Obesity-independent hyperinsulinemia in nondiabetic first-degree relatives of individuals with type 2 diabetes

A close association between obesity and hyperinsulinemia is well recognized, but it is not known whether this relationship is affected by the genetic susceptibility to type 2 diabetes. Insulin response to a 75-g oral glucose load was evaluated in healthy nondiabetic Caucasians with first-degree family history of diabetes (relatives, n = 55) and those without family history (nonrelatives, n = 33). A significant correlation between the BMI and insulin response (area under the curve [AUC] during the 2-h period) was seen in nonrelatives (r = 0.68, P < 0.0001) but not in the relatives (r = 0.12, P = 0.37). Multivariate analysis revealed that obesity (BMI) was the primary determinant of insulin response in nonrelatives (P < 0.001), whereas among the relatives, BMI had no significant impact (P = 0.28). Thus, these distinctions between the relatives and nonrelatives remained after adjusting for glucose level, age, and gender. Among first-degree relatives, the commonly observed association between BMI and insulin response is lost, and hyperinsulinemia is present even in the absence of obesity. First-degree family history of diabetes may confer insulin resistance that is independent of obesity. Alternatively, this could suggest a pathological regulation of an obesity-insulin feedback loop, e.g., a defective recognition of adiposity.