Skeletal Muscle Glucose Transport: Exercise and Insulin

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型糖尿病的基本缺陷，可能是主要缺陷。广泛而长期的目标是充分理解胰岛素和运动相互作用共同调节骨骼肌葡萄糖运输的机制，这是葡萄糖处理的限速步骤。在这个项目中，我们关注急性运动的一个关键健康益处：胰岛素刺激的葡萄糖运输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（基本和短暂的先决条件），这些触发事件诱发一个或多个记忆元素（将触发器与下游介质连接起来的持久的运动后结果）。运动后，介质是关键的胰岛素信号传导步骤，作为记忆元素的结果，在生理胰岛素浓度的参与下，导致胰岛素作用的改善。介质导致细胞表面定位的GLUT4增加，这是最终负责增加胰岛素刺激的葡萄糖运输的末端执行器。我们有4个具体目标：1)确定体液激肽激肽系统（KKS）的元素是否是胰岛素刺激下骨骼肌运动后葡萄糖运输升高的必要触发因素。2)确定amp活化蛋白激酶（AMPK）是否是运动后胰岛素刺激的骨骼肌葡萄糖运输升高的必要触发因素。3)阐明胰岛素和运动对与TUG相关的GLUT4 （TUG-GLUT4）数量的影响，并确定可能的触发因子（体液- kks和AMPK）与TUG-GLUT4的关系。4)识别从触发到记忆元件到胰岛素信号传导的顺序联系；这些步骤介导GLUT4募集到细胞表面，从而导致胰岛素刺激的葡萄糖运输升高。我们将探讨模型组件之间的关系，因为只有全面的方法才能揭示这个复杂过程的集成机制。由于体育活动太普遍了，数百万美国人可以通过锻炼来改善他们的胰岛素敏感性。阐明运动后胰岛素作用改善的机制应该有助于设计适合每个人能力的最佳运动计划，并开发其他干预措施，以改善那些不能进行足够运动的人的胰岛素作用。

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 one 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.