The relationship between insulin sensitivity and overall obesity is well established. However, there remains debate as to which of the fat depots, visceral abdominal tissue (VAT) or subcutaneous abdominal tissue (SAT), is of greater importance. Also, the relationship between fat distribution and insulin secretion is largely unknown. We studied SI, acute insulin response (AIR), and disposition index (DI), as obtained by minimal model analysis, in 999 Hispanic and 458 African-American men and women as part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. VAT and SAT were measured from computed tomography scans performed at the L4/L5 vertebral region. A mixed-model approach was used to determine the relationship between each of the glucose homeostasis measures (SI, AIR, and DI) versus abdominal fat measures. Mean values were as follows: age, 41 years; SI, 1.98 10(-4).min(-1).microU(-1).ml(-1); AIR, 840 pmol.ml(-1).min(-1); BMI, 28.5 kg/m2; VAT, 100 cm2; and SAT, 333 cm2. SAT, VAT, and their joint interaction were each inversely and significantly associated with SI, adjusting for age, sex, ethnicity, and BMI. SAT, but not VAT, was positively associated with AIR, except when additionally adjusting for SI, in which case VAT was inversely associated with AIR. VAT and the joint interaction of VAT and SAT were inversely associated with DI. The fat measures explained 27% of the model R2 for SI, 16% for AIR, and 16% for DI. Thus, fat distribution is an important determinant of both insulin resistance and insulin secretion.