South Asians (SA) are insulin-resistant (IR) and are at increased risk for developing type 2 diabetes mellitus (T2DM) when compared with Caucasians (CA). However, the changes in pancreatic β-cell responsivity, glucose effectiveness (Sg), and insulin clearance in SA are not well characterized. Healthy SA (n=30) and CA (n=30) matched for age, sex, and BMI and with no history of T2DM were evaluated in the Clinical Center. A frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mixed meal test (MMT) were used for minimal modeling (MM). Insulin sensitivity, beta-cell function, and glucose effectiveness were calculated. Tissue-specific surrogate indices of insulin sensitivity and post-prandial incretin levels were also measured. SA were less insulin-sensitive (SI: 3.30±2.72 vs. 7.31±4.89, minutes-1/µU/mL, p<0.001; Matsuda index: 4.34±3.69 vs. 13.26±7.17, p<0.05). Tissue specific IR surrogate indices (hepatic IR index and adipocyte IR index) were higher and muscle insulin sensitivity index was lower in SA. Sg derived from an FSIVGTT was lower in SA (0.025 ± 0.033 vs. 0.012 ± 0.006, minutes-1, p<0.001). Beta-cell responsivity indices estimated by the C-peptide MM [phi (dynamic), phi (static), and phi (total)] were not different between the groups, but the disposition indices were significantly lower in SA. Post-prandial GIP but not GLP-1 levels were higher in SA than in CA. Insulin clearance at baseline and following MMT was also significantly lower in SA. Thus, when compared with age-, sex-, and BMI-matched CA, SA exhibit reduced overall insulin sensitivity in the muscle, liver, and adipose tissue. Despite similar β-cell responsivity to glucose, the disposition indices in SA were lower, suggesting diminished beta-cell compensation. In addition to defects in insulin-mediated glucose disposal and impaired beta-cell compensation, normoglycemic SA have reduced glucose effectiveness. These results suggest different approaches to prevent and treat T2DM in SA.

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