Skeletal Muscle Glucose Transport: Exercise and Insulin

骨骼肌葡萄糖转运：运动和胰岛素

• 批准号: 7143435
• 负责人: Gregory D. Cartee
• 金额: $ 30.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143435
• 关键词: biological signal transduction; exercise; glucose metabolism; glucose transport; glucose transporter; hormone regulation /control mechanism; insulin; insulin sensitivity /resistance; kallikreins; kinins; laboratory rat; muscle contraction; muscle metabolism; phosphorylation; protein kinase A; striated muscles

DESCRIPTION (provided by applicant): Insulin resistance for glucose disposal by skeletal muscle is an essential and perhaps primary defect for Type 2 diabetes. The broad, long-term objective is to fully understand the mechanisms whereby insulin-and exercise intersect to co-regulate skeletal muscle glucose transport, a rate-limiting step for glucose disposal. In this project, we focus on a key health benefit of acute exercise: a substantial and long-lasting increase in insulin-stimulated glucose transport. We will test a novel model that proposes that the mechanism for this exercise effect begins with, Triggering Events (essential and transient prerequisites) that induce 1 or more Memory Element (persistent, post-exercise outcomes linking triggers to downstream mediators). After exercise, Mediators are the key insulin signaling steps that, as a consequence of Memory Elements, and upon engagement by a physiologic insulin concentration, lead to improved insulin action. The Mediators lead to increased cell-surface localized GLUT4, which is the End-effector ultimately responsible for increased insulin-stimulated glucose transport. We have 4 Specific Aims: 1) Determine if elements of the humoral kallikrein-kinin system (KKS) are essential triggers for elevated post-exercise glucose transport in insulin- stimulated skeletal muscle. 2) Determine if AMP-activated protein kinase (AMPK) is an essential trigger for post-exercise elevation in insulin-stimulated glucose transport in skeletal muscle. 3) Elucidate the effects of insulin and exercise on the amount of GLUT4 associated with TUG (TUG-GLUT4) and determine the relationship of putative triggers (humoral-KKS and AMPK) with TUG-GLUT4. 4) Identify sequential links from triggers to memory elements to insulin signaling; steps that mediate GLUT4 recruitment to the cell surface thereby leading to elevated insulin-stimulated glucose transport. We will probe relationships among the model's components because only a comprehensive approach can reveal the integrated mechanisms for this complex process. Because physical activity is all too common, millions of Americans can potentially improve their insulin sensitivity via exercise. Illuminating the mechanisms for post-exercise improvement in insulin action should facilitate the design of optimal exercise programs for each person's abilities and development of other interventions to improve insulin action in those who cannot perform sufficient exercise.

描述（由申请人提供）：骨骼肌对葡萄糖处理的胰岛素抵抗是2型糖尿病的一个基本缺陷，可能是主要缺陷。广泛的，长期的目标是充分了解胰岛素和运动交叉共同调节骨骼肌葡萄糖转运的机制，这是葡萄糖处置的限速步骤。在这个项目中，我们专注于急性运动的一个关键健康益处：胰岛素刺激的葡萄糖转运的大量和持久的增加。我们将测试一个新的模型，该模型提出这种运动效应的机制始于触发事件（必要和短暂的先决条件），这些事件诱导1个或多个记忆元素（将触发因素与下游介质联系起来的持久的运动后结果）。运动后，介体是关键的胰岛素信号传导步骤，作为记忆元件的结果，并且在生理胰岛素浓度的参与下，导致改善的胰岛素作用。介体导致细胞表面定位的GLUT 4增加，GLUT 4是最终负责增加胰岛素刺激的葡萄糖转运的末端效应物。我们有四个具体目标：1）确定体液激肽释放酶-激肽系统（KKS）的元件是否是胰岛素刺激的骨骼肌中运动后葡萄糖转运升高的必要触发因素。2)确定AMP激活蛋白激酶（AMPK）是否是运动后胰岛素刺激的骨骼肌葡萄糖转运升高的重要触发因素。3)阐明胰岛素和运动对与TUG相关的GLUT 4量（TUG-GLUT 4）的影响，并确定推定触发因子（体液-KKS和AMPK）与TUG-GLUT 4的关系。4)确定从触发器到记忆元件再到胰岛素信号传导的顺序链接;介导GLUT 4募集到细胞表面从而导致胰岛素刺激的葡萄糖转运升高的步骤。我们将探讨模型的组件之间的关系，因为只有一个全面的方法可以揭示这个复杂的过程的综合机制。由于体力活动太普遍了，数百万美国人可以通过锻炼来改善他们的胰岛素敏感性。阐明运动后改善胰岛素作用的机制，应有助于为每个人的能力设计最佳运动计划，并制定其他干预措施，以改善那些不能进行足够运动的人的胰岛素作用。