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）：骨骼肌处理葡萄糖的胰岛素抵抗性是2型糖尿病的必不可少的，也许是主要缺陷。广泛的长期目标是充分了解胰岛素和运动相交以共同调节骨骼肌葡萄糖的机制，这是葡萄糖处置的限制步骤。在这个项目中，我们专注于急性运动的关键健康益处：胰岛素刺激的葡萄糖转运的大幅增长。我们将测试一个新型模型，该模型提出这种运动效应的机制始于触发事件（必不可少的和瞬态的先决条件），该事件诱导1个或更多的记忆元素（持续的，运动后的结果将触发器与下游介体联系起来）。锻炼后，介体是记忆元素的关键胰岛素信号传导步骤，并在生理胰岛素浓度的互动后导致胰岛素作用改善。介体导致细胞表面局部glut4增加，这是最终导致胰岛素刺激的葡萄糖转运增加的终极效果。我们有4个具体目标：1）确定体液kallikrein-Kinin系统（KKS）的元素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不可少的触发因素。 2）确定AMP激活的蛋白激酶（AMPK）是否是骨骼肌中胰岛素刺激的葡萄糖转运后运动后升高的重要触发因素。 3）阐明胰岛素和运动对与拖船（Tug-Glut4）相关的GLUT4量的影响，并确定推定触发器（Mumoral-KKS和AMPK）与Tug-Glut4的关系。 4）确定从触发器到内存元素到胰岛素信号传导的顺序链接；介导GLUT4募集到细胞表面的步骤，从而导致胰岛素刺激的葡萄糖转运升高。我们将在模型的组件之间进行探测关系，因为只有一种全面的方法才能揭示此复杂过程的综合机制。由于体育活动太普遍了，因此数百万的美国人可以通过运动来提高胰岛素敏感性。阐明运动后改善胰岛素作用的机制，应促进为每个人的能力和开发其他干预措施的最佳运动计划的设计，以改善无法进行足够运动的人的胰岛素动作。