Intact proinsulin, des 31,32 proinsulin, and specific insulin concentrations among nondiabetic and diabetic subjects in populations at varying risk of type 2 diabetes

OBJECTIVE - To examine hyperinsulinemia, insulin secretion, and beta-cell function in Pima Indians, South Asians, and whites, populations at varying risk of diabetes. RESEARCH DESIGN AND METHODS-We investigated 136 Pima Indian, 98 Asian, and 80 white nondiabetic and 172 Pima Indian, 40 Asian, and 49 white diabetic subjects. Highly specific assays for insulin, intact proinsulin, and des 31,32 proinsulin were used. Insulin secretion was assessed using ratio of increment (0 to 30 min) in insulin to glucose concentrations during an oral glucose tolerance test (OGTT). RESULTS-Nondiabetic Pima Indians were significantly more obese than Asians and whites. Pima Indian subjects had significantly higher (P < 0.01) fasting insulin concentrations (median 109 pmol/l, range 40-250) than Asian (37 pmol/l, range 17-91) and white (30 pmol/l, range 10-82) subjects. These differences remained significant when controlled for obesity Nondiabetic Pima Indians also had higher fasting C-peptide concentrations and higher early insulin secretion during an OGTT Fasting concentrations of intact proinsulin and des 31,32 proinsulin were also significantly higher in Pima Indians (P < 0.01). However, the proportion of proinsulin-like molecules was significantly lower (P < 0.01) in Pima Indians (median 7.9% vs. 12.7% for South Asians and 12.2% for whites). Subjects with diabetes from the three ethnic groups showed significantly higher fasting insulin concentrations but lower 30-min insulin and lower ratios of increment (0-30 min) in insulin to glucose concentrations than did nondiabetic subjects, The proportion of proinsulin-like molecules was not significantly different in diabetic subjects from the three ethnic groups. CONCLUSIONS - These specific assays for insulin indicate that after adjusting for obesity, nondiabetic Pima Indians are truly hyperinsulinemic, which is consistent with their insulin resistance as measured by other methods. Hyperinsulinemia in this population with a high risk of diabetes is likely to be due to enhanced insulin secretion. Furthermore, in Pima Indians, the predominant beta-cell secretory product is insulin and not its precursors. We conclude that the differences in the risk of diabetes among these three groups are not due to differences in insulin secretion or insulin processing. Subjects with type 2 diabetes have defective early insulin secretion during OGTTs but show fasting hyperinsulinemia even when specific assays for insulin are used.