Skeletal Muscle Glucose Transport: Exercise and Insulin

描述(由申请人提供)：胰岛素抵抗导致骨骼肌代谢葡萄糖是2型糖尿病的基本缺陷，也可能是主要缺陷。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运输的机制，这是葡萄糖处置的限速步骤。在这个项目中，我们重点关注急性运动对健康的一个关键好处：胰岛素刺激的葡萄糖转运的显著和持久的增加。我们将测试一个新的模型，该模型提出这种锻炼效果的机制始于触发事件(基本和瞬时先决条件)，这些事件诱导一个或多个记忆元素(持久的、锻炼后的结果，将触发因素与下游中介联系起来)。运动后，介质是胰岛素信号传递的关键步骤，作为记忆因素的结果，当被生理浓度的胰岛素参与时，会导致胰岛素作用的改善。这些介质导致细胞表面定位的GLUT4增加，GLUT4是最终导致胰岛素刺激的葡萄糖转运增加的最终效应器。我们有四个具体的目标：1)确定体液激肽释放酶-激肽释放酶系统(KKS)是否是胰岛素刺激的骨骼肌运动后葡萄糖转运增加的必要触发因素。2)确定AMP激活的蛋白激酶(AMPK)是否是运动后骨骼肌胰岛素刺激的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GLUT4(TUG-GLUT4)的影响，并确定体液KKS和AMPK与TUG-GLUT4的关系。4)确定从触发因素到记忆元件再到胰岛素信号的顺序联系；介导GLUT4募集到细胞表面从而导致胰岛素刺激的葡萄糖转运增加的步骤。我们将探索模型组件之间的关系，因为只有全面的方法才能揭示这一复杂过程的集成机制。由于体力活动太普遍了，数百万美国人可以通过锻炼潜在地改善他们对胰岛素的敏感性。阐明运动后改善胰岛素作用的机制应该有助于为每个人的能力设计最优的运动计划，并开发其他干预措施来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.