CHRONIC HYPERGLYCEMIA IMPAIRS ENDOTHELIAL FUNCTION AND INSULIN SENSITIVITY VIA DIFFERENT MECHANISMS IN INSULIN-DEPENDENT DIABETES-MELLITUS

Background We explored whether chronic hyperglycemia is associated wit h defects in endothelium-dependent vasodilatation in vivo and whether defects in the hemodynamic effects of insulin explain insulin resistan ce. Methods and Results Vasodilator responses to brachial artery infus ions of acetylcholine, sodium nitroprusside, and N-G-monomethyl-L-argi nine and, on another occasion, in vivo insulin sensitivity (euglycemic insulin clamp combined with the forearm catheterization technique) we re 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). T he defect in forearm glucose uptake was attributable to a defect in gl ucose extraction (glucose AV difference, 1.1+/-0.2 versus 1.9+/-0.2 mm ol/L, P<.001, IDDM versus normal subjects), not blood flow. Within the group of IDDM patients, hemoglobin A(1c) was inversely correlated wit h forearm blood flow during administration of acetylcholine (r=.50, P< .02) but not sodium nitroprusside (r=.07). The ratio of endothelium-de pendent to endothelium-independent blood flow was approximate to 40% l ower in patients with poor glycemic control than in normal subjects or patients with good or moderate glycemic control. Conclusions We concl ude 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 hyperglycem ia. impairs vascular function and insulin action via distinct mechanis ms. The defect in endothelium-dependent vasodilatation could contribut e to the increased cardiovascular risk in diabetes.