Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity, Eight obese (age 26+/-1 yr, body mass index 37 +/- 1 kg/m(2)) and seven nonobese males (25 +/- yr, 23 +/- 1 kg/m(2)) received an infusion of bradykinin into the femoral artery of one leg hinder intravenously maintained normoglycemic hyperinsulinemic conditions, Blood flow was measured simultaneously in he bradykinin and insulin-and the insulin-infused leg before and during hyperinsulinemia using [O-15]-labeled water ([O-15]H2O) and positron emission tomography (PET), Glucose uptake was quantitated immediately thereafter in both legs using [F-18]-fluoro-deoxy-glucose ([F-18]PDG) and PET. Whole body insulin-stimulated glucose uptake was lower Ire the obese (507+/-47 mu mol/m(2).min) than the nonobese (1205+/-97 mu mol/m(2).min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 mu mol/kg muscle.min) than in the nonobese (56+/-9 mu mol/kg muscle.min, P < 0.005) subjects, Bradykinin increased blood flow during hyperinsulinemia in the obese subjects (19+/-4 from 16 +/- 1 to 28+/-4 ml/kg muscle.min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle.min (P < 0.05), However, this flow increase required twice as much bradykinin in the obese (51+/-3 mu g over 100 min) than in the normal(25+/-1 mu g, P < 0.001) subjects, In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28 +/- 4 ml/kg muscle min) was comparable to that ire the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle min), Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mu mol/kg.min) compared with the insulin-infused leg (19+/-4 mu mol/kg muscle min) in the obese subjects, Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs, 56+/-9 mu mol/kg.min, bradykinin and insulin versus insulin leg), These data demonstrate that obesity is characterized by two distinct defects ire skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation, Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.