The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

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.

OBJECTIVE: We conducted a prospective study among Japanese Americans of diabetes incidence in relation to visceral and regional adiposity, fasting insulin and C-peptide, and a measure of insulin secretion, because little prospective data exist on these associations. RESEARCH DESIGN AND METHODS: Baseline variables included plasma glucose, C-peptide, and insulin measured after an overnight fast and 30 and 120 min after a 75-g oral glucose tolerance test; abdominal, thoracic, and thigh fat areas by computed tomography (CT); BMI (kg/m2); and insulin secretion (incremental insulin response [IIR]). RESULTS: Study subjects included 290 second-generation (nisei) and 230 third-generation (sansei) Japanese Americans without diabetes, of whom 65 and 13, respectively, developed diabetes. Among nisei, significant predictors of diabetes risk for a 1 SD increase in continuous variables included intra-abdominal fat area (IAFA) (odds ratio, 95% CI) (1.6, 1.1-2.3), fasting plasma C-peptide (1.4, 1.1-1.8), and the IIR (0.5, 0.3-0.9) after adjusting for age, sex, impaired glucose tolerance, family diabetes history, and CT-measured fat areas other than intra-abdominal. Intra-abdominal fat area remained a significant predictor of diabetes incidence even after adjustment for BMI, total body fat area, and subcutaneous fat area, although no measure of regional or total adiposity was related to development of diabetes. Among sansei, all adiposity measures were related to diabetes incidence, but, in adjusted models, only IAFA remained significantly associated with higher risk (2.7, 1.4-5.4, BMI-adjusted). CONCLUSIONS: Greater visceral adiposity precedes the development of type 2 diabetes in Japanese Americans and demonstrates an effect independent of fasting insulin, insulin secretion, glycemia, total and regional adiposity, and family history of diabetes.