Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans - Implications for primary diabetes prevention

OBJECTIVE - We examined the determinants of impaired glucose tolerance (IGT) and type 2 diabetes in first-degree relatives of African-American type 2 diabetic patients over 5-8 years (median 6). RESEARCH DESIGN AND METHODS - A total of 81 healthy subjects (age 41.5 +/- 4.8 years; BMI 31.3 +/- 3.6 kg/m(2)) participated in the study. Each subject underwent an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test at baseline. Insulin sensitivity index (S-i) and glucose effectiveness index (S) were determined by the minimal model method. Homeostasis model assessment (HOMA) was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B). A total of 18 subjects progressed to either IGT or type 2 diabetes (progressors), whereas 19 subjects maintained normal glucose tolerance (nonprogressors). RESULTS - Comparing the progressors and nonprogressors, mean fasting serum glucose levels (95 +/- 8 vs. 80 +/- 14 mg/dl, P < 0.01) and 2-h serum glucose levels (149 +/- 27 vs. 100 +/- 60 mg/dl, P < 0.01) as well as 2-h serum insulin levels (117 +/- 81 vs. 72 +/- 87 muU/ml, P < 0.01), during OGTT were higher at baseline. Mean acute first-phase insulin secretion (205 217 vs., 305 +/- 230 muU/ml), HOMA-%B (148 +/- 60 vs. 346 +/- 372, P < 01), S-i (1.61 +/- 1.13 vs. 2.48 +/- 1.25 X 10(-4) (.) min(-1) [muU/ml](-1)), and S-g (1.48 +/- 0.61 vs. 2.30 +/- 0.97 X 10(-2) (.) min(-1)) were lower in the progressors than in the nonprogressors at baseline. Mean HOMA-IR (3.31 +/- 1.64 vs. 2.36 +/- 1.64) was significantly greater in the progressors than the nonprogressors. At the time of diagnosis of glucose intolerance (IGT + diabetes), HOMA-%B (101 +/- 48 vs. 148 +/- 60, P < 0.001) and HOMA-IR (5.44 +/- 2.55 vs. 3.31 +/- 1.64, P < 0.003) deteriorated in the progressors versus baseline. CONCLUSIONS - We conclude that nondiabetic, first-degree relatives of African-American type 2 diabetic patients who progressed to IGT and type 2 diabetes manifest triple defects (decreased insulin secretion, insulin action, and glucose effectiveness) that antecede the disease.