MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE

糖尿病和运动中的肌肉葡萄糖代谢

• 批准号: 2634245
• 负责人: GERALD Lynis DOHM
• 金额: $ 12.63万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2634245
• 关键词: diabetes mellitus; enzyme activity; genetically modified animals; glucose metabolism; insulin; insulin receptor; insulin sensitivity /resistance; isozymes; laboratory mouse; laboratory rat; lipids; muscle metabolism; obesity; phosphoproteins; protein kinase C; striated muscles

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.

描述（根据申请人的申请改编）：长期目标 这项研究是了解胰岛素的分子机制 骨骼肌的阻力。 最近的实验表明蛋白质 激酶C（PKC）可能参与胰岛素中胰岛素信号的降低 抗肌肉。 将胰岛素耐药肌纤维带与A孵育 PKC抑制剂明显增加了对胰岛素的反应。 调查人员 认为这些数据不仅指出蛋白激酶C是 肌肉胰岛素抵抗，但建议使用PKC抑制剂很可能是 有效的糖尿病药理治疗方法。 这是他们的假设 胰岛素抵抗是由升高的肌肉脂质升高引起的 PKC的活性，磷酸化并使胰岛素失活 受体。 由于运动会逆转胰岛素抵抗，因此他们也相信 通过锻炼来减少PKC活性，恢复 胰岛素受体。 为了研究他们的中心假设，他们提出了 以下特定目的：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 C同工型在胰岛素抵抗肌肉中被激活。 3。调查 转基因小鼠中肌肉蛋白激酶C的过表达是否导致 胰岛素受体和胰岛素抵抗的磷酸化； 4 研究改变肌肉脂质对胰岛素受体的影响 激酶和蛋白激酶C活性； 5。调查是否运动 减少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 允许他们研究肥胖症中胰岛素抵抗的原因 NIDDM。 人类肌肉的研究补充了 胰岛素抵抗肥胖的扎克大鼠的肌肉。 这些模型与 他们开发的技术以及与其他的合作 他们已经建立的实验室，使它们具有独特的资格 为理解原因做出重大贡献 肥胖和NIDDM中的胰岛素抵抗。