African-American females with type 2 diabetes mellitus are at greater risk for cardiovascular morbidity and mortality when compared to diabetic African-American males and whites. To explain the gender differences in morbidity and mortality secondary to cardiovascular diseases (CVD) associated with type 2 diabetes mellitus (DM) in middle-aged, African Americans (AA), we have postulated that increased incidence of CVD in AA females could be ascribed in part to greater clustering of pre-existing CVD risks when compared to their AA male counterparts. We have therefore investigated the metabolic and anthropometric risk factors for CVD in an AA population who are genetically at greater risk for type 2 DM. We studied 84 healthy first-degree relatives of AA patients with type 2 diabetes, 42 males and 42 females with a mean age 42.5+/-8.4 years, age range 25-65 years, matched for age and waist-to-hip circumference ratio (WHR) in order to determine the impact of body fat distribution pattern on CVD risks. A standard oral glucose tolerance test (OGTT) and an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test were performed for each subject. In addition, lipid and lipoprotein levels, anthropometric parameters, blood pressure, sociodemographics and physical activity levels were obtained for each subject. Insulin sensitivity index (Si) and glucose-dependent glucose disposal (Sg) were determined using Bergman's Minimal Model method. Hepatic insulin extraction (HIE) was calculated as the molar ratio of basal and postprandial c-peptide and insulin concentrations. Mean age, annual income and percent participation in physical activity did not differ between genders. Despite the identical WHR, body mass index (BMI) (34.8+/-7.5 vs 30.3+/-6.7 kg/m2, P=0.005), and % body fat (43.8+/-7.3 vs 28.1+/-7.7%, P=0.001) were greater in females than males, respectively. The systolic blood pressure(SBP), but not the diastolic blood pressure (DBP), was significantly lower in our female vs male group. Mean fasting and 2-hour postprandial serum glucose and insulin levels were significantly greater in the female group. In contrast, the corresponding serum c-peptide levels were not significantly different between the groups. Thus, the basal and postprandial hepatic insulin extractions (HIE) were 30% lower in the females than in the males. The mean absolute levels of cholesterol (C), low density lipoprotein-C (LDL-C), very low-density lipoprotein-C (VLDL-C), high-density lipoprotein-C (HDL-C), and triglycerides were not significantly different between the genders. Mean Si was significantly lower in the females when compared to males (Si, 1.62+/-1.66 vs 2.45+/-1.81 x 10(-4) x min(-1) (microU/ml)(-1), P=0.03). The mean Sg was identical in both groups (2.66+/-1.99 vs 2.67+/-1.35 x 10(-2) x min(-1), P=0.97). We found no significant correlations between Si and SBP and DBP, WHR, or lipids and lipoproteins in the females. In contrast, Si correlated significantly with WHR (R=-0.346, P=0.05), HDL-C (R=0.310, P=0.05), but not with BP, LDL-C, and triglyceride levels in the males. We conclude that nondiabetic African-American females manifest several metabolic and anthropometric risk factors for cardiovascular diseases that precede the disease by decades. Therefore, obese AA females with family history of type 2 DM should be particularly targeted for diabetes and CVD risk prevention programs using effective and practical weight reduction modalities.