Reduced beta-cell compensation to the insulin resistance associated with obesity in members of Caucasian familial type 2 diabetic kindreds

OBJECTIVE - Both obesity and a family history of diabetes reduce insulin se nsitivity but the impact of obesity on insulin secretion among individuals predisposed to diabetes is uncertain. We used a pedigree-based approach to test the hypothesis that p-cell compensation to the insulin resistance asso ciated with obesity is defective among individuals predisposed to diabetes by virtue of a strong family history of type 2 diabetes before the developm ent of diabetes or glucose intolerance. RESEARCH DESIGN AND METHODS - A total of 126 members of 26 families ascerta ined for at least a sib pair with type 2 diabetes with onset before age 65 years underwent a tolbutamide-modified frequently sampled intravenous gluco se tolerance rest (FSIGT). Family members included 26 individuals with impa ired glucose tolerance and 100 individuals with normal glucose tolerance (N GT). The acute insulin response to glucose (AIR(glucose)) was determined an d insulin sensitivity (S-I) estimated by minimal model analysis of FSIGT da ta. The beta-cell compensation for insulin sensitivity was estimated from t he disposition index (DI), calculated as the product of SI and AIR(glucose) . Obesity was measured by BMI. RESULTS - Among all individuals, BMI was a significant predictor of both SI and AIR(glucose), as expected. However, BMI also significantly predicted D I (P = 0.002) after correcting for age, sex, family membership, and glucose tolerance status. The relationship of BMI and DI was confirmed in 85 indiv iduals with NGT who were aged <45 (P = 0.002) but not in 91 unrelated contr ol individuals without a family history of diabetes. When normoglycemic ind ividuals aged <45 were separated into three classes by BMI (less than or eq ual to 27, 27-30, >30), S-I decreased progressively and significantly with obesity, whereas AIR(glucose) rose significantly from lean to most obese cl asses. In contrast to the expectation of complete beta-cell compensation wi th obesity DI fell significantly (P = 0.004) among obese family members. Th is relationship was not observed in control subjects CONCLUSIONS - Individuals with a genetic predisposition to diabetes show a reduced beta-cell compensatory response to the reduced insulin sensitivity associated with obesity We propose that this impaired compensation may be o ne manifestation of the underlying genetic defect in susceptible individual s. This finding helps explain the multiplicative effects of family history and obesity on risk of type 2 diabetes.