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FAM13A affects body fat distribution and adipocyte function. Nature communications Fathzadeh, M. n., Li, J. n., Rao, A. n., Cook, N. n., Chennamsetty, I. n., Seldin, M. n., Zhou, X. n., Sangwung, P. n., Gloudemans, M. J., Keller, M. n., Attie, A. n., Yang, J. n., Wabitsch, M. n., Carcamo-Orive, I. n., Tada, Y. n., Lusis, A. J., Shin, M. K., Molony, C. M., McLaughlin, T. n., Reaven, G. n., Montgomery, S. B., Reilly, D. n., Quertermous, T. n., Ingelsson, E. n., Knowles, J. W. 2020; 11 (1): 1465
Abstract

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

View details for DOI 10.1038/s41467-020-15291-z

View details for PubMedID 32193374
Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control MATRIX BIOLOGY Nagy, N., Sunkari, V. G., Kaber, G., Hasbun, S., Lam, D. N., Speake, C., Sande, S., McLaughlin, T. L., Wight, T. N., Long, S. R., Bollyky, P. L. 2019; 80: 46?58
View details for DOI 10.1016/j.matbio.2018.09.003

View details for Web of Science ID 000471739100004
Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia OBESITY SURGERY Mulla, C. M., Goldfine, A. B., Dreyfuss, J. M., Houten, S., Pan, H., Pober, D. M., Albrechtsen, N., Svane, M. S., Schmidt, J. B., Holst, J., Craig, C. M., McLaughlin, T. L., Patti, M. 2019; 29 (7): 2092?99
View details for DOI 10.1007/s11695-019-03845-0

View details for Web of Science ID 000469767700012
Generating biosimilar therapeutic drugs through innovative technology and operational excellence NATURE Zhou, B. 2019; 569 (7755)
View details for Web of Science ID 000467473600008
A longitudinal big data approach for precision health NATURE MEDICINE Rose, S., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792-+
View details for DOI 10.1038/s41591-019-0414-6

View details for Web of Science ID 000468247800023
Longitudinal multi-omics of host-microbe dynamics in prediabetes. Nature Zhou, W., Sailani, M. R., Contrepois, K., Zhou, Y., Ahadi, S., Leopold, S. R., Zhang, M. J., Rao, V., Avina, M., Mishra, T., Johnson, J., Lee-McMullen, B., Chen, S., Metwally, A. A., Tran, T. D., Nguyen, H., Zhou, X., Albright, B., Hong, B., Petersen, L., Bautista, E., Hanson, B., Chen, L., Spakowicz, D., Bahmani, A., Salins, D., Leopold, B., Ashland, M., Dagan-Rosenfeld, O., Rego, S., Limcaoco, P., Colbert, E., Allister, C., Perelman, D., Craig, C., Wei, E., Chaib, H., Hornburg, D., Dunn, J., Liang, L., Rose, S. M., Kukurba, K., Piening, B., Rost, H., Tse, D., McLaughlin, T., Sodergren, E., Weinstock, G. M., Snyder, M. 2019; 569 (7758): 663?71
Abstract

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2Dbetter, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

View details for DOI 10.1038/s41586-019-1236-x

View details for PubMedID 31142858
Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia. Obesity surgery Mulla, C. M., Goldfine, A. B., Dreyfuss, J. M., Houten, S., Pan, H., Pober, D. M., Wewer Albrechtsen, N. J., Svane, M. S., Schmidt, J. B., Holst, J. J., Craig, C. M., McLaughlin, T. L., Patti, M. 2019
Abstract

BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics.RESULTS: The top-ranking differentially abundant protein at 120min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094�141 vs. 428�45, P<0.001, FDR<0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360�70 vs. 103�18, P=0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH.CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.

View details for PubMedID 30976983
A longitudinal big data approach for precision health. Nature medicine Sch�ssler-Fiorenza Rose, S. M., Contrepois, K. n., Moneghetti, K. J., Zhou, W. n., Mishra, T. n., Mataraso, S. n., Dagan-Rosenfeld, O. n., Ganz, A. B., Dunn, J. n., Hornburg, D. n., Rego, S. n., Perelman, D. n., Ahadi, S. n., Sailani, M. R., Zhou, Y. n., Leopold, S. R., Chen, J. n., Ashland, M. n., Christle, J. W., Avina, M. n., Limcaoco, P. n., Ruiz, C. n., Tan, M. n., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E. n., McLaughlin, T. L., Haddad, F. n., Snyder, M. P. 2019; 25 (5): 792?804
Abstract

Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n?=?109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8?years (median, 2.8?years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

View details for PubMedID 31068711
High Frequency Actionable Pathogenic Exome Variants in an Average-Risk Cohort. Cold Spring Harbor molecular case studies Rego, S., Dagan-Rosenfeld, O., Zhou, W., Sailani, M. R., Limcaoco, P., Colbert, E., Avina, M., Wheeler, J., Craig, C., Salins, D., Rost, H. L., Dunn, J., McLaughlin, T., Steinmetz, L. M., Bernstein, J. A., Snyder, M. P. 2018
Abstract

Exome sequencing is increasingly utilized in both clinical and non-clinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study. We analyzed exomes by identifying rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We then used American College of Medical Genetics (ACMG) guidelines for the classification of rare sequence variants. Additionally, we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes. Five had phenotypes or family histories associated with their genetic variants. The frequency of actionable variants is higher than that reported in most previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 63 participants (90%) had additional non-actionable findings, including 60 who were found to be carriers for recessive diseases and 21 who have increased Alzheimer's disease risk due to heterozygous or homozygous APOE e4 alleles (18 participants had both). Our results suggest that exome sequencing may have considerable more utility for health management in the general population than previously thought.

View details for PubMedID 30487145
Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control. Matrix biology : journal of the International Society for Matrix Biology Nagy, N., Sunkari, V. G., Kaber, G., Hasbun, S., Lam, D. N., Speake, C., Sanda, S., McLaughlin, T. L., Wight, T. N., Long, S. R., Bollyky, P. L. 2018
Abstract

Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is implicated in the pathogenesis of both type 1 diabetes (T1D) as well as type 2 diabetes (T2D) and has been postulated to be increased in these diseases due to hyperglycemia. We have examined the serum and tissue distribution of HA in human subjects with T1D and T2D and in mouse models of these diseases and evaluated the relationship between HA levels and glycemic control. We found that serum HA levels are increased in T2D but not T1D independently of hemoglobin-A1c, C-peptide, body mass index, or time since diabetes diagnosis. HA is likewise increased in skeletal muscle in T2D subjects relative to non-diabetic controls. Analogous increases in serum and muscle HA are seen in diabetic db/db mice (T2D), but not in diabetic DORmO mice (T1D). Diabetes induced by the beta-cell toxin streptozotozin (STZ) lead to an increase in blood glucose but not to an increase in serum HA. These data indicate that HA levels are increased in multiple tissue compartments in T2D but not T1D independently of glycemic control. Given that T2D but not T1D is associated with systemic inflammation, these patterns are consistent with inflammatory factors and not hyperglycemia driving increased HA. Serum HA may have value as a biomarker of systemic inflammation in T2D.

View details for PubMedID 30196101
Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Salehi, M., Vella, A., McLaughlin, T., Patti, M. 2018; 103 (8): 2815?26
Abstract

Hypoglycemia, occurring after bariatric and other forms of upper gastrointestinal surgery, is increasingly encountered by clinical endocrinologists. The true frequency of this condition remains uncertain, due, in part, to differences in the diagnostic criteria and in the affected populations, as well as relative lack of patient and physician awareness and understanding of this condition. Postbariatric hypoglycemia can be severe and disabling for some patients, with neuroglycopenia (altered cognition, seizures, and loss of consciousness) leading to falls, motor vehicle accidents, and job and income loss. Moreover, repeated episodes of hypoglycemia can result in hypoglycemia unawareness, further impairing safety and requiring the assistance of others to treat hypoglycemia.In this review, we summarize and integrate data from studies of patients affected by hypoglycemia after Roux-en-Y gastric bypass (RYGB) surgery, obtained from PubMed searches (1990 to 2017) and reference searches of relevant retrieved articles. Whereas hypoglycemia can also be observed after sleeve gastrectomy and fundoplication, this review is focused on post-RYGB, given the greater body of published clinical studies at present.Data addressing specific aspects of diagnosis, pathophysiology, and treatment were reviewed by the authors; when not available, the authors have provided opinions based on clinical experience with this challenging condition.Hypoglycemia, occurring after gastric bypass surgery, is challenging for patients and physicians alike. This review provides a systematic approach to diagnosis and treatment based on the underlying pathophysiology.

View details for PubMedID 30101281
Glucotypes reveal new patterns of glucose dysregulation. PLoS biology Hall, H., Perelman, D., Breschi, A., Limcaoco, P., Kellogg, R., McLaughlin, T., Snyder, M. 2018; 16 (7): e2005143
Abstract

Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called "glucotypes" that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.

View details for PubMedID 30040822
Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia DIABETES OBESITY & METABOLISM Craig, C. M., Liu, L., Thi Nguyen, Price, C., Bingham, J., McLaughlin, T. L. 2018; 20 (2): 352?61
Abstract

To evaluate the efficacy, pharmacokinetic (PK) profile and tolerability of subcutaneous (s.c.). exendin 9-39 (Ex-9) injection in patients with post-bariatric hypoglycaemia (PBH).Nine women who had recurrent symptomatic hypoglycaemia after undergoing Roux-en-Y gastric bypass were enrolled in this 2-part, single-blind, single-ascending-dose study. In Part 1, a single participant underwent equimolar low-dose intravenous (i.v.) vs s.c. Ex-9 administration; in Part 2, 8 participants were administered single ascending doses of s.c. Ex-9 during an oral glucose tolerance test (OGTT). Glycaemic, hormonal, PK and symptomatic responses were compared with those obtained during the baseline OGTT.Although an exposure-response relationship was observed, all doses effectively prevented hyperinsulinaemic hypoglycaemia and improved associated symptoms. On average, the postprandial glucose nadir was increased by 66%, peak insulin was reduced by 57%, and neuroglycopenic symptoms were reduced by 80%. All doses were well tolerated with no treatment-emergent adverse events observed.Injection s.c. of Ex-9 appears to represent a safe, effective and targeted therapeutic approach for treatment of PBH. Further investigation involving multiple doses with chronic dosing is warranted.

View details for PubMedID 28776922
Integrative Personal Omics Profiles during Periods of Weight Gain and Loss. Cell systems Piening, B. D., Zhou, W. n., Contrepois, K. n., R�st, H. n., Gu Urban, G. J., Mishra, T. n., Hanson, B. M., Bautista, E. J., Leopold, S. n., Yeh, C. Y., Spakowicz, D. n., Banerjee, I. n., Chen, C. n., Kukurba, K. n., Perelman, D. n., Craig, C. n., Colbert, E. n., Salins, D. n., Rego, S. n., Lee, S. n., Zhang, C. n., Wheeler, J. n., Sailani, M. R., Liang, L. n., Abbott, C. n., Gerstein, M. n., Mardinoglu, A. n., Smith, U. n., Rubin, D. L., Pitteri, S. n., Sodergren, E. n., McLaughlin, T. L., Weinstock, G. M., Snyder, M. P. 2018
Abstract

Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers. Most data are available open access and serve as a valuable resource for the community.

View details for PubMedID 29361466
Metabolic markers, regional adiposity, and adipose cell size: relationship to insulin resistance in African-American as compared with Caucasian women. International journal of obesity (2005) Allister-Price, C. n., Craig, C. M., Spielman, D. n., Cushman, S. S., McLaughlin, T. L. 2018
Abstract

African-American women have the greatest prevalence of obesity in the United States, and higher rates of type 2 diabetes than Caucasian women, yet paradoxically lower plasma triglycerides (TG), visceral fat and intrahepatic fat, and higher high-density lipoprotein (HDL)-cholesterol. Visceral fat has not been evaluated against insulin resistance in African-American women, and TG/HDL-cholesterol has been criticized as a poor biomarker for insulin resistance in mixed-sex African-American populations. Adipocyte hypertrophy, reflecting adipocyte dysfunction, predicts insulin resistance in Caucasians, but has not been studied in African-Americans. Our goal was to assess whether traditional correlates of insulin resistance, measures of adiposity and adipocyte characteristics similarly predict peripheral insulin resistance in African-American and Caucasian women.Thirty-four healthy African-American (n?=?17) and Caucasian (n?=?17) women, matched for age (mean?=?53.0?yrs) and body mass index (BMI) (mean?=?30?kg/m2), underwent a steady-state plasma glucose test to measure insulin sensitivity; computed tomography (fat distribution); and a periumbilical scalpel biopsy (adipocyte characterization). By-race analyzes utilized analysis of covariance; linear regressions evaluated relationships between metabolic/adipose variables. All analyses adjusted for BMI and menopausal status.Insulin sensitivity did not differ between groups (p?=?0.65). Neither BMI, nor %body fat or thigh fat predicted insulin resistance in African-American women. Fasting TG (p?=?0.046), HDL-cholesterol (p?=?0.0006) and TG/HDL-cholesterol ratio (p?=?0.009) strongly predicted insulin resistance in African-American women. Despite being lower in African-American women, hepatic fat and visceral adipose tissue (VAT) correlated with insulin resistance in both groups, as did fasting glucose, VAT/SAT (subcutaneous adipose tissue) ratio, and %SAT (inverse).Total adiposity measures and adipocyte hypertrophy did not predict insulin resistance in African-American women, but did in Caucasian women. Plasma TG and HDL-cholesterol were significant predictors of insulin resistance in African-American women. Our findings demonstrate the need to identify race and sex-specific biomarkers for metabolic risk profiling.

View details for PubMedID 30127463
T-Cells in Human Subcutaneous Adipose Tissue Mclaughlin, T., Liu, L., Craig, C., Perelman, D., Choi, O., Tolentino, L., Engleman, E. AMER DIABETES ASSOC. 2017: A90
View details for Web of Science ID 000408064100339
Substituting poly- and mono-unsaturated fat for dietary carbohydrate reduces hyperinsulinemia in women with polycystic ovary syndrome GYNECOLOGICAL ENDOCRINOLOGY Perelman, D., Coghlan, N., Lamendola, C., Carter, S., Abbasi, F., McLaughlin, T. 2017; 33 (4): 324-327
View details for DOI 10.1080/09513590.2016.1259407

View details for Web of Science ID 000399565100016
Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. Diabetologia Craig, C. M., Liu, L., Deacon, C. F., Holst, J. J., McLaughlin, T. L. 2017; 60 (3): 531-540
Abstract

Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1).We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs).Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion.GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy.ClinicalTrials.gov NCT02550145.

View details for DOI 10.1007/s00125-016-4179-x

View details for PubMedID 27975209

View details for PubMedCentralID PMC5300915
Role of innate and adaptive immunity in obesity-associated metabolic disease JOURNAL OF CLINICAL INVESTIGATION McLaughlin, T., Ackerman, S. E., Shen, L., Engleman, E. 2017; 127 (1): 5-13
Abstract

Chronic inflammation in adipose tissue, possibly related to adipose cell hypertrophy, hypoxia, and/or intestinal leakage of bacteria and their metabolic products, likely plays a critical role in the development of obesity-associated insulin resistance (IR). Cells of both the innate and adaptive immune system residing in adipose tissues, as well as in the intestine, participate in this process. Thus, M1 macrophages, IFN-?-secreting Th1 cells, CD8+ T cells, and B cells promote IR, in part through secretion of proinflammatory cytokines. Conversely, eosinophils, Th2 T cells, type 2 innate lymphoid cells, and possibly Foxp3+ Tregs protect against IR through local control of inflammation.

View details for DOI 10.1172/JCI88876

View details for Web of Science ID 000392271300002

View details for PubMedID 28045397

View details for PubMedCentralID PMC5199693
Adipose tissue macrophages impair preadipocyte differentiation in humans. PloS one Liu, L. F., Craig, C. M., Tolentino, L. L., Choi, O., Morton, J., Rivas, H., Cushman, S. W., Engleman, E. G., McLaughlin, T. 2017; 12 (2)
Abstract

The physiologic mechanisms underlying the relationship between obesity and insulin resistance are not fully understood. Impaired adipocyte differentiation and localized inflammation characterize adipose tissue from obese, insulin-resistant humans. The directionality of this relationship is not known, however. The aim of the current study was to investigate whether adipose tissue inflammation is causally-related to impaired adipocyte differentiation.Abdominal subcutaneous(SAT) and visceral(VAT) adipose tissue was obtained from 20 human participants undergoing bariatric surgery. Preadipocytes were isolated, and cultured in the presence or absence of CD14+ macrophages obtained from the same adipose tissue sample. Adipocyte differentiation was quantified after 14 days via immunofluorescence, Oil-Red O, and adipogenic gene expression. Cytokine secretion by mature adipocytes cultured with or without CD14+macrophages was quantified.Adipocyte differentiation was significantly lower in VAT than SAT by all measures (p<0.001). With macrophage removal, SAT preadipocyte differentiation increased significantly as measured by immunofluorescence and gene expression, whereas VAT preadipocyte differentiation was unchanged. Adipocyte-secreted proinflammatory cytokines were higher and adiponectin lower in media from VAT vs SAT: macrophage removal reduced inflammatory cytokine and increased adiponectin secretion from both SAT and VAT adipocytes. Differentiation of preadipocytes from SAT but not VAT correlated inversely with systemic insulin resistance.The current results reveal that proinflammatory immune cells in human SAT are causally-related to impaired preadipocyte differentiation, which in turn is associated with systemic insulin resistance. In VAT, preadipocyte differentiation is poor even in the absence of tissue macrophages, pointing to inherent differences in fat storage potential between the two depots.

View details for DOI 10.1371/journal.pone.0170728

View details for PubMedID 28151993

View details for PubMedCentralID PMC5289462
Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information. PLoS biology Li, X., Dunn, J., Salins, D., Zhou, G., Zhou, W., Sch�ssler-Fiorenza Rose, S. M., Perelman, D., Colbert, E., Runge, R., Rego, S., Sonecha, R., Datta, S., McLaughlin, T., Snyder, M. P. 2017; 15 (1)
Abstract

A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography.

View details for DOI 10.1371/journal.pbio.2001402

View details for PubMedID 28081144
Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information PLOS BIOLOGY Li, X., Dunn, J., Salins, D., Zhou, G., Zhou, W., Rose, S. M., Perelman, D., Colbert, E., Runge, R., Rego, S., Sonecha, R., Datta, S., McLaughlin, T., Snyder, M. P. 2017; 15 (1)
Abstract

A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography.

View details for DOI 10.1371/journal.pbio.2001402

View details for Web of Science ID 000393787500010
Substituting poly- and mono-unsaturated fat for dietary carbohydrate reduces hyperinsulinemia in women with polycystic ovary syndrome. Gynecological endocrinology Perelman, D., Coghlan, N., Lamendola, C., Carter, S., Abbasi, F., McLaughlin, T. 2016: 1-4
Abstract

Hyperinsulinemia is a prevalent feature of polycystic ovary syndrome (PCOS), contributing to metabolic and reproductive manifestations of the syndrome. Weight loss reduces hyperinsulinemia but weight regain is the norm, thus preventing long-term benefits. In the absence of weight loss, replacement of dietary carbohydrate (CHO) with mono/polyunsaturated fat reduces ambient insulin concentrations in non-PCOS subjects. The current study evaluated whether this dietary intervention could ameliorate hyperinsulinemia in women with PCOS.Obese women with PCOS (BMI 39?�?7?kg/m(2)) and insulin resistance completed a crossover study (Stanford University Clinical Research Center) comparing two isocaloric diets, prepared by research dietitians, containing 60% CHO/25% fat versus 40% CHO/45% fat (both 15% protein and ?7% saturated fat). After 3 weeks on each diet, daylong glucose, insulin, and fasting lipid/lipoproteins were measured.Daylong glucose did not differ according to diet. Daylong insulin concentrations were substantially (30%) and significantly lower on the low CHO/higher fat diet. Beneficial changes in lipid profile were also observed.Replacement of dietary CHO with mono/polyunsaturated fat yields clinically important reductions in daylong insulin concentrations, without adversely affecting lipid profile in obese, insulin-resistant women with PCOS. This simple and safe dietary intervention may constitute an important treatment for PCOS. ClinicalTrials.gov Identifier: NCT00186459.

View details for PubMedID 27910718
A glucocorticoid- and diet-responsive pathway toggles adipocyte precursor cell activity in vivo. Science signaling Wong, J. C., Krueger, K. C., Costa, M. J., Aggarwal, A., Du, H., McLaughlin, T. L., Feldman, B. J. 2016; 9 (451): ra103-?
Abstract

Obesity is driven by excess caloric intake, which leads to the expansion of adipose tissue by hypertrophy and hyperplasia. Adipose tissue hyperplasia results from the differentiation of adipocyte precursor cells (APCs) that reside in adipose depots. Investigation into this process has elucidated a network of mostly transcription factors that drive APCs through the differentiation process. Using in vitro and in vivo approaches, our study revealed a signaling pathway that inhibited the initiation of the adipocyte differentiation program. Mouse adipocytes secreted the extracellular protease ADAMTS1, which triggered the production of the cytokine pleiotrophin (PTN) through the Wnt/?-catenin pathway, and promoted proliferation rather than differentiation of APCs. Glucocorticoid exposure in vitro or in vivo reduced ADAMTS1 abundance in adipocytes. In addition, mice fed a high-fat diet showed decreased Adamts1 expression in the visceral perigonadal adipose depot, which expanded by adipogenesis in response to the diet, and increased Adamts1 expression in the subcutaneous inguinal adipose depot, which did not induce adipogenesis. Similar to what occurred in mouse subcutaneous adipose tissue, diet-induced weight gain increased the expression of ADAMTS1, PTN, and certain Wnt target genes in the subcutaneous adipose depot of human volunteers, suggesting the relevance of this pathway to physiological adipose tissue homeostasis and the pathogenesis of obesity. Thus, this pathway functions as a toggle on APCs, regulating a decision between differentiation and proliferation and coordinating the response of adipose tissue to systemic cues.

View details for PubMedID 27811141
Subcutaneous Exendin (9-39) Effectively Treats Postbariatric Hyper insulinemic Hypoglycemia Craig, C. M., Mclaughlin, T. L. AMER DIABETES ASSOC. 2016: A7?A8
View details for Web of Science ID 000398372800028
Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans DIABETES McLaughlin, T., Craig, C., Liu, L., Perelman, D., Allister, C., Spielman, D., Cushman, S. W. 2016; 65 (5): 1245-1254
Abstract

Obesity is associated with insulin resistance (IR), but significant variability exists between similarly-obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin-suppression-of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or IR. At baseline, IR subjects exhibited significantly-greater visceral adipose tissue(VAT), intrahepatic lipid(IHL), plasma FFAs , adipose cell diameter, and %small adipose cells. With weight gain (3.1+1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin-suppression-of lipolysis, and only 8% worsening of insulin-mediated glucose uptake (IMGU).Alternatively, IS subjects demonstrated significant adipose cell enlargement, decrease in %small adipose cells, increase in VAT, IHL, lipolysis, 45% worsening of IMGU, and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL, VAT, and decrease in insulin-suppression-of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between worsening insulin resistance and changes in adipose cell size, VAT, IHL, and insulin-suppression-of lipolysis highlight these factors as potential mediators between obesity and insulin resistance.

View details for DOI 10.2337/db15-1213

View details for Web of Science ID 000375028000015

View details for PubMedID 26884438
Pasireotide Induced Adrenal Insufficiency. Clinical endocrinology Weaver, K. n., Craig, C. n., McLaughlin, T. n. 2016
Abstract

We report the case of secondary adrenal insufficiency in a 56-year-old woman with a history of post-Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia, undergoing experimental treatment with pasireotide. This article is protected by copyright. All rights reserved.

View details for PubMedID 26733356
Macro fat and micro fat: insulin sensitivity and gender dependent response of adipose tissue to isocaloric diet change ADIPOCYTE Li, Y., Gaillard, J. R., McLaughlin, T., Sorensen, T. A., Periwal, V. 2015; 4 (4): 256?63
Abstract

The adipose cell-size distribution is a quantitative characterization of adipose tissue morphology. At a population level, the adipose cell-size distribution is insulin-sensitivity dependent, and the observed correlation between obesity and insulin resistance is believed to play a key role in the metabolic syndrome. Changes in fat mass can be induced by altered energy intake or even diet composition. These macroscopic changes must manifest themselves as dynamic adipose cell-size distribution alterations at the microscopic level. The dynamic relationship between these 2 independent measurements of body fat is unknown. In this study, we investigate adipose tissue dynamics in response to various isocaloric diet compositions, comparing gender- and insulin sensitivity-dependent differences. A body composition model is used to predict fat mass changes in response to changes in diet composition for 28 individuals, separated into 4 subgroups according to gender and insulin sensitivity/resistance. Adipose cell-size distribution changes in each individual are simulated with a dynamic model and parameters corresponding to lipid turnover and cell growth rates are determined for each subgroup to match the relative change of fat mass for each diet composition, respectively. We find that adipose cell-size dynamics are associated with different modulations dependent on gender and insulin resistance. Larger turnover and growth/shrinkage rates in insulin resistant individuals suggest they may be more sensitive to changes in energy intake and diet composition than insulin sensitive subjects. The different cell-size distribution changes of adipose cells of various sizes in different subject groups further suggest distinct modulations of adipose cell dynamics.

View details for PubMedID 26451281

View details for PubMedCentralID PMC4573186
The receptor CD44 is associated with systemic insulin resistance and proinflammatory macrophages in human adipose tissue DIABETOLOGIA Liu, L. F., Kodama, K., Wei, K., Tolentino, L. L., Choi, O., Engleman, E. G., Butte, A. J., McLaughlin, T. 2015; 58 (7): 1579-1586
Abstract

Proinflammatory immune cell infiltration in human adipose tissue is associated with the development of insulin resistance. We previously identified, via a gene expression-based genome-wide association study, the cell-surface immune cell receptor CD44 as a functionally important gene associated with type 2 diabetes. We then showed that, compared with controls, Cd44 knockout mice were protected from insulin resistance and adipose tissue inflammation during diet-induced obesity. We thus sought to test whether CD44 is associated with adipose tissue inflammation and insulin resistance in humans.Participants included 58 healthy, overweight/moderately obese white adults who met predetermined criteria for insulin resistance or insulin sensitivity based on the modified insulin-suppression test. Serum was collected from 43 participants to measure circulating concentrations of CD44. Subcutaneous adipose tissue was obtained from 17 participants to compare CD44, its ligand osteopontin (OPN, also known as SPP1) and pro-inflammatory gene expression. CD44 expression on adipose tissue macrophage (ATM) surfaces was determined by flow cytometry.Serum CD44 concentrations were significantly increased in insulin-resistant (IR) participants. CD44 gene expression in subcutaneous adipose tissue was threefold higher in the IR subgroup. The expression of OPN, CD68 and IL6 was also significantly elevated in IR individuals. CD44 gene expression correlated significantly with CD68 and IL6 expression. CD44 density on ATMs was associated with proinflammatory M1 polarisation.CD44 and OPN in human adipose tissue are associated with localised inflammation and systemic insulin resistance. This receptor-ligand pair is worthy of further research as a potentially modifiable contributor to human insulin resistance and type 2 diabetes.

View details for DOI 10.1007/s00125-015-3603-y

View details for Web of Science ID 000356528900023

View details for PubMedID 25952479
In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans. Journal of lipid research Allister, C. A., Liu, L., Lamendola, C. A., Craig, C. M., Cushman, S. W., Hellerstein, M. K., McLaughlin, T. L. 2015; 56 (2): 435-439
Abstract

Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25-35 kg/m(2), classified as IR or IS by the modified insulin suppression test, consumed deuterated water ((2)H2O) for 4 weeks. Deuterium incorporation into glycerol, palmitate, and DNA indicated TG synthesis, DNL, and adipocyte proliferation, respectively. Net TG synthesis and DNL in adipose cells were significantly lower in IR as compared with IS subjects, whereas adipocyte proliferation did not differ significantly. Plasma FFAs measured during an insulin suppression test were 2.5-fold higher in IR subjects, indicating resistance to insulin suppression of lipolysis. Adipose TG synthesis correlated directly with DNL but not with proliferation. These results provide direct in vivo evidence for impaired TG storage in subcutaneous adipose tissue of IR as compared with IS. Relative inability to store TG in the subcutaneous depot may represent a mechanism contributing to the development of insulin resistance in the setting of obesity.

View details for DOI 10.1194/jlr.M052860

View details for PubMedID 25418322

View details for PubMedCentralID PMC4306696
T-Cell Profile in Adipose Tissue Is Associated With Insulin Resistance and Systemic Inflammation in Humans ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY McLaughlin, T., Liu, L., Lamendola, C., Shen, L., Morton, J., Rivas, H., Winer, D., Tolentino, L., Choi, O., Zhang, H., Chng, M. H., Engleman, E. 2014; 34 (12): 2637-2643
Abstract

The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity.Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT and VAT correlated directly, whereas Th2 frequency in VAT correlated inversely, with plasma high-sensitivity C-reactive protein concentrations. Th2 in both depots and peripheral blood was inversely associated with systemic insulin resistance. Furthermore, Th1 in SAT correlated with plasma interleukin-6. Relative expression of associated cytokines, measured by real-time polymerase chain reaction, reflected flow cytometry results. Most notably, adipose tissue expression of anti-inflammatory interleukin-10 was inversely associated with insulin resistance.CD4 and CD8 T cells populate human adipose tissue and the relative frequency of Th1 and Th2 are highly associated with systemic inflammation and insulin resistance. These findings point to the adaptive immune system as a potential mediator between obesity and insulin resistance or inflammation. Identification of antigenic stimuli in adipose tissue may yield novel targets for treatment of obesity-associated metabolic disease.

View details for DOI 10.1161/ATVBAHA.114.304636

View details for Web of Science ID 000345443400019

View details for PubMedCentralID PMC4445971
T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arteriosclerosis, thrombosis, and vascular biology McLaughlin, T., Liu, L., Lamendola, C., Shen, L., Morton, J., Rivas, H., Winer, D., Tolentino, L., Choi, O., Zhang, H., Hui Yen Chng, M., Engleman, E. 2014; 34 (12): 2637-2643
Abstract

The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity.Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT and VAT correlated directly, whereas Th2 frequency in VAT correlated inversely, with plasma high-sensitivity C-reactive protein concentrations. Th2 in both depots and peripheral blood was inversely associated with systemic insulin resistance. Furthermore, Th1 in SAT correlated with plasma interleukin-6. Relative expression of associated cytokines, measured by real-time polymerase chain reaction, reflected flow cytometry results. Most notably, adipose tissue expression of anti-inflammatory interleukin-10 was inversely associated with insulin resistance.CD4 and CD8 T cells populate human adipose tissue and the relative frequency of Th1 and Th2 are highly associated with systemic inflammation and insulin resistance. These findings point to the adaptive immune system as a potential mediator between obesity and insulin resistance or inflammation. Identification of antigenic stimuli in adipose tissue may yield novel targets for treatment of obesity-associated metabolic disease.

View details for DOI 10.1161/ATVBAHA.114.304636

View details for PubMedID 25341798
Subcutaneous Adipose Cell Size and Distribution: Relationship to Insulin Resistance and Body Fat OBESITY McLaughlin, T., Lamendola, C., Coghlan, N., Liu, T. C., Lerner, K., Sherman, A., Cushman, S. W. 2014; 22 (3): 673-680
Abstract

Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell size distribution, body fat, and insulin-mediated glucose uptake in overweight/moderately obese individuals. A total of 148 healthy nondiabetic subjects with BMI 25-38 kg/m(2) underwent subcutaneous adipose tissue biopsies and quantification of insulin-mediated glucose uptake with steady-state plasma glucose (SSPG) concentrations during the modified insulin suppression test. Cell size distributions were obtained with Beckman Coulter Multisizer. Primary endpoints included % small adipose cells and diameter of large adipose cells. Cell-size and metabolic parameters were compared by regression for the whole group, according to insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and by body fat quintile. Both large and small adipose cells were present in nearly equal proportions. Percent small cells was associated with SSPG (r = 0.26, P = 0.003). Compared to BMI-matched IS individuals, IR counterparts demonstrated fewer, but many large adipose cells, and a greater proportion of small-to-large adipose cells. Diameter of the large adipose cells was associated with % body fat (r = 0.26, P = 0.014), female sex (r = 0.21, P = 0.036), and SSPG (r = 0.20, P = 0.012). In the highest versus lowest % body fat quintile, adipose cell size increased by only 7%, whereas adipose cell number increased by 74%. Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m(2) . Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance.

View details for DOI 10.1002/oby.20209

View details for Web of Science ID 000332224800011

View details for PubMedID 23666871
The Winged Helix Transcription Factor Foxa3 Regulates Adipocyte Differentiation and Depot-Selective Fat Tissue Expansion MOLECULAR AND CELLULAR BIOLOGY Xu, L., Panel, V., Ma, X., Du, C., Hugendubler, L., Gavrilova, O., Liu, A., McLaughlin, T., Kaestner, K. H., Muellera, E. 2013; 33 (17): 3392-3399
Abstract

Conversion of mesenchymal stem cells into terminally differentiated adipocytes progresses sequentially through regulated transcriptional steps. While it is clear that the late phases of adipocyte maturation are governed by the nuclear receptor PPAR?, less is known about the transcriptional control of the initial stages of differentiation. To identify early regulators, we performed a siRNA screen of Forkhead-box genes in adipocytes and show here for the first time that the winged helix factor Foxa3 promotes adipocyte differentiation by cooperating with C/EBP? and ? to transcriptionally induce PPAR? expression. Furthermore we demonstrate that mice with genetic ablation of Foxa3 have a selective decrease in epididymal fat depot and a cell-autonomous defect to induce PPAR? specifically in their visceral adipocytes. In obese subjects, FOXA3 is differentially expressed in visceral and subcutaneous adipose depots. Overall our study implicates Foxa3 in the regulation of adipocyte differentiation and depot-selective adipose tissue expansion.

View details for DOI 10.1128/MCB.00244-13

View details for Web of Science ID 000322817600001

View details for PubMedID 23798556
Use of a two-stage insulin infusion study to assess the relationship between insulin suppression of lipolysis and insulin-mediated glucose uptake in overweight/obese, nondiabetic women METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Yee, G., Glassford, A., Lamendola, C., Reauen, G. 2011; 60 (12): 1741-1747
Abstract

Differences in insulin regulation of free fatty acids (FFAs) are not readily apparent at the same insulin concentrations used to differentiate relative insulin-mediated glucose disposal. Resistance to insulin-mediated glucose disposal and higher daylong FFA concentrations occur more commonly in obese individuals. However, the relationship between the ability of insulin to suppress FFA release from adipose tissue and stimulate glucose disposal in muscle has not been clearly defined in this population. The current study was initiated to test the hypothesis that these 2 facets of insulin action are related, with greater defects in insulin-mediated glucose disposal associated with less effective insulin inhibition of FFA release from adipose tissue. Subjects included 56 healthy nondiabetic overweight/moderately obese women classified as insulin resistant or insulin sensitive based on whole-body glucose disposal. All underwent a modified 240-minute 2-stage insulin infusion with basal (?15 �U/mL) and physiologically elevated (?80 �U/mL) steady-state insulin concentrations. Plasma glucose, insulin, FFA, and glycerol were measured throughout. Whereas plasma glucose differed most during physiological hyperinsulinemia in insulin-resistant vs insulin-sensitive subjects, plasma FFA/glycerol differed most during basal insulin concentrations. The FFA concentrations during the basal insulin steady state correlated highly (r = 0.85, P < .001) with glucose concentrations during the hyperinsulinemic steady state. Overweight/moderately obese women exhibit dramatic differences in the ability of insulin to suppress plasma FFA, which correlate highly with differences in insulin-mediated glucose disposal. Variability in insulin regulation of FFA is most apparent at basal insulin concentrations, whereas differences in glucose disposal are most apparent during physiologic hyperinsulinemia. Both can be quantified using a simple 2-stage insulin infusion study, with first-stage FFA concentrations and second-stage glucose concentrations being most informative.

View details for DOI 10.1016/j.metabol.2011.05.008

View details for Web of Science ID 000297528400014

View details for PubMedID 21820141
Preferential Fat Deposition in Subcutaneous Versus Visceral Depots Is Associated with Insulin Sensitivity JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Lamendola, C., Liu, A., Abbasi, F. 2011; 96 (11): E1756-E1760
Abstract

Studies on the relationship between regional fat and insulin resistance yield mixed results. Our objective was to determine whether regional fat distribution, independent of obesity, is associated with insulin resistance.Subjects included 115 healthy, overweight/moderately obese adults with body mass index (BMI) 25-36.9 kg/m(2) who met predetermined criteria for being insulin resistant (IR) or insulin sensitive (IS) based on the modified insulin suppression test. Computerized tomography was used to quantify visceral adipose tissue (VAT), sc adipose tissue (SAT), and thigh adipose tissue. Fat mass in each depot was compared according to IR/IS group, adjusting for BMI and sex.Despite nearly identical mean BMI in the IR vs. IS groups, VAT and %VAT were significantly higher in the IR group, whereas SAT, %SAT, and thigh sc fat were significantly lower. In logistic regression analysis, each sd increase in VAT increased the odds of being IR by 80%, whereas each increase in SAT decreased the odds by 48%; each increase in thigh fat decreased the odds by 59% and retained significance after adjusting for other depots. When grouped by VAT tertile, IS vs. IR individuals had significantly more SAT. There was no statistically significant interaction between sex and these relationships.These data demonstrate that after adjustment for BMI and VAT mass, sc abdominal and thigh fat are protective for insulin resistance, whereas VAT, after adjustment for SAT and BMI, has the opposite effect. Whether causal in nature or a marker of underlying pathology, these results clarify that regional distribution of fat-favoring sc depots is associated with lower risk for insulin resistance.

View details for DOI 10.1210/jc.2011-0615

View details for Web of Science ID 000296750600005

View details for PubMedID 21865361

View details for PubMedCentralID PMC3205890
B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies NATURE MEDICINE Winer, D. A., Winer, S., Shen, L., Wadia, P. P., Yantha, J., Paltser, G., Tsui, H., Wu, P., Davidson, M. G., Alonso, M. N., Leong, H. X., Glassford, A., Caimol, M., Kenkel, J. A., Tedder, T. F., McLaughlin, T., Miklos, D. B., Dosch, H., Engleman, E. G. 2011; 17 (5): 610-U134
Abstract

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

View details for DOI 10.1038/nm.2353

View details for Web of Science ID 000290250400038

View details for PubMedID 21499269

View details for PubMedCentralID PMC3270885
Differential adipogenic and inflammatory properties of small adipocytes in Zucker Obese and Lean rats DIABETES & VASCULAR DISEASE RESEARCH Liu, A., Sonmez, A., Yee, G., Bazuine, M., Arroyo, M., Sherman, A., McLaughlin, T., Reaven, G., Cushman, S., Tsao, P. 2010; 7 (4): 311-318
Abstract

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

View details for DOI 10.1177/1479164110386126

View details for Web of Science ID 000285080700008

View details for PubMedID 20961992

View details for PubMedCentralID PMC3462589
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
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
Reversible Hyperinsulinemic Hypoglycemia after Gastric Bypass: A Consequence of Altered Nutrient Delivery JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Peck, M., Holst, J., Deacon, C. 2010; 95 (4): 1851-1855
Abstract

Severe hypoglycemia after Roux-en-Y gastric bypass surgery (RYGB) is an increasingly recognized condition, characterized by neuroglycopenia and inappropriately elevated insulin concentrations that occur primarily in the postprandial state. Both pathophysiology and treatment of this disorder remain elusive, but it has been postulated that hyperplasia and/or hypertrophy of beta-cells due to morbid obesity and/or postsurgical nesidioblastosis may contribute.The objective of this study was to elucidate the pathophysiology of this condition; specifically, we hypothesized that metabolic abnormalities were a function of altered nutrient transit through the gastrointestinal tract rather than anatomical changes to pancreatic beta-cells that would lead to consistently high insulin secretion irrespective of nutrient transit route. DESIGN/SETTING/SUBJECT/OUTCOME MEASURES: We describe a unique case wherein gastrostomy tube (GT) insertion into the remnant stomach reversed neuroglycopenic symptoms. This subject was admitted to a university hospital research center for standardized measurement of glucose, insulin, and incretin hormones including glucagon-like peptide-1, gastric-inhibitory peptide, and glucagon.Standardized liquid meal administration via GT vs. oral route demonstrated complete reversal of severe metabolic abnormalities that included hypersecretion of insulin and GLP-1.Post-RYGB hyperinsulinemia and hypoglycemia result entirely from altered nutrient delivery rather than generalized hyperfunction of beta-cells due to presurgical hypertrophy/hyperfunction or postsurgical nesidioblastosis. These findings support the use of GT for treatment of severe cases and have implications for surgical manipulations that may reverse/prevent this condition.

View details for DOI 10.1210/jc.2009-1628

View details for Web of Science ID 000276402300045

View details for PubMedID 20133462
Using Pre-existing Microarray Datasets to Increase Experimental Power: Application to Insulin Resistance PLOS COMPUTATIONAL BIOLOGY Daigle, B. J., Deng, A., McLaughlin, T., Cushman, S. W., Cam, M. C., Reaven, G., Tsao, P. S., Altman, R. B. 2010; 6 (3)
Abstract

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

View details for DOI 10.1371/journal.pcbi.1000718

View details for Web of Science ID 000278125200026

View details for PubMedID 20361040

View details for PubMedCentralID PMC2845644
Inflammation in subcutaneous adipose tissue: relationship to adipose cell size DIABETOLOGIA McLaughlin, T., Deng, A., Yee, G., Lamendola, C., Reaven, G., Tsao, P. S., Cushman, S. W., Sherman, A. 2010; 53 (2): 369-377
Abstract

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

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

View details for Web of Science ID 000273084400019

View details for PubMedID 19816674
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
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

View details for PubMedCentralID PMC3181138
Plasma Glucose and Insulin Regulation Is Abnormal Following Gastric Bypass Surgery with or without Neuroglycopenia Kim, S. H., Liu, T. C., Abbasi, F., Lamendola, C., Morton, J. M., Reaven, G. M., McLaughlin, T. AMER DIABETES ASSOC. 2009: A10
View details for Web of Science ID 000266352600037
Microvascular Dysfunction and Suboptimal Glycemic Control Predicts Poor Outcome Following Heart Transplantation 58th Annual Scientific Session of the American-College-of-Cardiology Khazanie, P., Haddad, F., Simos, A. M., Pham, M., Weisshaar, D. M., Desai, S. V., Shah, M. G., McLaughlin, T. L., Hunt, S. A., Valantine, H. A., Fearon, W. ELSEVIER SCIENCE INC. 2009: A182?A182
View details for Web of Science ID 000263864200760
Does Synchronizing Initiation of Therapy Affect Adherence to Concomitant Use of Antihypertensive and Lipid-Lowering Therapy? AMERICAN JOURNAL OF THERAPEUTICS Agarwal, S., Tang, S. S., Rosenberg, N., Pettitt, D., McLaughlin, T., Joyce, A., Schwartz, J. S. 2009; 16 (2): 119-126
Abstract

Although efficacious medications are available to treat hypertension and dyslipidemia, treatment adherence is often poor. This retrospective study evaluated adherence in patients newly initiating antihypertensive (AH) and lipid-lowering (LL) therapies simultaneously versus within 180 days of one another. Data were analyzed for US managed care plan enrollees initiating AH before LL (cohort 1;n = 7099), LL before AH (cohort 2; n = 3229), or AH/LL simultaneously (cohort 3; n = 5072). A multivariate model evaluated potential predictors of adherence (medication possession ratio >or= 0.80 over a bimonthly period). Percentages of patients adherent to AH/LL at 2, 6, and 12 months were as follows: 59.4%, 32.7%, and 31.3% in cohort 1; 45.0%, 30.8%, and 31.0% in cohort 2; and 75.2%, 34.4%, and 34.0% in cohort 3, respectively. After adjustment for potential confounders, patients initiating AH before LL therapy, or LL before AH therapy, were less likely to be adherent than patients prescribed both agents simultaneously (odds ratios = 0.838 and 0.691, respectively; P , 0.0001). Synchronous initiation of AH and LL therapies is an important predictor of adherence.

View details for Web of Science ID 000264495800004

View details for PubMedID 19114872
Persistence of improvement in insulin sensitivity following a dietary weight loss programme DIABETES OBESITY & METABOLISM McLaughlin, T., Schweitzer, P., Carter, S., Yen, C., Lamendola, C., Abbasi, F., Reaven, G. 2008; 10 (12): 1186-1194
Abstract

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

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

View details for Web of Science ID 000260528300005

View details for PubMedID 18476986
Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women DIABETOLOGIA McLaughlin, T., Deng, A., Gonzales, O., AILLAUD, M., Yee, G., Lamendola, C., Abbasi, F., Connolly, A. J., Sherman, A., Cushman, S. W., Reaven, G., Tsao, P. S. 2008; 51 (12): 2303-2308
Abstract

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

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

View details for Web of Science ID 000260686000019

View details for PubMedID 18825363
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
Clinical experience with a relatively low carbohydrate, calorie-restricted diet improves insulin sensitivity and associated metabolic abnormalities in overweight, insulin resistant South Asian Indian women ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION Backes, A. C., Abbasi, F., Lamendola, C., McLaughlin, T. L., Reaven, G., Palaniappan, L. P. 2008; 17 (4): 669-671
Abstract

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

View details for Web of Science ID 000262520400020

View details for PubMedID 19114407
Small adipocytes: implications for inflammation and insulin resistance Sonmez, A., Sung, K., Yee, G., Deng, A., Mullen, S., McLaughlin, T., Cushman, S., Reaven, G., Tsao, P. OXFORD UNIV PRESS. 2007: 619?619
View details for Web of Science ID 000208702203225
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
Clinical efficacy of two hypocaloric diets that vary in overweight patients with type 2 diabetes - Comparison of moderate fat versus carbohydrate reductions DIABETES CARE McLaughlin, T., Carter, S., Lamendola, C., Abbasi, F., Schaaf, P., Basina, M., Reaven, G. 2007; 30 (7): 1877-1879
View details for DOI 10.2337/dc07-0301

View details for Web of Science ID 000247768400036

View details for PubMedID 17475941
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
Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults DIABETES CARE Ryan, M. C., Carter, S., Abbasi, F., McLaughlin, T. L., Lamendola, C. 2007; 30 (5): 1075-1080
Abstract

Although weight loss interventions have been shown to reduce steatosis in nonalcoholic fatty liver disease (NAFLD), the impact of dietary macronutrient composition is unknown. We assessed the effect on serum alanine aminotransferase (ALT) concentrations of two hypocaloric diets varying in amounts of carbohydrate and fat in obese insulin-resistant individuals, a population at high risk for NAFLD.Post hoc analysis of ALT concentrations was performed in 52 obese subjects with normal baseline values and insulin resistance, as quantified by the steady-state plasma glucose (SSPG) test, who were randomized to hypocaloric diets containing either 60% carbohydrate/25% fat or 40% carbohydrate/45% fat (15% protein) for 16 weeks. The primary end point was change in ALT, which was evaluated according to diet, weight loss, SSPG, and daylong insulin concentrations.Although both diets resulted in significant decreases in weight and SSPG, daylong insulin, and serum ALT concentrations, the 40% carbohydrate diet resulted in greater decreases in SSPG (P < 0.04), circulating insulin (P < 0.01), and ALT (9.5 +/- 9.4 vs. 4.2 +/- 8.3 units/l; P < 0.04) concentrations. ALT changes correlated with improvement in insulin sensitivity (P = 0.04) and daylong insulin (P < 0.01). Individuals with ALT concentrations above the proposed upper limits experienced significant declines in ALT, unlike those with lower ALT levels.In a population at high risk for NAFLD, a hypocaloric diet moderately lower in carbohydrate decreased serum ALT concentrations to a greater degree than a higher-carbohydrate/low-fat diet, despite equal weight loss. This may result from a relatively greater decline in daylong insulin concentrations. Further research with histological end points is needed to further explore this finding.

View details for DOI 10.2337/dc06-2169

View details for Web of Science ID 000246291400007

View details for PubMedID 17351275
Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo DIABETES CARE Beysen, C., Turner, H. C., Murphy, E. J., Awada, M., McLaughlin, T., Turner, S. M., Riiff, T., Reaven, G., Lamendola, C., Hellerstein, M. K. 2007; 30 (5): 1143-1149
Abstract

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

View details for DOI 10.2337/dc06-1809

View details for Web of Science ID 000246291400019

View details for PubMedID 17259480
Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals - Effect of differences in insulin sensitivity ARCHIVES OF INTERNAL MEDICINE McLaughlin, T., Abbasi, F., Lamendola, C., Reaven, G. 2007; 167 (7): 642-648
Abstract

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

View details for Web of Science ID 000245628700003

View details for PubMedID 17420421
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
Effects of moderate variations in macronutrient composition on weight loss and reduction in cardiovascular disease risk in obese, insulin-resistant adults AMERICAN JOURNAL OF CLINICAL NUTRITION McLaughlin, T., Carter, S., Lamendola, C., Abbasi, F., Yee, G., Schaaf, P., Basina, M., Reaven, G. 2006; 84 (4): 813-821
Abstract

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

View details for Web of Science ID 000241140700019

View details for PubMedID 17023708
Differential effects of two hypocaloric diets (restricted carbohydrate versus restricted fat) on hepatic aminotransferases in obese insulin resistant individuals: An intervention study 57th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases Ryan, M. C., McLaughlin, T. L., Reaven, G. M. WILEY-BLACKWELL. 2006: 646A?646A
View details for Web of Science ID 000241362302319
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
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
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
Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? AMERICAN JOURNAL OF CARDIOLOGY McLaughlin, T., Reaven, G., Abbasi, F., Lamendola, C., Saad, M., Waters, D., Simon, J., Krauss, R. M. 2005; 96 (3): 399-404
Abstract

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

View details for DOI 10.1016/j.amjcard.2005.03.085

View details for Web of Science ID 000231057000017

View details for PubMedID 16054467
Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals DIABETES Kim, S. H., Abbasi, F., Chu, J. W., McLaughlin, T. L., Lamendola, C., Polonsky, K. S., Reaven, G. M. 2005; 54 (8): 2447-2452
Abstract

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

View details for Web of Science ID 000230869500023

View details for PubMedID 16046313
Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects. Diabetes & vascular disease research Chu, J. W., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. M., Tsao, P. S. 2005; 2 (1): 37-41
Abstract

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

View details for PubMedID 16305071
Comparative effects of rosuvastatin and gomfibrozil on glucose, insulin, and lipid metabolism in insulin m resistant, nondiabetic patients with combined dyslipidemia AMERICAN JOURNAL OF CARDIOLOGY Lamendola, C., Abbasi, F., Chu, J. W., Hutchinson, H., Cain, V., Leary, E., McLaughlin, T., Stein, E., Reaven, G. 2005; 95 (2): 189-193
Abstract

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

View details for DOI 10.1016/j.amjcard.2004.09.005

View details for Web of Science ID 000226461000006

View details for PubMedID 15642550
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
Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Allison, G., Abbasi, F., Lamendola, C., Reaven, G. 2004; 53 (4): 495-499
Abstract

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

View details for Web of Science ID 000220581500016

View details for PubMedID 15045698
Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Abbasi, F., Lamendola, C., Frayo, R. S., Cummings, D. E. 2004; 89 (4): 1630-1635
Abstract

Ghrelin, an orexigenic hormone that may play a role in body weight regulation, is reduced in states of obesity. Because obesity is associated with insulin resistance and compensatory hyperinsulinemia, we determined whether these metabolic characteristics were independently associated with suppressed ghrelin concentrations. To investigate this hypothesis, using steady-state plasma glucose concentrations, we identified 20 insulin-resistant (IR) and 20 insulin-sensitive (IS) individuals who were equally obese. The mean body mass indexes were 32.5 +/- 0.4 and 32.0 +/- 0.4 kg/m(2) for the IR and IS groups, respectively. Fasting insulin concentrations were 19.5 and 7.4 micro U/ml (P < 0.001), respectively. Ghrelin concentrations were suppressed in the IR group (252 +/- 19 pg/ml) relative to the IS group (412 +/- 35 pg/ml; P < 0.001). Ghrelin correlated inversely with both insulin resistance (r = -0.64; P < 0.001) and fasting insulin concentration (r = -0.58; P < 0.001). Multivariate analysis confirmed that both insulin resistance and hyperinsulinemia independently predicted low ghrelin concentrations. Our results demonstrate that in obese individuals, insulin resistance and hyperinsulinemia are inversely associated with ghrelin concentrations. Thus, insulin resistance or related metabolic abnormalities may constitute part of a feedback mechanism by which body weight is regulated in humans.

View details for DOI 10.1210/jc.2003-031572

View details for Web of Science ID 000220714500018

View details for PubMedID 15070922
Rosuvastatin is efficacious as monotherapy in patients with combined dyslipidemia 53rd Annual Scientific Session of the American-College-of-Cardiology Abbasi, F., Chu, J. W., Lamendola, C., McLaughlin, T., Cain, V., Hutchinson, H. G., Reaven, G. M. ELSEVIER SCIENCE INC. 2004: 480A?480A
View details for Web of Science ID 000189388502033
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
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
Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Chu, J. W., McLaughlin, T., Lamendola, C., Leary, E. T., Reaven, G. M. 2004; 53 (2): 159-164
Abstract

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

View details for DOI 10.1016/j.metabol.2003.07.020

View details for Web of Science ID 000188797400007

View details for PubMedID 14767866
Obesity, insulin resistance, and cardiovascular disease RECENT PROGRESS IN HORMONE RESEARCH, VOL 59 Reaven, G., Abbasi, F., McLaughlin, T. 2004; 59: 207-223
Abstract

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

View details for Web of Science ID 000189490300010

View details for PubMedID 14749503
Use of metabolic markers to identify overweight individuals who are insulin resistant ANNALS OF INTERNAL MEDICINE McLaughlin, T., Abbasi, F., Cheal, K., Chu, J., Lamendola, C., Reaven, G. 2003; 139 (10): 802-809
Abstract

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

View details for Web of Science ID 000186663500002

View details for PubMedID 14623617
Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance AMERICAN JOURNAL OF CARDIOLOGY Tuan, C. Y., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. 2003; 92 (5): 606-610
Abstract

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

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

View details for Web of Science ID 000185060700024

View details for PubMedID 12943888
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
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
Rosiglitazone in insulin-resistant women with polycystic ovary syndrome: effects on ovarianfunction and metabolism Cataldo, N. A., Abbasi, F., McLaughlin, T. L., Chu, J. W., Basina, M., Fechner, P. Y., Reaven, G. M., Giudice, L. C. OXFORD UNIV PRESS. 2003: 43?43
View details for Web of Science ID 000208316000118
Differentiation between obesity and insulin resistance in the association with C-reactive protein CIRCULATION McLaughlin, T., Abbasi, F., Lamendola, C., Liang, L., Reaven, G., Schaaf, P., Reaven, P. 2002; 106 (23): 2908-2912
Abstract

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

View details for DOI 10.1161/01.CIR.0000041046.32962.86

View details for Web of Science ID 000179698600011

View details for PubMedID 12460870
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
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
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
Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus AMERICAN JOURNAL OF CARDIOLOGY Abbasi, F., Asagmi, T., Cooke, J. P., Lamendola, C., McLaughlin, T., Reaven, G. M., Stuehlinger, M., Tsao, P. S. 2001; 88 (10): 1201-?
View details for Web of Science ID 000172412300025

View details for PubMedID 11703973
Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone 83rd Annual Meeting of the Endocrine-Society Cataldo, N. A., Abbasi, F., McLaughlin, T. L., Lamendola, C., Reaven, G. M. ELSEVIER SCIENCE INC. 2001: 1057?59
Abstract

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

View details for Web of Science ID 000172083900034

View details for PubMedID 11704136
Effect of insulin resistance on postprandial elevations of remnant lipoprotein concentrations in postmenopausal women AMERICAN JOURNAL OF CLINICAL NUTRITION Kim, H. S., Abbasi, F., Lamendola, C., McLaughlin, T., Reaven, G. M. 2001; 74 (5): 592-595
Abstract

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

View details for Web of Science ID 000171779500009

View details for PubMedID 11684526
Relationship between insulin resistance, weight loss, and coronary heart disease risk in healthy, obese women METABOLISM-CLINICAL AND EXPERIMENTAL McLaughlin, T., Abbasi, F., Kim, H. S., Lamendola, C., Schaaf, P., Reaven, G. 2001; 50 (7): 795-800
Abstract

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

View details for DOI 10.1053/meta.2001.24210

View details for Web of Science ID 000169829600010

View details for PubMedID 11436184
Metabolic 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
Carbohydrate-induced hypertriglyceridemia: An insight into the link between plasma insulin and triglyceride concentrations JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Abbasi, F., Lamendola, C., Yeni-Komshian, H., Reaven, G. 2000; 85 (9): 3085-3088
Abstract

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

View details for Web of Science ID 000089166200016

View details for PubMedID 10999790
Insulin resistance and hypertension - Patients in double jeopardy for cardiovascular disease GERIATRICS McLaughlin, T., Reaven, G. 2000; 55 (6): 28-?
Abstract

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

View details for Web of Science ID 000087657800008

View details for PubMedID 10872343
Plasma insulin concentration is more tightly linked to plasma leptin concentration than is the body mass index METABOLISM-CLINICAL AND EXPERIMENTAL Abbasi, F., Carantoni, M., McLaughlin, T., Reaven, G. M. 2000; 49 (4): 544-547
Abstract

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

View details for Web of Science ID 000086444800023

View details for PubMedID 10778883
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 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
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
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
Differences in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM McLaughlin, T., Abbasi, F., Carantoni, M., Schaaf, P., Reaven, G. 1999; 84 (2): 578-581
Abstract

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

View details for Web of Science ID 000078464000031

View details for PubMedID 10022419

Tracey McLaughlin

Professor of Medicine (Endocrinology) at the Stanford University Medical Center

Medicine - Endocrinology, Gerontology, & Metabolism

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