OBESITY-INDEPENDENT HYPERINSULINEMIA IN NONDIABETIC FIRST-DEGREE RELATIVES OF INDIVIDUALS WITH TYPE-2 DIABETES

A close association between obesity and hyperinsulinemia is well recog nized, but it is not known whether this relationship is affected by th e genetic susceptibility to type 2 diabetes. Insulin response to a 75- g oral glucose load was evaluated in healthy nondiabetic Caucasians wi th first-degree family history of diabetes (relatives, n = 55) and tho se without family history (nonrelatives, n = 33). A significant correl ation 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 re sponse in nonrelatives (P < 0.001), whereas among the relatives, BMI h ad no significant impact (P = 0.28). Thus, these distinctions between the relatives and nonrelatives remained after adjusting for glucose le vel, age, and gender. Among first-degree relatives, the commonly obser ved association between BMI and insulin response is lost, and hyperins ulinemia is present even in the absence of obesity. First-degree famil y history of diabetes may confer insulin resistance that is independen t of obesity. Alternatively, this could suggest a pathological regulat ion of an obesity-insulin feedback loop, e.g., a defective recognition of adiposity.