MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE

描述(根据申请者的申请改编)：长期目标 本研究的目的是了解胰岛素的分子机制(S) 骨骼肌的抵抗力。最近的实验表明，蛋白质 蛋白激酶C(PKC)可能参与了胰岛素信号转导的降低 抵抗力强的肌肉胰岛素抵抗肌纤维条与 PKC抑制剂显著增加对胰岛素的反应。调查人员 相信这些数据不仅表明蛋白激酶C可能是 肌肉胰岛素抵抗，但提示使用PKC抑制剂很可能是 治疗糖尿病的有效药物疗法。这是他们的假设 胰岛素抵抗是由升高的肌肉脂肪增加 蛋白激酶C的活性，它使胰岛素磷酸化并失活 受体。由于运动可以逆转胰岛素抵抗，他们还认为 运动可以降低PKC活性，恢复PKC的活性 胰岛素受体。为了研究他们的中心假说，他们提出了 具体目的如下：1.研究胰岛素的磷酸化 胰岛素抵抗肌肉中的受体；2.确定哪种蛋白激酶 胰岛素抵抗肌肉中C亚型被激活；3.研究 在转基因小鼠中过表达肌肉蛋白激酶C是否会导致 胰岛素受体的磷酸化与胰岛素抵抗； 改变肌脂对胰岛素受体的影响 蛋白激酶C活性；5.调查运动是否 降低肌肉脂质和蛋白激酶C，从而恢复 胰岛素受体。在体外研究人类肌肉的独特机会 使他们能够调查肥胖和胰岛素抵抗的原因 NIDDM。对人类肌肉的研究得到了平行研究的补充 胰岛素抵抗肥胖Zucker大鼠的肌肉。这些型号，链接到 他们开发的技术以及与其他公司的合作 他们建立的实验室，使他们有独特的资格 对理解……的原因做出了重大贡献 肥胖和NIDDM的胰岛素抵抗。

DESCRIPTION (Adapted from the applicant's application): The long term goal of this research is to understand the molecular mechanism(s) of insulin resistance in skeletal muscle. Very recent experiments suggest that protein kinase C (PKC) may be involved in decreased insulin signaling in insulin resistant muscle. Incubating insulin resistant muscle fiber strips with a PKC inhibitor markedly increased the response to insulin. The investigators believe these data not only point to protein kinase C as a possible cause of muscle insulin resistance but suggest that using PKC inhibitors may well be an effective pharmacological treatment for diabetes. It is their hypothesis that insulin resistance is caused by elevated muscle lipids increasing the activity of a PKC, which phosphorylates and inactivates the insulin receptor. Since exercise reverses insulin resistance, they also believe that PKC activity is reduced by exercise, restoring the activity of the insulin receptor. To investigate their central hypothesis they propose the following specific aims: 1. To investigate phosphorylation of the insulin receptor in insulin resistant muscle; 2. To determine which protein kinase C isoforms are activated in insulin resistant muscle; 3. To investigate whether overexpression of muscle protein kinase C in transgenic mice causes phosphorylation of the insulin receptor and insulin resistance; 4. To investigate the effects of altering muscle lipids on the insulin receptor kinase and protein kinase C activity; 5. To investigate whether exercise reduces muscle lipids and protein kinase C, thus restoring the activity of the insulin receptor. The unique opportunity to study human muscle in vitro allows them to investigate the causes of insulin resistance in obesity and NIDDM. Studies in human muscle are supplemented with parallel studies in muscles of insulin resistant obese Zucker rats. These models, linked with the techniques that they have developed and the collaborations with other laboratories that they have established, makes them uniquely qualified to make a substantial contribution toward an understanding of the causes of insulin resistance in obesity and NIDDM.