Context: The increased insulin secretion in response to reduced insulin sensitivity is heritable, but whether the genetic predisposition is restricted to members of high risk Caucasian families is unknown. Furthermore, the relative importance of insulin resistance and defective -cell compensation in the increased prevalence of type 2 diabetes (T2DM) in African-American compared with Caucasian individuals is uncertain.

Objective: We tested whether obese individuals with a family history of T2DM have decreased -cell compensation compared to obese controls without a family history of T2DM. Additionally, we compared insulin sensitivity and insulin secretion measures in African American and Caucasian individuals.

Design: Insulin sensitivity (S_I), insulin response to IV glucose (AIR_g), maximally potentiated insulin response to arginine (AIR_max) and disposition indexes (DI=S_I*AIR_g. DI_max= S_I*AIR_max) were compared among non-diabetic Caucasian and African American individuals with and without a family history of diabetes.

Setting: Ambulatory General Clinical Research Center.

Subjects: Healthy, nondiabetic individuals with or without a family history of T2DM.

Interventions: None

Main Outcome Measures: Comparison of S_I, AIR_g, AIR_max, DI and DI_max, between Caucasians and African Americans with or without a strong family history of T2DM.

Results: Obese subjects did not differ in S_I, AIR_g, or DI by family history of diabetes. African Americans had 8% lower S_I (p<0.001), but 68% higher AIR_g (p<0.001) and 46% higher DI (p=0.001) than age, gender, BMI matched Caucasian individuals. However, African Americans had lower DI_max compared to Caucasians.

Conclusions: We found no reduction in insulin secretion in obese subjects with a family history of T2DM compared to controls, but in general, African Americans were more insulin resistant and had lower maximal -cell response (DI_max). The paradoxical increased DI could be explained the by reduced hepatic insulin extraction.