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: 6192579
• 负责人: GERALD Lynis DOHM
• 金额: $ 20.93万
• 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 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192579
• 关键词: diabetes mellitus; enzyme activity; enzyme inhibitors; exercise; gene targeting; genetically modified animals; glucose metabolism; hyperinsulinism; insulin receptor; insulin sensitivity /resistance; laboratory mouse; muscle metabolism; obesity; okadaic acid; phosphomonoesterases; phosphoproteins; protein kinase C

The long range objective of this research is to understand the molecular mechanism of insulin resistance in muscle tissue of obese individuals and diabetic patients. The most likely cause of insulin resistance in human muscle is decreased insulin receptor tyrosine kinase activity. The hypothesis is that hyperinsulinemia causes activation of PKC-beta which then serine/threonine phosphorylates and inactivates the insulin receptor to cause insulin resistance in muscles of obese individuals. It was previously demonstrated that: (1) insulin resistance can be induced by incubating insulin sensitive muscle with an activator of PKC. (2) Insulin action and insulin receptor kinase activity are restored in insulin resistant muscles that are treated with a PKC inhibitor. (3) PKC-beta is increased in muscle of obese individuals. (4) Insulin causes membrane associated PKC-beta to be increased in insulin resistant muscles. (5) Overexpression of PKC-beta decreases insulin signaling, and knockout of PKC-beta increases insulin signal transduction, in heart of transgenic mice. This proposal will continue to focus on the insulin receptor and PKC-beta to gain evidence to support the hypothesis. Specific Aim 1: To determine the phosphorylation pattern on the insulin receptor. Specific Aim 2: To investigate the role of hyperinsulinemia in activation of PKC-beta and phosphorylation of insulin receptors. Specific Aim 3: To study insulin action in muscle of PKC-beta knockout mice. Specific Aim 4: To study the serine/threonine phosphatase(s) that reactivates the insulin receptor. It will be possible to study these mechanisms because a large number of obese patients are available for study.

这项研究的远程目标是了解 肥胖个体肌肉组织中胰岛素抵抗的分子机制 和糖尿病患者。人类胰岛素抵抗的最可能原因 肌肉减少胰岛素受体酪氨酸激酶活性。假设 是高胰岛素血症会引起PKC-beta的激活，然后 丝氨酸/苏氨酸磷酸化并使胰岛素受体失活以引起 肥胖个体肌肉的胰岛素抵抗。以前是 证明：（1）可以通过孵育胰岛素来诱导胰岛素抵抗 具有PKC激活剂的敏感肌肉。 （2）胰岛素作用和胰岛素 受体激酶活性在胰岛素抵抗肌肉中恢复 用PKC抑制剂治疗。 （3）肥胖的肌肉中PKC-beta增加 个人。 （4）胰岛素导致膜相关的PKC-β在增加 胰岛素抵抗肌肉。 （5）PKC-BETA的过表达减少胰岛素 信号传导和PKC-beta的敲除增加胰岛素信号转导，在 转基因小鼠的心脏。该建议将继续关注胰岛素 受体和PKC-beta获得证据以支持该假设。具体目标 1：确定胰岛素受体上的磷酸化模式。具体的 目标2：研究高胰岛素血症在PKC-β激活中的作用 和胰岛素受体的磷酸化。特定目的3：研究胰岛素 在PKC-Beta敲除小鼠的肌肉中作用。特定目标4：研究 丝氨酸/苏氨酸磷酸酶（S）可重新激活胰岛素受体。会 可以研究这些机制，因为大量肥胖患者 可用于研究。