MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE

这项研究的长期目标是了解 肥胖和糖尿病患者肌肉胰岛素抵抗的机制(S) 病人。有相当多的证据表明肌肉葡萄糖的运输 在肥胖和非胰岛素依赖型糖尿病中减少 (NIDDM)。我们已经观察到50%的抑郁在最大程度上 但葡萄糖的转运只减少了20%的葡萄糖 胰岛素抵抗肌肉中的转运蛋白，表明有 胰岛素信号转导或移位的其他缺陷 葡萄糖转运蛋白进入细胞膜。我们提出机械论 研究探讨肌肉胰岛素抵抗的原因(S)。 通过与外科部门的合作研究，我们 有一个独特的机会从一个实质性的 病态肥胖糖尿病患者(NIDDM)的数量，我们计划 用这块组织来研究胰岛素抵抗的原因。 腹肌将从病态肥胖患者身上获得， 胃旁路手术和非肥胖症患者择期手术 腹部手术。从肌肉活组织检查看，细小的肌肉纤维条 固定在夹子中，在体外孵化。这个 导致人类肌肉中胰岛素抵抗的机制将是 使用这种独特的肌肉制剂进行了研究。 这些研究的假设是缺氧(或肌肉收缩) 而磷酸酶抑制剂通过使胰岛素抵抗 一种或多种必需的磷酸化蛋白质的积累 发出信号将葡萄糖转运体转移到细胞 薄膜。以下具体目标针对这一假设：(1) 判断低氧刺激葡萄糖转运是否正常 肥胖患者胰岛素抵抗肌肉中是否存在低氧 会增强这些肌肉中的胰岛素反应，就像肥胖者一样 动物模型；(2)研究胰岛素是否刺激 胰岛素抵抗肌肉中蛋白质的磷酸化改变 肥胖的病人。此外，我们还将测定磷酸化 低氧、低氧加胰岛素反应的蛋白质谱，以及 用磷酸酶抑制剂来确定是否有常见的 这些途径刺激的中间体；以及(3)研究 胰岛素、低氧和低氧对葡萄糖转运蛋白转运蛋白的影响 瘦肉者和肥胖者肌肉中的磷酸酶抑制物。

The long range objective of this research is to understand the mechanism(s) of insulin resistance in muscle of obese and diabetic patients. There is considerable evidence that muscle glucose transport is decreased in obesity and non-insulin dependent diabetes mellitus (NIDDM). We have observed a 50% depression in the maximal rate of glucose transport but only a 20% decrease in the number of glucose transporters in insulin resistant muscle, suggesting that there are additional defects in either insulin signalling or in translocation of glucose transporter protein to the cell membrane. We propose mechanistic studies to investigate the cause(s) of insulin resistance in muscle. Through a cooperative research effort with the Department of Surgery we have a unique opportunity to obtain muscle tissue from a substantial number of morbidly obese patients with diabetes (NIDDM) and we plan to use this tissue to investigate the cause of insulin resistance. Abdominal muscle will be obtained from morbidly obese patients undergoing gastric bypass surgery and from nonobese patients undergoing elective abdominal surgery. From the muscle biopsies thin muscle fiber strips are mounted in clamps at resting length and incubated in vitro. The mechanisms causing insulin resistance in human muscle will be investigated using this unique muscle preparation. The hypothesis for these studies is that hypoxia (or muscle contraction) and phosphatase inhibitors overcome insulin resistance by causing the accumulation of one or more phosphorylated proteins essential for signalling the translocation of glucose transporters to the cell membrane. The following specific aims address this hypothesis: (1) To determine whether stimulation of glucose transport by hypoxia is normal in insulin resistant muscle of obese human patients and whether hypoxia will enhance insulin responsiveness in these muscles as seen in obese animal models; (2) To investigate whether the insulin stimulated phosphorylation of proteins is altered in insulin resistant muscle of obese patients. In addition, we will determine the phosphorylation profile of proteins in response to hypoxia, hypoxia plus insulin, and phosphatase inhibitors to ascertain whether there are common intermediates in the stimulation by these pathways; and (3) To study glucose transporter translocation in response to insulin, hypoxia and phosphatase inhibitors in muscle of lean and obese individuals.