Aims/hypothesis. Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. Methods. We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S I ) in 182 subjects (76 M/106F). Results. Adiponectin concentrations were higher in women than in men (7.4±2.9 vs 5.4±2.3 µg/ml, p<0.0001) as were leptin concentrations (19.1±13.7 vs 6.9±5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S I : 6.8±3.9 vs 5.9±4.4×10 −5 min −1 /(pmol/l), p<0.01) and had more subcutaneous (240±133 vs 187±90 cm 2 , p<0.01), but less intra-abdominal fat (82±57 vs 124±68 cm 2 , p<0.0001). By simple regression, adiponectin was positively correlated with age (r=0.227, p<0.01) and S I (r=0.375, p<0.0001), and negatively correlated with BMI (r=−0.333, p<0.0001), subcutaneous (r=−0.168, p<0.05) and intra-abdominal fat (r=−0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides (r=−0.281, p<0.001) and positively correlated with HDL cholesterol (r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy (r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age (p<0.0001), sex (p<0.005) and intra-abdominal fat (p<0.01). S I was related to intraabdominal fat (p<0.0001) and adiponectin (p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. Conclusion/interpretation. These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile. [Diabetologia (2003) 46:459-469] Keywords Adiponectin, Acrp30, adipoQ, central obesity, subcutaneous fat, intra-abdominal fat, insulin sensitivity, lipids, hepatic lipase, cardiovascular disease, leptin. It is well recognized that obesity and insulin resistance are closely related [1,2,3,4]. Android body fat distribution is associated with insulin resistance more than is a gynoid body fat distribution [5], with the site of abdominal fat distribution being an additional determinant of insulin sensitivity [6,7,8,9,10,11]. We found in both lean and obese subjects that the intraabdominal fat (IAF) depot is a stronger determinant of insulin sensitivity than the subcutaneous fat (SCF) depot [11], while SCF is the main determinant of the plasma concentration of leptin [11], an adipocyte-derived hormone regulating energy metabolism [12,13].

The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n ‫؍‬ 89) and women (n ‫؍‬ 129) with a broad range of age (

OBJECTIVE -We sought to determine whether an oral disposition index (DI O ) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DI O by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and ␤-cell function.RESEARCH DESIGN AND METHODS -A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (⌬I 0 -30 /⌬G 0 -30 ).RESULTS -⌬I 0 -30 /⌬G 0 -30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the log e -transformed estimates included Ϫ1 for ⌬I 0 -30 /⌬G 0 -30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included Ϫ1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ⌬I 0 -30 /⌬G 0 -30 and 1/fasting insulin was calculated (DI O ) and decreased from NGT to IFG/IGT to diabetes (P Ͻ 0.001). Among nondiabetic subjects at baseline, baseline DI O predicted cumulative diabetes at 10 years (P Ͻ 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations.CONCLUSIONS -The DI O provides a measure of ␤-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.

THE AMERICAN DIABETES ASSOCIATIONGENNID STUDY GROUP* OBJECTIVE -We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with firstdegree relatives with type 2 diabetes.RESEARCH DESIGN AND METHODS -Women with (n ϭ 332) and without (n ϭ 663) a history of GDM were compared regarding 1) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2) the prevalence of type 2 diabetes, and 3) self-reported CVD.RESULTS -Women with prior GDM were younger (48.6 Ϯ 0.7 vs. 52.4 Ϯ 0.6 years [means Ϯ SE]; P Ͻ 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P Ͻ 0.005). Although both groups were obese (BMI 34.4 Ϯ 1.2 vs. 33.7 Ϯ 0.6 kg/m 2 ), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P Ͻ 0.001) and type 2 diabetes (93.4 vs. 63.3%; P Ͻ 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21-2.82]; P ϭ 0.005) that occurred at a younger age (45.5 Ϯ 2.2 vs. 52.5 Ϯ 1.9 years; P ϭ 0.02) and was independent of metabolic syndrome (1.74 [1.10 -2.76]; P ϭ 0.02) and type 2 diabetes (1.56 [1.002-2.43]; P Ͻ 0.05).CONCLUSIONS -Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes.