Kelley D E, Mintun M A, Watkins S C, Simoneau J A, Jadali F, Fredrickson A, Beattie J, Thériault R
Department of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.
J Clin Invest. 1996 Jun 15;97(12):2705-13. doi: 10.1172/JCI118724.
Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin-stimulated conditions (40 mU/m2 per min), in eight lean nondiabetic, eight obese nondiabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis muscle was obtained by percutaneous biopsy during basal and insulin-stimulated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser scanning microscopy was used to ascertain Glut 4 at the sarcolemma as an index of insulin-regulated translocation. In lean individuals, insulin stimulated a 10-fold increase of 2-deoxy-2[18F]fluoro-D-glucose (FDG) clearance into muscle and significant increases in the rate constants for inward transport and phosphorylation of FDG. In obese individuals, the rate constant for inward transport of glucose was not increased by insulin infusion and did not differ from values in NIDDM. Insulin stimulation of the rate constant for glucose phosphorylation was similar in obese and lean subjects but reduced in NIDDM. Insulin increased by nearly twofold the number and area of sites labeling for Glut 4 at the sarcolemma in lean volunteers, but in obese and NIDDM subjects translocation of Glut 4 was attenuated. Activities of skeletal muscle HK I and II were similar in lean, obese and NIDDM subjects. These in vivo and ex vivo assessments indicate that impaired glucose transport plays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the insulin resistance of NIDDM.
葡萄糖转运和磷酸化缺陷可能是肥胖症和非胰岛素依赖型糖尿病（NIDDM）中胰岛素抵抗的潜在原因。为了验证这一假设，在基础状态和胰岛素刺激状态（40 mU/m²每分钟）下，使用正电子发射断层扫描对八名体重正常的非糖尿病患者、八名肥胖的非糖尿病患者和八名患有NIDDM的肥胖患者的大腿中部肌肉进行了¹⁸F-2-脱氧葡萄糖摄取的动态成像。在另外的研究中，在基础状态和胰岛素刺激状态下通过经皮活检获取股外侧肌，用于检测己糖激酶和柠檬酸合酶，并对葡萄糖转运蛋白4（Glut 4）进行免疫组织化学标记。使用定量共聚焦激光扫描显微镜确定肌膜处的Glut 4，作为胰岛素调节转位的指标。在体重正常的个体中，胰岛素刺激使肌肉中2-脱氧-2-[¹⁸F]氟-D-葡萄糖（FDG）清除率增加了10倍，并使FDG向内转运和磷酸化的速率常数显著增加。在肥胖个体中，胰岛素输注并未增加葡萄糖向内转运的速率常数，且该值与NIDDM患者的值无差异。肥胖和体重正常的受试者中，胰岛素对葡萄糖磷酸化速率常数的刺激相似，但在NIDDM患者中降低。胰岛素使体重正常志愿者肌膜处Glut 4标记位点的数量和面积增加了近两倍，但在肥胖和NIDDM患者中，Glut 4的转位减弱。体重正常、肥胖和NIDDM患者的骨骼肌己糖激酶I和II的活性相似。这些体内和体外评估表明，葡萄糖转运受损在NIDDM和肥胖症的胰岛素抵抗中起关键作用，并且在NIDDM的胰岛素抵抗中，葡萄糖磷酸化的额外受损也很明显。
