Effects of Exercise and GLP-1R Agonism on Muscle Microvascular Perfusion and Insulin Action

运动和 GLP-1R 激动对肌肉微血管灌注和胰岛素作用的影响

• 批准号: 10396551
• 负责人: ZHENQI LIU
• 金额: $ 65.68万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396551
• 关键词: Acute; Address; Adult; Affect; Agonist; Applications Grants; Area; Attenuated; Biopsy; Blood Vessels; Blood Volume; Blood capillaries; Body Weight; Cardiac; Cardiovascular system; Closure by clamp; Coronary; Data; Death Rate; Diabetes Mellitus; Diabetes prevention; Diagnostic; Endothelium; Equilibrium; Event; Exercise; Exhibits; Future; GLP-I receptor; High Fat Diet; Human; Impairment; Insulin; Insulin Resistance; Intervention; Life Style Modification; Light; Mediating; Metabolic; Metabolic syndrome; Microcirculation; Mitochondria; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Myocardial Infarction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Patients; Perfusion; Physical activity; Prediabetes syndrome; Prevention; Receptor Activation; Regulation; Reporting; Resistance; Rodent Model; Role; Skeletal Muscle; Stroke; Surface; Techniques; Testing; Therapeutic Studies; angiogenesis; arteriole; cardiorespiratory fitness; cardiovascular disorder prevention; cardiovascular effects; cardiovascular risk factor; contrast enhanced; density; exercise training; glucagon-like peptide 1; improved; insulin sensitizing drugs; liraglutide; mortality; patient population; preservation; prevent; recruit; response; skeletal; translational approach; ultrasound

Project Summary/Abstract Patients with metabolic syndrome exhibit metabolic insulin resistance, have increased risks of cardiovascular events and are prone to developing type 2 diabetes mellitus. Substantial evidence has established the value of high levels of physical activity, exercise training, and overall cardiorespiratory fitness in the prevention of cardiovascular diseases. Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to reduce the new onset of diabetes in adult humans with prediabetes and the rate of major adverse cardiovascular events among patients with type 2 diabetes. The mechanisms underpinning the cardiovascular benefits of exercise and GLP-1 receptor agonism remain elusive. In the proposed studies, we will test an overarching hypothesis that exercise and GLP-1 receptor agonism each enhance insulin-mediated microvascular perfusion and muscle angiogenesis, leading to increased muscle delivery and action of insulin in the insulin resistant state. We further hypothesize that the combination of both would be more effective. We will use a translational approach to examine the effects of exercise and GLP-1 receptor agonism on both skeletal muscle and coronary microvasculature in humans with metabolic syndrome and the role of endothelial AMPK and mitochondrial fission in the pathogenesis of microvascular insulin resistance. We will use a state-of-the-art technique, contrast-enhanced ultrasound, in combination with arteriovenous balance, muscle biopsy and insulin clamp to quantify the effects of exercise training and GLP-1 receptor agonism on microvascular and metabolic responses to insulin in humans with insulin resistance/metabolic syndrome and open a new avenue for future mechanistic and/or therapeutic studies. We will further use a variety of rodent models to explore the underlying mechanisms. By understanding the regulation of skeletal and cardiac muscle microvascular function and insulin responses in humans with metabolic syndrome, it may be possible to correct vascular and ameliorate metabolic insulin resistance to prevent diabetes and decrease the associated cardiovascular risks.

项目概要/摘要 代谢综合征患者表现出代谢性胰岛素抵抗，体重增加 心血管事件的风险，并且容易患上 2 型糖尿病。 大量证据证实了高水平体力活动的价值， 运动训练和整体心肺健康，以预防 心血管疾病。胰高血糖素样肽 1 (GLP-1) 受体激动剂 已被证明可以减少患有前驱糖尿病的成年人中新发糖尿病的发生 2 型糖尿病患者主要不良心血管事件的发生率。这 运动和 GLP-1 受体对心血管有益的机制 激动仍然难以捉摸。在拟议的研究中，我们将测试一个总体假设 运动和 GLP-1 受体激动各自增强胰岛素介导的 微血管灌注和肌肉血管生成，导致肌肉输送增加 以及胰岛素抵抗状态下胰岛素的作用。我们进一步假设 两者结合起来会更有效。我们将使用翻译方法 检查运动和 GLP-1 受体激动剂对骨骼肌的影响 和冠状微血管在代谢综合征患者中的作用 内皮 AMPK 和线粒体分裂在微血管胰岛素发病机制中的作用 反抗。我们将使用最先进的技术，即对比增强超声， 结合动静脉平衡、肌肉活检和胰岛素钳进行量化 运动训练和 GLP-1 受体激动对微血管和 患有胰岛素抵抗/代谢综合征的人对胰岛素的代谢反应 并为未来的机制和/或治疗研究开辟新途径。我们将 进一步使用多种啮齿动物模型来探索潜在机制。经过 了解骨骼和心肌微血管功能的调节以及 患有代谢综合征的人的胰岛素反应，可能可以纠正 血管和改善代谢性胰岛素抵抗，以预防糖尿病和减少 相关的心血管风险。