Our investigation demonstrates 1) a functional abnormality of the coronary circulation in patients with insulin resistance but no other traditional risk factors for coronary artery disease except low HDL cholesterol levels and 2) reversal of this functional disturbance with thiazolidinediones, which are ligands to a nuclear receptor, peroxisome proliferator-activated receptor-γ. Patients with type 2 diabetes mellitus have both brachial and coronary artery endothelial dysfunction (24). Investigating earlier stages of insulin resistance, Caballero and colleagues (20) reported abnormalities in brachial artery endothelium-dependent and endothelium-independent blood flow responses in normoglycemic relatives of patients with type 2 diabetes. However, these relatives had higher blood pressure than age-, sex-, and weight-matched healthy control patients, which could explain the observation (20). Balletshofer and colleagues (25) also reported brachial artery endothelial dysfunction in normoglycemic insulin-resistant but not insulin-sensitive relatives of patients with diabetes. In fact, insulin resistance correlated with endothelial dysfunction independent of age, blood pressure, fasting insulin level, and lipid level (25). We believe that our observations are the first to suggest that insulin-resistant, otherwise healthy patients have coronary vasomotor abnormalities, regardless of whether they have a family history of diabetes. On average, myocardial blood flow responses to cold pressor test were reduced by 70% of that observed in age-matched insulin-sensitive patients. This abnormal cold pressor test response occurred despite a normal flow response to dipyridamole, indicating that vascular smooth-muscle cell responses were still preserved and suggesting a potential abnormality of the coronary endothelium.