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-beta-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 x 10(-4).min(-1)( micro U/ml)(-1)], when compared with those in tertile 1 [2.27 +/- 0.20 19 x 10(-4).min(-1)( micro U/ml)(-1)] and tertile 2 [2.61 +/- 0.19 x 10(-4).min(-1)( micro U/ml)(-1)]. The mean Sg was significantly (P < 0.02) lower in tertile 3 (1.95 +/- 0.12 x 10(-2).min(-1)), when compared with those of tertile 1 (2.27 +/- 0.10 x 10(-2).min(-1)) and tertile 2 (2.29 +/- 0.11 x 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-beta-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 beta-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.