Laine H, Yki-Jarvinen H, Kirvela O, Tolvanen T, Raitakari M, Solin O, Haaparanta M, Knuuti J, Nuutila P
Department of Medicine, University of Turku, Turku, Finland.
J Clin Invest. 1998 Mar 1;101(5):1156-62. doi: 10.1172/JCI1065.
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/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% 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 microg over 100 min) than in the normal (25+/-1 mug, 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 in 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 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/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 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in 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.
内皮依赖性血管舒张是人类肥胖中骨骼肌葡萄糖摄取胰岛素抵抗的一个决定因素。八名肥胖男性（年龄26±1岁，体重指数37±1kg/m²）和七名非肥胖男性（25±2岁，23±1kg/m²）在静脉维持正常血糖高胰岛素血症条件下，接受向一侧腿部股动脉输注缓激肽。在高胰岛素血症之前和期间，使用[15O]标记水（[15O]H2O）和正电子发射断层扫描（PET）同时测量缓激肽输注腿、胰岛素输注腿以及未输注胰岛素腿的血流量。此后立即使用[18F] - 氟 - 脱氧 - 葡萄糖（[18F]FDG）和PET对双腿的葡萄糖摄取进行定量。肥胖受试者全身胰岛素刺激的葡萄糖摄取（507±47μmol/m²·min）低于非肥胖受试者（1205±97μmol/m²·min，P<0.001）。肥胖受试者胰岛素输注腿的肌肉葡萄糖摄取（19±4μmol/kg肌肉·min）比非肥胖受试者（56±9μmol/kg肌肉·min，P<0.005）低66%。缓激肽使肥胖受试者高胰岛素血症期间的血流量增加75%，从16±1增加到28±4ml/kg肌肉·min（P<0.05），使正常受试者的血流量增加65%，从23±3增加到38±9ml/kg肌肉·min（P<0.05）。然而，肥胖受试者增加血流量所需的缓激肽量（100分钟内51±3μg）是正常受试者（25±1μg，P<0.001）的两倍。在肥胖受试者中，缓激肽和胰岛素输注腿的血流量（28±4ml/kg肌肉·min）与正常受试者高胰岛素血症期间胰岛素输注腿的血流量（24±5ml/kg肌肉·min）相当。尽管如此，肥胖受试者中缓激肽和胰岛素输注腿的胰岛素刺激的葡萄糖摄取（18±4μmol/kg·min）与胰岛素输注腿（19±4μmol/kg肌肉·min）相比没有变化。正常受试者中缓激肽也不影响胰岛素刺激的葡萄糖摄取（缓激肽和胰岛素组为58±10μmol/kg·min，胰岛素组为56±9μmol/kg·min）。这些数据表明，肥胖的特征是骨骼肌存在两个不同的缺陷：细胞葡萄糖摄取的胰岛素抵抗和内皮依赖性血管舒张受损。由于血流量增加75%并不会改变葡萄糖摄取，肥胖中的胰岛素抵抗无法通过使肌肉血流量正常化来克服。
