduced in SHR rats. In addition, the metabolic clearance rate of insulin was lower in the SHR rats. These data indicate that abnormalities in insulin secretion, action, and catabolism exist in rats with spontaneous hypertension. Whether this defect is unique to SHR rats, or common to all forms of experimental hypertension, is an important issue. Equally important is the relationship between the observed changes in insulin metabolism and the elevated blood pressure.

    View details for Web of Science ID A1988N034300001

    View details for PubMedID 3282146

  • COMPARISON OF PLASMA-GLUCOSE AND INSULIN RESPONSES TO MIXED MEALS OF HIGH-GLYCEMIC, INTERMEDIATE-GLYCEMIC, AND LOW-GLYCEMIC POTENTIAL DIABETES CARE Hollenbeck, C. B., Coulston, A. M., Reaven, G. M. 1988; 11 (4): 323-329

    Abstract

    Although plasma glucose and insulin responses have been shown to vary considerably when either normal subjects or patients with non-insulin-dependent diabetes mellitus (NIDDM) consume different carbohydrate-rich foods, it has been difficult to demonstrate this phenomenon when the same foods have been incorporated into a single mixed meal. To pursue this issue further, plasma glucose and insulin concentrations were determined at hourly intervals from 0800 to 2100 h in NIDDM patients in response to three meals (breakfast, lunch, and dinner) calculated to be of low-, intermediate-, and high-glycemic potency. The total integrated glucose response (mean +/- SE) during the day the low-glycemic meals were ingested was approximately 7% lower (2500 +/- 246 mg.dl-1.h-1) than on the days patients ate either the intermediate- (2701 +/- 280 mg.dl-1.h-1) or high- (2718 +/- 311 mg.dl-1.h-1) glycemic meals. When these data were analyzed by meal, it became apparent that the plasma glucose response to breakfast and dinner were essentially identical after consumption of the meals of either low-, intermediate-, or high-glycemic potency. Thus, the modest attenuation of the day-long glycemic response on the day patients ate the low-glycemic meal was due to a reduction in plasma glucose concentration after lunch. The day-long plasma insulin responses to the meals of different glycemic potency were qualitatively similar.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988M634100004

    View details for PubMedID 3042308

  • RESISTANCE TO INSULIN-STIMULATED-GLUCOSE UPTAKE IN PATIENTS WITH HYPERTENSION JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Shen, D. C., Shieh, S. M., Fuh, M. M., Wu, D. A., CHEN, Y. D., Reaven, G. M. 1988; 66 (3): 580-583

    Abstract

    Plasma glucose and insulin responses to a glucose challenge and insulin-stimulated glucose uptake were measured in 24 age-, weight-, and sex-matched Chinese men (8 with normal blood pressure, 8 with untreated hypertension, and 8 patients with hypertension treated with thiazide and beta-adrenergic antagonist drugs). Plasma glucose and insulin responses were determined by measuring plasma glucose and insulin concentrations before and at 30-min intervals for 2 h after a 75-g oral glucose dose. Insulin-stimulated glucose uptake was estimated by measuring the steady state plasma glucose (SSPG) and insulin (SSPI) concentrations achieved during the last 60 min of a 180-min continuous infusion of somatostatin, insulin, and glucose (insulin suppression test). Under these conditions endogenous insulin secretion was suppressed, and similar SSPI concentrations were achieved in all men; thus, the differences in the resultant SSPG concentrations allowed direct comparison of insulin's ability to stimulate disposal of an identical glucose load in different individuals. The results indicated that the men with hypertension, whether treated or untreated, had significantly elevated plasma glucose (P less than 0.001) and insulin (P less than 0.001) responses to the oral glucose dose compared to the normal men. Mean (+/- SE) SSPG concentrations were also higher (P less than 0.001) in the men with either untreated hypertension [219 +/- 9 mg/dL (12.2 +/- 0.5 mmol/L)] or treated hypertension [211 +/- 18 mg/dL (11.7 +/- 1.0 mmol/L)] than in the normal men [134 +/- 13 mg/dL (7.4 +/- 0.7 mmol/L)]. Since the mean SSPI concentrations were similar in the 3 groups [approximately 70 microU/mL (502 pmol/L)], insulin was less effective in promoting glucose disposal in both groups with hypertension. These results document the fact that patients with hypertension, whether treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic compared to a well-matched control group.

    View details for Web of Science ID A1988M305400018

    View details for PubMedID 3350907

  • ADDITIVE HYPOGLYCEMIC EFFECTS OF DRUGS THAT MODIFY FREE FATTY-ACID METABOLISM BY DIFFERENT MECHANISMS IN RATS WITH STREPTOZOCIN-INDUCED DIABETES DIABETES Reaven, G. M., Chang, H., Hoffman, B. B. 1988; 37 (1): 28-32

    Abstract

    In this study the effect of two drugs [etomoxir and nicotinic acid (NA)] on plasma glucose, free-fatty acid (FFA), and triglyceride (TG) concentrations was determined in rats with streptozocin (STZ)-induced diabetes. The two compounds modify FFA metabolism by different mechanisms, etomoxir (ethyl-2-[6-(4-cholorophenoxyl)-hexyl]oxirane-2-carboxylate) by inhibiting hepatic fatty acid oxidation, and NA by inhibiting lipolysis in adipose tissue. Diabetes was induced in male Sprague-Dawley rats, weighing approximately 400 g, by STZ injection (30 mg/kg i.v.), and the metabolic effects of the two drugs were studied 7-10 days later. The acute administration of either etomoxir or NA lowered plasma glucose concentrations in diabetic rats by approximately 150 mg/dl (P less than .001) in 4 h. However, the two drugs differed dramatically in their effects on plasma FFA and TG concentrations. Specifically, etomoxir produced striking increases in plasma FFA and TG concentrations, whereas NA administration caused a marked decrease. However, when NA was given in conjunction with etomoxir, NA prevented the increase in plasma FFA and TG concentration seen with etomoxir; the combination of NA and etomoxir approximately doubled the decrease in plasma glucose concentration produced by NA or etomoxir when given alone. Because plasma insulin concentrations did not change in response to either drug, whether administered singly or in combination, these metabolic effects do not result from a change in insulin secretion. These results suggest that modulation of FFA metabolism at the level of the adipocyte or the liver can have dramatic effects on carbohydrate and lipid metabolism.

    View details for Web of Science ID A1988L542900006

    View details for PubMedID 3275556

  • INSULIN-SECRETION AND INSULIN ACTION IN TAIWANESE WITH TYPE-2 DIABETES DIABETES RESEARCH AND CLINICAL PRACTICE Shen, D. C., Kuo, S. W., SHIAN, L. R., Fuh, M. T., Wu, D. A., CHEN, Y. D., Reaven, G. M. 1988; 4 (4): 289-293

    Abstract

    In contrast to the United State, type 2 diabetes appears to be a common occurrence in non-obese Asians. In order to evaluate the possibility that this epidemiologic difference was indicative of a basic metabolic phenomenon, estimates of insulin secretion and insulin action were generated in 32 Chinese males, 16 with type 2 diabetes and 16 with normal glucose tolerance. Half of the individuals in each diagnostic category were obese (body mass index greater than 28 kg/m2) and half were non-obese (less than 26 kg/m2). Plasma glucose responses to a 75-g oral glucose challenge were significantly higher in patients with type 2 diabetes, but did not vary significantly within either group as a function of obesity. Plasma insulin concentrations were lower than normal when patients with type 2 diabetes were compared to their weight-matched controls. In addition, the absolute insulin values also varied as a function of body weight, with higher plasma insulin concentrations observed in the obese individuals. Insulin action was estimated by determination of the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations during the last 60 min of a continuous 180-min intravenous infusion of somatostatin, crystalline insulin, and glucose. Under these conditions endogenous insulin secretion is suppressed, SSPI concentrations are similar in all individuals, and SSPG concentrations provide a quantitative estimate of insulin-stimulated glucose disposal. The results of these studies indicated that patients with type 2 diabetes had significantly elevated SSPG concentrations as compared to normals, and this was true whether the diabetic subjects were obese or non-obese.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988N153800007

    View details for PubMedID 2897274

  • LOWERING OF PLASMA-GLUCOSE IN DIABETIC RATS BY ANTILIPOLYTIC AGENTS AMERICAN JOURNAL OF PHYSIOLOGY Reaven, G. M., Chang, H., Ho, H., Jeng, C. Y., Hoffman, B. B. 1988; 254 (1): E23-E30

    Abstract

    Both nicotinic acid (NA) and the adenosine receptor agonist phenylisopropyladenosine (PIA) are potent antilipolytic agents. We have evaluated the ability of these compounds to lower plasma glucose concentration in 450-g male diabetic rats. Diabetes was induced by intravenous streptozotocin, and the rats were studied 7-10 days later. Mean (+/- SE) fasting glucose decreased 4 h after subcutaneous injections of PIA at 0 and 2 h. A similar change in plasma glucose level was also seen in rats injected with NA. The decrease in the concentration of plasma glucose in both instances was preceded by marked sustained reductions in plasma free fatty acid (FFA) concentrations; FFA decreased in PIA-injected rats and in response to NA. With injection of normal saline, neither plasma glucose nor FFA concentrations decreased in diabetic rats. There was no change in the plasma insulin concentration of rats that had hypoglycemic responses to PIA or NA. In vitro glucose uptake was determined in isolated adipocytes, and both PIA and NA were shown to increase basal and maximal insulin-stimulated glucose uptake. The stimulating effect of the two compounds was similar, and the magnitude of the effect was comparable in adipocytes from either normal or diabetic rats. As a result, neither NA nor PIA could restore the defects in glucose transport to normal in adipocytes from diabetic rats. Insulin-stimulated glucose uptake was assessed in vivo by determining the steady-state glucose response of diabetic rats to a continuous infusion of insulin and glucose and was found to be significantly enhanced in response to NA compared with NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1988L825500026

    View details for PubMedID 2962514

  • EFFECT OF INSULIN DEFICIENCY ON LOW-DENSITY LIPOPROTEIN METABOLISM IN RABBITS HORMONE AND METABOLIC RESEARCH Golay, A., ZECH, L., Shi, M. Z., CHIOU, Y. A., Reaven, G. M., CHEN, Y. D. 1988; 20 (1): 11-14

    Abstract

    These studies have been carried out in rabbits with alloxan-induced diabetes in order to see if insulin deficiency affects low density lipoprotein (LDL) catabolism. The results showed that plasma LDL-cholesterol was lower in diabetic rabbits, associated with a fall in the cholesterol to protein ratio of LDL particles. In addition, 125I-LDL disappeared more slowly from plasma of diabetic rabbits, leading to a significant reduction in fractional catabolic rate and a decrease in residence time of 125I-LDL. These data demonstrated that LDL composition and catabolism are greatly altered as a consequence of insulin deficiency.

    View details for Web of Science ID A1988M047700002

    View details for PubMedID 3286445

  • EVIDENCE OF A DEFECT IN INSULIN-RECEPTOR RECYCLING IN ADIPOCYTES FROM OLDER RATS AMERICAN JOURNAL OF PHYSIOLOGY Trischitta, V., Reaven, G. M. 1988; 254 (1): E39-E44

    Abstract

    Although insulin-stimulated glucose uptake is known to be decreased in adipocytes isolated from old obese rats, the cause of this defect is not totally understood. In the present study, we examined the possibility that insulin resistance is associated with defects in the intracellular processing of the insulin-receptor complex. Adipocytes were isolated from control (2-mo-old rats) and obese, insulin-resistant rats (12-mo-old rats), and the following measurements were made: 1) insulin-stimulated glucose uptake; 2) insulin binding; 3) insulin-receptor internalization and recycling; 4) accumulation of insulin within the cell; and 5) rate of loss of insulin from the cell. The results indicated that maximal insulin-stimulated glucose uptake was significantly reduced in adipocytes from obese, insulin-resistant rats (increase over basal value was 500 +/- 53% in obese rats and 1,200 +/- 96 in control rats, P less than 0.01). 125I-insulin (A14) binding (cell-associated radioactivity) and the internalization of the hormone-receptor complex were not different in the two groups of animals studied. In contrast, insulin-receptor recycling was significantly decreased in adipocytes from obese rats (72.0 +/- 6.1 vs. 93.6 +/- 2.6%, P less than 0.01). In addition, loss of intracellular radioactivity was significantly prolonged in insulin-resistant rats (t1/2 = 12.05 +/- 0.9 vs. 9.4 +/- 0.3 min, P less than 0.05). Thus adipocytes isolated from the older rats were resistant to the insulin effect on glucose uptake, and this defect was not associated with a reduction in insulin binding. However, there was a decrease in insulin receptor recycling, and this phenomenon may be related to the insulin resistance present in these cells.

    View details for Web of Science ID A1988L825500028

    View details for PubMedID 3276215

  • EFFECT OF AGE AND SEX ON RAT ENDOCRINE PANCREAS DIABETES REAVEN, E. P., Curry, D. L., Reaven, G. M. 1987; 36 (12): 1397-1400

    Abstract

    Maximal glucose-stimulated insulin secretion was quantified in perfused pancreases of 11-wk-old and 12-mo-old female and male rats. In addition, measurements were made of body weight, total pancreatic weight, and percentage of the pancreas occupied by islet tissue. Body weight (mean +/- SE) of male rats was greater than that of female rats at both 11 wk (319 +/- 3 vs. 237 +/- 13 g) and 12 mo (684 +/- 17 vs. 376 +/- 13 g) of age. Pancreatic weight and percentage of the pancreas occupied by islet tissue were also greater in male rats and increased in approximate proportion to the gain in weight. The first phase and the second phase of maximal glucose-stimulated insulin secretion were both qualitatively and quantitatively similar in all four groups of rats. However, because islet cell mass increased with age, maximal glucose-stimulated insulin secretion declined with age in rats of both sexes when expressed per unit islet tissue. Although the fall in insulin secretion (per islet cell mass) with age was observed in perfused pancreases from both male and female rats, the pancreases of female rats contained relatively less islet tissue and secreted more insulin per unit islet cell mass than pancreases of male rats at either age. Thus, there are sex differences in both islet cell structure and function, but the effect of age on endocrine pancreatic function seems to be independent of sex.

    View details for Web of Science ID A1987L177000007

    View details for PubMedID 3315787

  • FRUCTOSE-INDUCED INSULIN RESISTANCE AND HYPERTENSION IN RATS HYPERTENSION Hwang, I. S., Ho, H., Hoffman, B. B., Reaven, G. M. 1987; 10 (5): 512-516

    Abstract

    To determine if hypertension could be produced in normal rats by feeding them a fructose-enriched diet, Sprague-Dawley rats were fed either normal chow or a diet containing 66% fructose as a percentage of total calories for approximately 2 weeks. At the end of this period systolic blood pressure had increased from 124 +/- 2 to 145 +/- 2 (SEM) mm Hg in the fructose-fed rats, whereas no change occurred in the control group. In addition, hyperinsulinemia and hypertriglyceridemia were associated with hypertension in fructose-fed rats. The addition of clonidine to the drinking water inhibited fructose-induced hypertension, but not the increase in plasma insulin or triglyceride concentration seen in fructose-fed rats. Thus, the metabolic changes associated with fructose-induced hypertension are unlikely to be secondary to an increase in sympathetic activity. Whether or not this is also true of the hypertension remains to be clarified.

    View details for Web of Science ID A1987M462800008

    View details for PubMedID 3311990

  • IMPROVED INSULIN ACTION IN MUSCLE, LIVER, AND ADIPOSE-TISSUE IN PHYSICALLY TRAINED HUMAN-SUBJECTS AMERICAN JOURNAL OF PHYSIOLOGY Rodnick, K. J., Haskell, W. L., Swislocki, A. L., Foley, J. E., Reaven, G. M. 1987; 253 (5): E489-E495

    Abstract

    The present studies were initiated to assess the effect of insulin on muscle, liver, and adipose tissue in eight control and eight physically trained individuals matched for age and body mass index. Results indicated that percent body fat was 53% lower and maximal oxygen consumption 50% higher in physically trained subjects. Although the plasma glucose response to a standard oral glucose challenge was similar in the two groups, the insulin response was significantly lower in the trained individuals (P less than 0.001). Mean (+/- SE) insulin-stimulated glucose uptake, quantified in vivo by the euglycemic hyperinsulinemic clamp technique, was significantly greater in physically trained individuals at steady-state plasma insulin concentrations of approximately 10 microU/ml (3.41 +/- 0.14 vs. 2.73 +/- 0.22 mg.kg fat free mass-1.min-1, P less than 0.05) and 50 microU/ml (13.58 +/- 0.75 vs. 9.82 +/- 0.53 mg.kg fat free mass-1.min-1, P less than 0.001). In addition, mean (+/- SE) hepatic glucose production rate was lower in physically trained subjects at insulin levels of 10 microU/ml (0.63 +/- 0.19 vs. 1.19 +/- 0.22 mg.kg body wt-1.min-1, P less than 0.05) and 50 microU/min (0.18 +/- 0.14 vs. 0.60 +/- 0.17 mg.kg body wt-1.min-1, P less than 0.05). Finally, the ability of insulin to stimulate mean (+/- SE) glucose uptake above basal levels was greater in adipocytes isolated from trained individuals (94 +/- 10 vs. 56 +/- 14 fl.cell-1.s-1, P less than 0.01). On the other hand, no difference in specific binding of insulin to its receptor on monocytes was noted between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1987L134800018

    View details for PubMedID 3318492

  • STIMULATION AND INHIBITION OF LIPOLYSIS IN ISOLATED RAT ADIPOCYTES - EVIDENCE FOR AGE-RELATED-CHANGES IN RESPONSES TO FORSKOLIN AND PGE1 HORMONE AND METABOLIC RESEARCH Hoffman, B. B., Chang, H., Reaven, G. M. 1987; 19 (8): 358-360

    Abstract

    The ability of a number of hormones to activate cellular responses in a variety of cells declines with age. The mechanisms responsible for these alterations are complex and incompletely understood. Rat adipocytes have served as an important model to study blunted responses to stimulatory hormones which function by activating cAMP accumulation. We have previously found that the blunted lipolytic response of adipocytes from older rats to the beta adrenergic receptor agonist isoproterenol appeared to be due to a lessened ability of isoproterenol to activate cAMP accumulation. Further, the blunted response to isoproterenol was apparently caused by an accentuated inhibition of lipolysis, mediated by adenosine receptors activated by endogenously released adenosine. The present studies were designed to test and extend those conclusions. We have utilized forskolin to augment the cAMP accumulation that occurs in the presence of isoproterenol. Isoproterenol-activated lipolysis was greater in adipocytes from 2 month old rats compared with those from 12 month old rats (603 +/- 32 vs 450 +/- 29 nmol/10(5) cells/hr, P less than 0.01). However, in the presence of forskolin (10(-6) M), there was no significant difference in the response to isoproterenol between the two groups (646 +/- 23 vs 615 +/- 29 nmoles/10(5) cells/hr). As we had seen previously, the adenosine receptor agonist phenylisopropyladenosine more effectively inhibited lipolysis in the adipocytes from older rats. We now also find that PGE1 more efficaciously inhibits lipolysis in the cells from older rats. These data confirm that diminished cAMP accumulation in adipocytes from older rats appears to be a rate-limiting alteration in the regulation of lipolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1987J843800004

    View details for PubMedID 2822560

  • INSULIN SUPPRESSION OF PLASMA-FREE FATTY-ACID CONCENTRATION IN NORMAL INDIVIDUALS AND PATIENTS WITH TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES DIABETOLOGIA Swislocki, A. L., CHEN, Y. D., Golay, A., Chang, M. O., Reaven, G. M. 1987; 30 (8): 622-626

    Abstract

    In order to define the effect of Type 2 (non-insulin-dependent) diabetes mellitus on the ability of insulin to regulate plasma-free fatty acid (FFA) concentrations, we determined the plasma FFA response to the intravenous infusion of various amounts of insulin. Plasma FFA concentrations were higher in patients with Type 2 diabetes (two way analysis of variance, p less than 0.001) over a plasma insulin concentration which ranged from approximately 5 to 55 mU/l of insulin. Although plasma FFA concentrations were higher in patients with Type 2 diabetes at any given insulin concentration, the relative ability of insulin to suppress plasma FFA concentration to half the initial value was comparable in normal individuals and patients with Type 2 diabetes, occurring at a plasma insulin concentration of approximately 20 mU/l. These data demonstrate that plasma FFA levels are regulated over a narrow range of plasma insulin concentrations in humans, and that plasma concentrations are higher than normal in patients with Type 2 diabetes throughout this range.

    View details for Web of Science ID A1987J976200004

    View details for PubMedID 3308603

Conference Proceedings


  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • RELATIONSHIP BETWEEN INSULIN RESISTANCE AND HYPERTENSION Reaven, G. M. AMER DIABETES ASSOC. 1991: 33-38

    Abstract

    Patients with hypertension have been shown to be resistant to insulin-stimulated glucose uptake and to be both hyperinsulinemic and hypertriglyceridemic compared with matched normotensive control groups. These abnormalities are present before the institution of antihypertensive therapy and do not necessarily improve when blood pressure is effectively lowered. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and high blood pressure can be produced in fructose-fed Sprague-Dawley rats, but the development of these changes is inhibited by exercise training or somatostatin infusion. Furthermore, insulin-stimulated glucose uptake is lower in spontaneously hypertensive rats (SHRs) than Wistar-Kyoto rats, and this is associated with higher plasma triglyceride concentrations and blood pressure. In addition, a defect in insulin-stimulated glucose uptake can be shown in adipocytes isolated from SHRs, and the greater the degree of in vitro insulin resistance, the higher the plasma insulin concentration and blood pressure. These data strongly support the view that abnormalities of insulin and lipid metabolism are associated with high blood pressure in both patients and rodent models of experimental hypertension. In the latter context, endogenous hyperinsulinemia and hypertriglyceridemia are risk factors for coronary heart disease. The fact that antihypertensive treatment has not focused on correcting these metabolic abnormalities may explain why it has been difficult to show that lowering blood pressure decreases the risk of coronary heart disease. It can be argued that abnormalities of carbohydrate and lipoprotein metabolism play a role in both the etiology of hypertension and the clinical course of hypertensive patients.

    View details for Web of Science ID A1991GN81900006

    View details for PubMedID 1748055

  • INSULIN AND HYPERTENSION Reaven, G. M. MARCEL DEKKER INC. 1990: 803-816

    Abstract

    Patients with hypertension have been shown to be resistant to insulin-stimulated glucose uptake and hyperinsulinemic when compared to matched control groups with normal blood pressure. In addition, insulin resistance and hyperinsulinemia have been demonstrated in rat models of hypertension-including SHR rats and Sprague-Dawley rats fed a fructose-enriched diet. Furthermore, fructose-induced hypertension can be attenuated by experimental interventions which decrease insulin resistance and/or hyperinsulinemia. These observations raise the possibility that insulin resistance and hyperinsulinemia may play a role in blood pressure regulation. Finally, insulin resistance and hyperinsulinemia increase risk of coronary artery decrease in patients with hypertension, both directly, and indirectly by their influence on very low density and high density lipoprotein metabolism.

    View details for Web of Science ID A1990DT56600010

    View details for PubMedID 2208752

  • ROLE OF ABNORMALITIES OF CARBOHYDRATE AND LIPOPROTEIN METABOLISM IN THE PATHOGENESIS AND CLINICAL COURSE OF HYPERTENSION Reaven, G. M. LIPPINCOTT-RAVEN PUBL. 1990: S4-S7

    Abstract

    Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake. They are also hyperinsulinemic and hypertriglyceridemic when compared with matched control groups with normal blood pressure. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in rat models of hypertension, including spontaneous hypertensive rats and Sprague-Dawley rats fed a fructose-enriched diet. The defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Furthermore, experimental interventions that prevent insulin resistance or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate increases in blood pressure. Endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease (CAD), and they may contribute to the increased prevalence of ischemic heart disease in patients with high blood pressure. The fact that past antihypertensive treatment has not focused on these metabolic abnormalities, and indeed may have exacerbated them, could help explain why it has been difficult to show that lowering blood pressure decreases the risk of CAD. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and the clinical course of hypertension.

    View details for Web of Science ID A1990DG33600002

    View details for PubMedID 1694930

Stanford Medicine Resources: