BACKGROUND: This work was conducted to evaluate associations of insulin secretion with overall and central obesity, dietary fats, physical activity, and alcohol. METHODS: A frequently sampled intravenous glucose tolerance test (FSIGT) was used to assess acute insulin response to glucose (AIR) and insulin sensitivity (S(I)) among adult participants (n=675 with normal, NGT; n=332 with impaired glucose tolerance, IGT) in the Insulin Resistance Atherosclerosis Study (IRAS). Disposition index (DI) was calculated as the sum of the log-transformed AIR and S(I) to reflect pancreatic compensation for insulin resistance. Obesity was measured as body mass index (kg/m(2), BMI) and central fat distribution by waist circumference (cm). Dietary fat intake (total, saturated, polyunsaturated, oleic acid), physical activity, and alcohol intake were assessed by standardized interview. RESULTS: In unadjusted analyses, BMI and waist were each positively correlated with AIR among NGTs (r=0.26 and 0.23, respectively; p<0.0001) but correlations were weaker among the IGTs (r=0.10, NS; r=0.13, p<0.05 for BMI and waist, respectively). BMI and waist were inversely correlated with DI among NGTs (r=-0.13 and -0.20, respectively; p<0.0001) and among IGTs (r=-0.20 and -0.19, respectively, p<0.0001). Dietary fat variables were positively related, and alcohol was inversely related, to AIR among NGTs (p<0.01) but not among IGTs. With all factors considered simultaneously in a pooled analysis of IGTs and NGTs, waist, but not BMI, was positively associated with AIR (p<0.001) and inversely associated with DI (p<0.01). None of the behavioral variables were independently related to either outcome. CONCLUSION: Among non-diabetic patients, central obesity appears to be related to higher insulin secretion, but to lower capacity of the pancreas to respond to the ambient insulin resistance.