MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE

这项研究的长期目标是了解 肥胖者肌肉组织胰岛素抵抗的分子机制 和糖尿病患者。最有可能导致人类胰岛素抵抗的原因 肌肉中胰岛素受体酪氨酸激酶活性降低。假说 是高胰岛素血症导致PKC-β激活，然后 丝氨酸/苏氨酸磷酸化并使胰岛素受体失活 肥胖人群肌肉中的胰岛素抵抗。以前是这样的 证明：(1)孵育胰岛素可诱导胰岛素抵抗。 使用PKC激活剂的敏感肌肉。(2)胰岛素作用与胰岛素 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)肥胖者肌肉中PKC-β水平升高 个人。(4)胰岛素可引起膜相关PKC-β增加。 胰岛素抵抗肌肉。(5)PKC-β过表达降低胰岛素水平 信号转导和PKC-β基因敲除增加胰岛素信号转导，在 转基因小鼠的心脏。这项提案将继续专注于胰岛素 受体和PKC-β来获得支持这一假说的证据。特定目标 1：测定胰岛素受体的磷酸化模式。特定的 目的2：探讨高胰岛素血症在PKC-β活化中的作用 和胰岛素受体的磷酸化。具体目标3：研究胰岛素 对PKC-β基因敲除小鼠肌肉的作用。具体目标4：研究 丝氨酸/苏氨酸磷酸酶(S)，重新激活胰岛素受体。会的 研究这些机制是可能的，因为大量的肥胖患者 可供研究。

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.