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Genetic predisposition increases the risk of type 2 diabetes (T2DM). Disposition index (DI), a measure β-cell compensation for insulin resistance, is heritable. Hence, reduced DI may predate abnormal glucose metabolism. We investigated insulin sensitivity (S[sub I]) and insulin secretion in 333 healthy nondiabetic African Americans (AA) and Caucasians (C) who were matched for age, sex, body mass index (BMI) and waist circumference. To investigate the role of family history (FH) of T2DM, we compared insulin secretion and sensitivity measures in an obese subgroup (BMI≥30; n=141) of subjects selected for either a strong FH of T2DM or no FH. We compared oral glucose tolerance (OGT), S[sub I], acute insulin response to IV glucose (AIR[sub g]), insulin response to glucose potentiated arginine stimulation (AIR[sub max]) and disposition indexes (DI, DI[sub max]) with respect to FH and ethnicity. Among the obese subgroup, individuals with and without a FH did not differ by age, sex, or obesity measures. We found no differences in S[sub I], AIR[sub g], AIR[sub max], DI or DI[sub max] (S[sub I] * AIR[sub max]) by FH in either C or AA tested separately or together. When the larger cohort of lean and obese individuals was examined without regard to FH, AA subjects were more insulin resistant (S[sub I] = 3.85 ± 3.87 vs. 4.22 ± 3.29, p<0.0001, AA vs. C) and had markedly greater AIR[sub g] and DI than Caucasians (AA vs C; AIR[sub g]: 806.5 ± 626.7 vs. 478.7 ± 361.0, p<0.0001; DI: 2331.8 ± 1970.2 vs. 1597.9 ±1220.4, p=0.0104), despite matching for age, sex, and obesity measures. Interestingly, AIR[sub max] did not differ among ethnic groups, and DI[sub max], a measure of β-cell reserve, was lower in AA compared to C. Fasting glucose and fasting and 2 h insulin levels were similar between groups, but AA had lower 2 h glucose and decreased glucose AUC during OGT. We find no defect in β-cell compensation (DI) related to a FH of T2DM in either ethnic group. Over a wide range of BMI, AA had lower S[sub I], and increased AIR[sub g] and DI than C which over-compensated for decreased S[sub I]. The decreased AIR[sub max] suggested lower β-cell reserve in AA compared to C, which might explain the increased prevalence of T2DM in AA. ADA-Funded Research [ABSTRACT FROM AUTHOR]

PPARγplays a major role in cell differentiation, lipid metabolism and apoptosis and is the target of thiazolidinediones which are widely used to improve insulin sensitivity and for treatment of diabetes mellitus. Recently a SUMOylation (small ubiquitin-like modifier) site was identified on PPARγsuggesting that it might be a target for modification by SUMO-1. SUMOylation, a process similar to ubiquitination, regulates many cellular processes including nuclear transport, transcription, apuptosis and protein stability. SUMOylation of PPARγhas been proposed to play a role in the transrepression of inflammatory genes. We hypothesized that pioglitazone (pin) would increase the amount of PPARγmodified by SUMO-1, and that this could be part of the anti-inflammatory effect of TZDs. To evaluate SUMOylation we examined human adipose tissue mRNA levels for SUMO-1 in 18 impaired glucose tolerant subjects in response to two insulin-sensitizing drugs (pin and metfromin). We found that pin treatment increased expression of SUMO-1 by 23% (p<0.002). When added to adipocytes in vitro, pin also increased SUMO-1 suggesting a direct effect of TZDs on adipocytes. Next, we examined the expression of SUMO-1 and NCOR (nuclear receptor corepressor protein) in adipose tissue from 86 subjects (54 NGT and 32 IGT) covering a broad range of BMI and S[sub 1]. SUMO-1 and NCOR correlated strongly with each other (r=0.8, p<0.001) suggesting that they are tightly associated in a large complex as described previously in cultured macrophages where SUMOylation of PPARγ promotes interaction with the NCOR-histone deacetylase3 complex and represses target genes. Although SUMO-1 and NCOR were not significantly associated with BMI or S[sub 1] in this group, they were highly associated with inflammatory markers. Adipose CD68 and MCP1 mRNA levels correlated strongly with SUMO-1 and NCOR (r=0.5 and 0.6, p<0.001 respectively). Overall these results show that SUMOylation of PPARγcan be regulated by pin treatment and suggest that the anti-inflammatory effects of pio may be controlled by the degree of SUMO-1 modification of PPARγ. [ABSTRACT FROM AUTHOR]

Retinol binding protein 4 (RBP4) was overexpressed in adipose tissue of Glut4 KO mice, and elevated RBP4 has been associated with insulin resistance in mouse and human studies. To determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans, RBP4 gene expression measured by real-time RT-PCR and blood levels measured by ELISA and Western blotting were studied in adipose tissue and muscle of 85 non-diabetic humans over a wide range of BMI (19-55 Kg/m²) and S[sub I] (1.02-26.77 x 10[sup -5] x min[sup -1]/pM), and RBP4 expression was also measured from visceral (VAT) and subcutaneous adipose tissue (SAT) from 16 surgical patients. RBP4 expression was 3-fold higher in SAT vs VAT (p<0.005), and RBP4 was 7-fold higher in the adipocyte (vs stromal) fraction, and undetectable in preadipocytes. Neither SAT RBP4 expression nor blood RBP4 level showed a significant relationship with BMI or S[sub I]. However, there was a strong positive correlation between RBP4 mRNA and the inflammation markers MCP1 (r=0.42, p<0.0001) and CD68 (r=0.46, p<0.0001)). Adipose GLUT4 mRNA was also highly associated with RBP4 (r=0.53, p<0.0001). These relationships remained significant after adjustment for BMI and St. Impaired glucose tolerant subjects were treated with pioglitazone, resulting in an increase in S[sub 1] along with a 60% increase in RBP4 expression, but no change in plasma RBP4. The in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA. Hence, RBP4 expression in humans was not significantly associated with obesity or insulin resistance, and actually increased with TZD treatment. However, RBP4 was associated with inflammatory markers and GLUT 4 expression, suggesting a complex role in metabolic syndrome. [ABSTRACT FROM AUTHOR]