Impaired Insulin Sensitivity, Insulin Secretion, and Glucose Effectiveness Predict Future Development of Impaired Glucose Tolerance and Type 2 Diabetes in Pre-Diabetic African Americans

Abstract

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/m2) 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 (Si) and glucose effectiveness index (Sg) were determined by the minimal model method. Homeostasis model assessment (HOMA) was used to estimate insulin resistance (HOMA-IR) and β-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 μU/ml, P < 0.01) during OGTT were higher at baseline. Mean acute first-phase insulin secretion (205 ± 217 vs. 305 ± 230 μU/ml), HOMA-%B (148 ± 60 vs. 346 ± 372, P < 01), Si (1.61 ± 1.13 vs. 2.48 ± 1.25 × 10−4 · min−1 [μU/ml]−1), and Sg (1.48 ± 0.61 vs. 2.30 ± 0.97 × 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.