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

项目总结/摘要 代谢综合征患者表现出代谢性胰岛素抵抗， 心血管事件的风险，并容易发展为2型糖尿病。 大量的证据已经证明了高水平的身体活动的价值， 运动训练和整体心肺健康， 心血管疾病胰高血糖素样肽1（GLP-1）受体激动剂已被广泛应用于临床。 显示出减少患有前驱糖尿病的成年人的糖尿病新发， 2型糖尿病患者主要心血管不良事件发生率。的 运动和GLP-1受体的心血管益处的基础机制 激动作用仍然难以捉摸。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， 两者的结合会更有效。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 和冠状动脉微血管系统的作用 内皮细胞AMPK和线粒体分裂在微血管胰岛素发病机制中的作用 阻力我们将使用最先进的技术超声造影 结合动静脉平衡、肌肉活检和胰岛素钳夹定量 运动训练和GLP-1受体激动剂对微血管和 胰岛素抵抗/代谢综合征患者对胰岛素的代谢反应 并为未来的机制和/或治疗研究开辟了新的途径。我们将 进一步使用各种啮齿动物模型来探索潜在的机制。通过 了解骨骼肌和心肌微血管功能的调节， 在代谢综合征患者的胰岛素反应中， 改善代谢性胰岛素抵抗，预防糖尿病， 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.