OBJECTIVE:Diabetic individuals have impaired endothelium-dependent forearm vasodilatory responses to ischemia, acetylcholine, and other endothelium-dependent agonists. The functional significance of impaired endothelium-dependent dilation in diabetic individuals is uncertain but is most likely to be manifest during leg muscle exercise and may have relevance to peripheral vascular disease and leg ischemia, which is prevalent in diabetic individuals. The current study aimed to determine the relationship between leg blood flow (LBF) responses to endothelium-dependent vasodilation and dynamic large muscle exercise. RESEARCH DESIGN AND METHODS:LBF responses (thermodilution) to intrafemoral arterial infusions of an endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilator and a standardized 25-min cycling bout at 60% VO(2peak) were compared in nine male type 2 diabetic subjects and nine age-, sex-, VO(2peak)-, and weight-matched control subjects. RESULTS:LBF responses to acetylcholine and exercise but not sodium nitroprusside were significantly (P < 0.05) attenuated in patients with diabetes compared with healthy control subjects. The percentage increase in LBF in response to exercise and acetylcholine were significantly correlated (r = 0.54, P = 0.02). Furthermore, resting plasma glucose was significantly related to the LBF response to exercise (r = -0.66, P = 0.003) independently of insulin, HbA(1c), lipids, BMI, and blood pressure. CONCLUSIONS:The increase in LBF during exercise is substantially attenuated in type 2 diabetic compared with matched control subjects. Impaired endothelium-dependent vasodilation secondary to elevated plasma glucose may underlie this observation. This mechanism may be of importance in determining the leg ischemic threshold in diabetic individuals with peripheral vascular disease.