Background We explored whether chronic hyperglycemia is associated with defects in endothelium-dependent vasodilatation in vivo and whether defects in the hemodynamic effects of insulin explain insulin resistance.

Methods and Results Vasodilator responses to brachial artery infusions of acetylcholine, sodium nitroprusside, and N^G-monomethyl-l-arginine and, on another occasion, in vivo insulin sensitivity (euglycemic insulin clamp combined with the forearm catheterization technique) were determined in 18 patients with insulin-dependent diabetes mellitus (IDDM) and 9 normal subjects. At identical glucose and insulin levels, insulin stimulation of whole-body and forearm glucose uptake was 57% reduced in the IDDM patients compared with normal subjects (P<.001). The defect in forearm glucose uptake was attributable to a defect in glucose extraction (glucose AV difference, 1.1±0.2 versus 1.9±0.2 mmol/L, P<.001, IDDM versus normal subjects), not blood flow. Within the group of IDDM patients, hemoglobin A_1c was inversely correlated with forearm blood flow during administration of acetylcholine (r=−.50, P<.02) but not sodium nitroprusside (r=.07). The ratio of endothelium-dependent to endothelium-independent blood flow was ≈40% lower in patients with poor glycemic control than in normal subjects or patients with good or moderate glycemic control.

Conclusions We conclude that chronic hyperglycemia is associated with impaired endothelium-dependent vasodilatation in vivo and with a glucose extraction defect during insulin stimulation. These data imply that chronic hyperglycemia impairs vascular function and insulin action via distinct mechanisms. The defect in endothelium-dependent vasodilatation could contribute to the increased cardiovascular risk in diabetes.