Coronary artery disease (CAD) is the leading cause of morbidity and mortality among blacks. The purpose of this project is to investigate the potential central role of hyperinsulinemia in the pathogenesis of CAD in this ethnic group. Hyperinsulinemia has been associated with increased CAD risk and is commonly associated with glucose intolerance, hypertension, and obesity in blacks. High insulin or proinsulin may be atherogenic via several mechanisms including: 1) increased androgens in women, 2) coronary artery endothelial dysfunction, 3) vascular smooth muscle proliferation and 4) abnormalities of the coagulation and fibrinolytic system. We propose five overlapping studies to investigate multiple aspects of insulin action: 1) Using new assay techniques we will profile both insulin and proinsulin activity in blacks versus whites with catheterization documented premature CAD compared to normals. 2) Androgen status will be related to insulin/proinsulin profiles in black and white premenopausal women. 3) Endothelial-dependent vasoreactivity will be measured using new Doppler techniques in a subgroup of catheterized nonCAD blacks in relation to insulin/proinsulin profile. 4) using new immunochemistry techniques we will demonstrate any specific abnormalities of insulin binding and growth factors in atheroma and arterial segments of black and white CAD patients. 5) Using highly sensitive assays we will evaluate hematological effects associated with insulin abnormalities. This study will provide initial information that could shed light on specific mechanisms of CAD in blacks. Hopefully this data will help further development of new prevention and therapeutic trials.