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

项目摘要/摘要 代谢综合征患者表现出代谢性胰岛素抵抗， 有发生心血管事件的风险，并容易发展为2型糖尿病。 大量证据已经证实了高水平体力活动的价值， 运动训练和整体心肺功能在预防高血压中的作用 心血管疾病。高血糖素样多肽1(GLP-1)受体激动剂已被 显示可减少患有糖尿病前期的成人患者的新发糖尿病 2型糖尿病患者的主要心血管不良事件发生率。这个 运动和GLP-1受体对心血管益处的机制 激励性仍然难以捉摸。在拟议的研究中，我们将检验一个重要的假设 运动和GLP-1受体激动剂均增强胰岛素介导 微血管灌流和肌肉血管生成，导致肌肉输送增加 胰岛素在胰岛素抵抗状态下的作用。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来 检测运动和GLP-1受体激动剂对双侧骨骼肌的影响 代谢综合征患者的冠脉微血管构筑及其作用 内皮AMPK和线粒体分裂在微血管胰岛素发病机制中的作用 抵抗。我们将使用最先进的技术，对比增强超声，在 动静脉平衡、肌肉活检、胰岛素钳夹联合定量 运动训练和GLP-1受体激动剂对微血管和血管的影响 胰岛素抵抗/代谢综合征患者对胰岛素的代谢反应 并为未来的机械学和/或治疗研究开辟了一条新的途径。我们会 进一步利用多种啮齿动物模型探索其潜在的机制。通过 了解骨骼肌和心肌微血管功能的调节和 代谢综合征患者的胰岛素反应，有可能纠正 血管和改善代谢性胰岛素抵抗预防和降低糖尿病 相关的心血管风险。

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.