Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among th ose whose mothers were diabetic during pregnancy. To define the metabolic a bnormalities predisposing individuals in these high-risk groups to diabetes , we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subje cts, acute insulin secretory response (AIR) to a 25-g intravenous glucose c hallenge correlated with the age at onset of diabetes in the mother (r = 0. 23, P = 0.03) and, in multiple regression analyses, the age at onset of dia betes in the father (P = 0.02), after adjusting for maternal age at onset a nd after allowing for an interaction between these terms. In contrast, insu lin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabe tes in the parents affected insulin secretion in the offspring across a ran ge of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compare d with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% Cl] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lowe r in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the bir th of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant off spring of people with early onset type 2 diabetes. This impairment may be w orsened by exposure to a diabetic environment in utero.