ObjectiveWe measured insulin sensitivity with euglycemic clamp (Si-clamp) in initially normoglycemic African Americans (AA) and European Americans (EA), to probe the existence of subphenotypes of obesity and leanness, and their impact on incident dysglycemia during longitudinal follow-up.Research design and methods320 healthy subjects (176 AA, 144 EA; mean age 44.2±10.6 years) underwent baseline assessments, including Si-clamp and homeostasis model of insulin resistance (HOMA-IR) and were stratified into: insulin-resistant obese (IRO) (body mass index (BMI) >30 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive obesity (ISO) (BMI >30 kg/m2, Si-clamp >0.1, HOMA-IR <2.5); insulin-resistant non-obese (IRN) (BMI <28 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive non-obese (ISN) (BMI <28 kg/m2, Si-clamp >0.1, HOMA-IR <2.5). Outcome measures were cardiometabolic risks and incident pre-diabetes/type 2 diabetes (T2D) during 5.5 years.ResultsCompared with IRO, subjects with ISO had lower abdominal fat, triglycerides and high-sensitivity C reactive protein and higher adiponectin (p=0.015 to <0.0001). IRN subjects had higher cardiometabolic risk markers than ISN (p=0.03 to <0.0001). During 5.5-year follow-up, incident pre-diabetes/T2D was lower in ISO (31.3% vs 48.7%) among obese subjects and higher in IRN (47.1% vs. 26.0%) among non-obese subjects (p=0.0024). Kaplan-Meier analysis showed significantly different pre-diabetes/T2D survival probabilities across insulin sensitivity/adiposity phenotypes (p=0.0001).ConclusionsInsulin sensitivity predicts ~40% decrease in the relative risk of incident pre-diabetes/T2D among obese persons, whereas insulin resistance predicts ~80% increased risk among non-obese persons. This is the first documentation of healthy and unhealthy phenotypes of obesity and leanness in a prospective biracial cohort, using rigorous measurement of insulin sensitivity.

BackgroundAdiponectin levels display ethnic disparities, and are inversely associated with the risk of type 2 diabetes (T2DM). However, the association of adiponectin with prediabetes risk in diverse populations has not been well-studied. Here, we assessed baseline adiponectin levels in relation to incident prediabetes in a longitudinal biracial cohort.Research design and methodsThe Pathobiology of Prediabetes in A Biracial Cohort study followed non-diabetic offspring of parents with T2DM for the occurrence of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance. Assessments at enrollment and during follow-up included a 75 g oral glucose tolerance test, anthropometry, biochemistries (including fasting insulin and adiponectin levels), insulin sensitivity and insulin secretion. Logistic regression was used to evaluate the contribution of adiponectin to risk of progression to prediabetes.ResultsAmong the 333 study participants (mean (SD) age 44.2 (10.6) year), 151(45.3%) were white and 182 (54.8%) were black. During approximately 5.5 (mean 2.62) years of follow-up, 110 participants (33%) progressed to prediabetes (N=100) or T2DM (N=10), and 223 participants (67%) were non-progressors. The mean cohort adiponectin level was 9.41+5.30 μg/mL (range 3.1–45.8 μg/mL); values were higher in women than men (10.3+5.67 μg/mL vs 7.27+3.41 μg/mL, p<0.0001) and in white than black offspring (10.7+5.44 μg/mL vs 8.34+4.95 μg/mL, p<0.0001). Adiponectin levels correlated inversely with adiposity and glycemia, and positively with insulin sensitivity and high-density lipoprotein cholesterol levels. Baseline adiponectin strongly predicted incident prediabetes: the HR for prediabetes per 1 SD (approximately 5 μg/mL) higher baseline adiponectin was 0.48 (95% CI 0.27 to 0.86, p=0.013).ConclusionsAmong healthy white and black adults with parental history of T2DM, adiponectin level is a powerful risk marker of incident prediabetes. Thus, the well-known association of adiponectin with diabetes risk is evident at a much earlier stage in pathogenesis, during transition from normoglycemia to prediabetes.

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Background-Dietary and exercise data are frequently recorded in clinical research, but their correlation with metabolic measures needs further evaluation.Objective-We examined the association of food and exercise habits with body size, lipid profile, and glycemia in a prospective biracial cohort.Address for correspondence and reprints: Samuel Dagogo-Jack, MD, Division of Endocrinology, Diabetes and Metabolism, 920 Madison Avenue, Suite 300A, University of Tennessee Health Science Center, Memphis, TN 38163, sdj@uthsc.edu. Conflicts of Interest:The authors have no relevant conflict of interest to disclose with regard to the content of this manuscript. DISCLOSURE STATEMENTThe authors have no relevant conflict of interest to disclose with regard to the content of this manuscript. AUTHORS' CONTRIBUTIONSS.D.-J., as the principal investigator and developed the study concept and design, and wrote the manuscript; A.B. collected data, reviewed and revised the manuscript; E.A.O.A. collected data, reviewed and revised the manuscript; S.E. collected data, reviewed and reviewed the manuscript; I.O. collected data, reviewed and revised the manuscript; S.E. collected data, conducted statistical analysis and reviewed the manuscript; A.K.G. reviewed and revised the manuscript; J.W. performed statistical analyses; C.E. collected data and reviewed and revised the manuscript. S.D-J. had primary responsibility for final content. All authors read and approved the final manuscript. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 POP-ABC Research Group HHS Public Access Conclusions-AmongAfrican-American and Caucasian offspring of parents with T2DM, selfreported dietary and exercise habits correlated with measures of adiposity and dyslipidemia; however, physical activity, but not dietary recall, significantly predicted incident dysglycemia during 5.5 years of follow-up.

Dyslipidemia and dysglycemia are etiologically associated, but the direction, chronology, and mechanisms of the association are not fully understood. We, therefore, analyzed data from 335 healthy adults (184 black, 151 white) enrolled in the Pathobiology of Prediabetes in A Biracial Cohort study. Subjects underwent oral glucose tolerance test (OGTT) and were enrolled if they had normal fasting and 2-h plasma glucose levels. Assessments during year 1 included anthropometry, fasting lipid profile, insulin sensitivity, and insulin secretion. Thereafter, OGTT was assessed annually for 5.5 years. The primary outcome was occurrence of prediabetes (impaired fasting glucose or impaired glucose tolerance) or diabetes. During a mean follow-up of 2.62 years, 110 participants (32.8%) developed prediabetes (N ¼ 100) or diabetes (N ¼ 10). In multivariate logistic regression models, higher baseline low-density lipoprotein (LDL) cholesterol and triglyceride levels and lower HDL cholesterol levels significantly increased the risk of incident prediabetes. The combined relative risk (95% confidence interval [CI]) of prediabetes for participants with lower baseline HDL cholesterol (10th vs. 90th percentile), higher LDL cholesterol (90th vs. 10th percentile) and high triglycerides levels (90th vs. 10th percentile) was 4.12 (95% CI 1.61-10.56), P ¼ 0.0032. At baseline, lipid values showed significant associations with measures of adiposity, glycemia, insulin sensitivity, and secretion. In both ethnic groups, waist circumference correlated positively with triglycerides and inversely with HDL cholesterol levels (P ¼ 0.0004-<0.0001); fasting plasma glucose correlated positively with triglycerides and LDL cholesterol levels and inversely with HDL cholesterol levels (P ¼ 0.006-<0.0001); insulin sensitivity correlated positively with HDL cholesterol and inversely with triglyceride levels (P < 0.0001), and insulin secretion correlated positively with triglycerides (P ¼ 0.01) and inversely with HDL cholesterol (P < 0.0001). We conclude that a baseline lipidemic signature identifies normoglycemic individuals at high risk for future glycemic progression, via congruent associations with adiposity and glucoregulatory mechanisms. These findings suggest that early lifestyle intervention could ameliorate progressive dyslipidemia and dysglycemia.