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 患者 有相当多的证据表明，肌肉葡萄糖转运 在肥胖和非胰岛素依赖型糖尿病患者中 （NIDDM）。 我们已经观察到，在最大比率中， 葡萄糖转运，但葡萄糖转运的数量仅减少20%， 胰岛素抵抗肌肉中的转运蛋白，这表明 胰岛素信号传导或胰岛素转运中的其他缺陷 葡萄糖转运蛋白的细胞膜。 我们建议机械 研究调查肌肉中胰岛素抵抗的原因。 通过与外科部门的合作研究， 有一个独特的机会，获得肌肉组织从一个实质性的 糖尿病（NIDDM）的病态肥胖患者的数量，我们计划 用这个组织来研究胰岛素抵抗的原因。 腹肌将从接受手术的病态肥胖患者中获得 胃旁路手术和非肥胖患者接受择期 腹部手术 从肌肉活检来看， 以静止长度固定在夹子中并在体外孵育。 的 导致人体肌肉胰岛素抵抗的机制将是 使用这种独特的肌肉制剂进行研究。 这些研究的假设是，缺氧（或肌肉收缩） 磷酸酶抑制剂通过引起胰岛素抵抗来克服胰岛素抵抗。 一种或多种磷酸化蛋白质的积累， 发出葡萄糖转运蛋白易位到细胞的信号 膜的 以下具体目标针对这一假设：（1） 确定缺氧刺激葡萄糖转运是否正常 在肥胖人类患者的胰岛素抵抗肌肉中以及是否缺氧 将增强这些肌肉中的胰岛素反应性， （2）观察胰岛素是否刺激了胰岛素抵抗的发生， 蛋白质的磷酸化在胰岛素抵抗的肌肉中改变， 肥胖患者。 此外，我们将确定磷酸化 蛋白质对缺氧、缺氧加胰岛素的反应谱，以及 磷酸酶抑制剂，以确定是否有共同的 这些途径的刺激中的中间体;（3）研究 葡萄糖转运蛋白转位反应胰岛素，缺氧和 磷酸酶抑制剂在瘦和肥胖个体的肌肉中。

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.