Skeletal Muscle Glucose Transport: Exercise and Insulin

骨骼肌葡萄糖转运：运动和胰岛素

• 批准号: 7254719
• 负责人: Gregory D. Cartee
• 金额: $ 29.75万
• 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/7254719
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Acute; Adipocytes; American; Binding; Binding Proteins; Bradykinin; Cell surface; Cells; Complex; Defect; Development, Other; Dose; Elements; Elevation; Event; Exercise; Figs - dietary; GLUT4 gene; Health Benefit; IRS2 gene; In Vitro; Insulin; Insulin Resistance; Intervention; Kallikrein-Kinin System; Kininogens; Lead; Link; Localized; Mediating; Mediator of activation protein; Memory; Modeling; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Persons; Phosphorylation; Physical activity; Physiological; Plasma Kallikrein; Process; Rate; Recovery; Research Personnel; Rest; Serum; Signal Transduction; Site; Skeletal Muscle; Testing; design; glucose disposal; glucose transport; human IRS2 protein; improved; insulin sensitivity; insulin signaling; novel; programs; tetrahydrobiopterin

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.

描述（由申请人提供）：骨骼肌处理葡萄糖的胰岛素抵抗是 2 型糖尿病的一个基本缺陷，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交叉共同调节骨骼肌葡萄糖转运的机制，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转运的大幅且持久的增加。我们将测试一种新颖的模型，该模型提出这种运动效果的机制始于诱发一个或多个记忆元素（将触发器与下游调节因素联系起来的持久的运动后结果）的触发事件（基本和短暂的先决条件）。运动后，介质是关键的胰岛素信号传导步骤，由于记忆元件的作用，并且在生理胰岛素浓度的参与下，导致胰岛素作用的改善。介体导致细胞表面局部 GLUT4 增加，这是最终负责增加胰岛素刺激的葡萄糖转运的末端效应器。我们有 4 个具体目标：1) 确定体液激肽释放酶-激肽系统 (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重要触发因素。 2) 确定 AMP 激活蛋白激酶 (AMPK) 是否是运动后骨骼肌中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 量 (TUG-GLUT4) 的影响，并确定假定的触发因素（体液-KKS 和 AMPK）与 TUG-GLUT4 的关系。 4) 识别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 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。我们将探讨模型组件之间的关系，因为只有综合方法才能揭示这个复杂过程的集成机制。由于体力活动非常普遍，数百万美国人可以通过锻炼提高胰岛素敏感性。阐明运动后改善胰岛素作用的机制应有助于针对每个人的能力设计最佳运动计划，并制定其他干预措施，以改善无法进行充分运动的人的胰岛素作用。