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 (S_i) and glucose effectiveness index (S_g) 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), S_i (1.61 ± 1.13 vs. 2.48 ± 1.25 × 10⁻⁴ · min⁻¹ [μU/ml]⁻¹), and S_g (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.

Glycosylated hemoglobin (Hb)A1c provides a practical assessment of long-term glycemic control in patients with diabetes. However, whether HbA1c has any clinical significance in metabolic syndrome (MS) in nondiabetic subjects remains debatable. Therefore, we examined the impact of different levels of HbA1c on insulin sensitivity (Si), non-insulin-dependent glucose disposal, and blood pressure (BP), as well as lipids and lipoproteins in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes.The study consisted of 219 nondiabetic, first-degree relatives (offspring and siblings) of African-American patients with type 2 diabetes. To examine the metabolic impact of HbA1c in our population, HbA1c was divided into tertiles (normal range, 3.3–6.4%). The mean HbA1c was 4.7% (range, 3.3–4.8%, n = 74) for tertile 1, 5.4% (range, 4.9–5.6%, n = 73) for tertile 2, and 5.8% (range, 5.7–6.4%, n = 72) for tertile 3. Si and glucose effectiveness (Sg) were determined by the Bergman’s minimal model method. Homeostasis model assessment (HOMA)-insulin resistance and HOMA-β-cell function were also estimated. BP, body compositional variables, and body fat distribution, as well as fasting serum lipid and lipoprotein concentrations, were determined in each subject.The mean age, body weight, body mass index, waist and hip circumference, and systolic and diastolic BPs were significantly (P < 0.02–0.001) greater in the subjects in tertile 3 than those in tertiles 1 and 2. The mean fasting serum glucose was significantly (P < 0.01) higher in tertile 3 (95.5 ± 3.2 mg/dl) than in tertile 2 (83.0 ± 2.7 mg/dl) and tertile 1 (78.8 ± 1.5 mg/dl). Mean fasting serum insulin and c-peptide levels tended to be higher in tertile 3 subjects than in those in tertiles 1 and 2, but the mean differences did not reach statistical significance. The mean Si was significantly (P < 0.001) lower in the subjects in tertile 3 [1.66 ± 0.2019 × 10−4·min−1(μU/ml)−1], when compared with those in tertile 1 [2.27 ± 0.20 19 × 10−4·min−1(μU/ml)−1] and tertile 2 [2.61 ± 0.19 × 10−4·min−1(μU/ml)−1]. The mean Sg was significantly (P < 0.02) lower in tertile 3 (1.95 ± 0.12 × 10−2·min−1), when compared with those of tertile 1 (2.27 ± 0.10 × 10−2·min−1) and tertile 2 (2.29 ± 0.11 × 10−2·min−1). In addition, the (HOMA)-insulin resistance was significantly (P < 0.01) higher in tertile 3 (3.62 ± 0.26) than in tertile 1 (2.6 ± 0.21) and tertile 2 (2.55 ± 0.31) HbA1c. In contrast, HOMA-β-cell function, was not different among tertiles 1, 2, and 3. Mean fasting serum triglycerides, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels also were not significantly different in subjects in tertile 3, when compared with those in tertiles 1 and 2.In summary, the present study demonstrates that the upper tertile HbA1c level (tertile 3) reflects some components of MS in the nondiabetic, obese, first-degree relatives of African-Americans who are genetically predisposed to type 2 diabetes. The metabolic abnormalities in the upper tertile 3 subjects included a reduced insulin action (Si) and reduced Sg, as well as elevated systolic and diastolic BPs, but not β-cell secretion and lipids and lipoproteins. We conclude that the upper tertile of HbA1c should be considered as a major surrogate of MS in high-risk African-Americans who are genetically predisposed to type 2 diabetes.

OBJECTIVE: To examine the significance of alterations in insulin sensitivity index (S1), glucose effectiveness (Sg), and β-cell function in the pathogenesis of type II diabetes in African-Americans with varying degrees of glucose intolerance. RESEARCH DESIGN AND METHODS: A total of 154 African-Americans residing in Franklin County, Ohio, were studied. There were 101 subjects with normal glucose tolerance (NGT), 36 with impaired glucose tolerance (IGT), and 17 with type II diabetes. An oral glucose tolerance test (OGTT) was performed on each subject. S1 and Sg were measured by insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: The mean fasting and postprandial serum glucose levels were significantly greater in the diabetic groups when compared with the IGT and NGT groups. In contrast, while fasting serum insulin and C-peptide levels tended to be greater in the type II diabetic and IGT groups, the postprandial responses were blunted at 30 min in the IGT and type II diabetic groups when compared with the NGT group. The mean acute first-phase insulin release after intravenous glucose was blunted also in the IGT and type II diabetic groups when compared with the NGT group. The S1 was significantly lower in the IGT (1.51 ± 0.19) and type II diabetic (0.61 ± 0.15) groups when compared with the NGT group (2.94 ± 0.20 × 10−4 · min−1 · μU−1 · ml−1). The Sg was not significantly different in the NGT (2.90 ± 0.20), IGT (2.47 ± 0.19), and the type II diabetic (2.35 ± 0.15 × 10−2/min) groups. The glucose effectiveness at theoretical zero insulin concentration (GEZI) followed similar patterns as the Sg. Furthermore, the basal insulin effect (BIE) was significantly lower in the IGT and type II diabetic groups compared with the NGT group. In addition, the glucose decay constant (Kg) was significantly lower (P < 0.001) in the IGT (1.21 ± 0.13) and the type II diabetic (1.07 ± 0.12) groups when compared with the NGT group (2.03 ± 0.10% per minute). CONCLUSIONS: Our present study demonstrates that African-American patients with IGT and mild type II diabetes have significant reduction in β-cell function, insulin sensitivity, and BEI but have normal and intact Sg and GEZI when compared with NGT subjects. We conclude the following: 1) a reduction in Sg does not appear to play a significant role in the pathogenetic mechanism of IGT and type II diabetes in African-American patients, and 2) the intact Sg in the IGT and type II diabetic groups could serve as a compensatory mechanism for hyperglycemia in African-Americans.