以胰岛素抵抗（IR）为主要特征的各种代谢性疾病已成为全球性健康威胁。依赖NO的微循环开放是改善骨骼肌IR的关键环节。我们前期研究发现胰高糖素样肽-1受体激动剂（GLP1RA）除促胰岛素分泌外，还可促进IR状态下血管内皮产生NO，提示其在IR时仍可发挥血管舒张作用，结合GLP1RA对高脂喂养的大鼠骨骼肌微循环的灌注改善，由此推测GLP1RA可能通过激活血管内皮GLP1R产生NO，增加微循环灌注，改善或逆转饮食诱导和/或遗传性慢性IR。本研究拟用对照增强超声,胰岛素钳夹,siRNA等技术，观察GLP1RA在体对IR大鼠骨骼肌微血管开放，胰岛素跨膜转运及葡萄糖的摄取，离体对IR内皮cAMP/PKA/eNOS通路的影响，研究创新性从血管扩张和胰岛素的代谢作用耦联的角度揭示GLP1RA增敏胰岛素的新机制，为该药延伸用于广大IR人群提供理论和实验依据。

Insulin resistance and endothelial dysfunction are cardinal features of many metabolic disorders such as type 2 diabetes（T2DM）. Insulin vascular and metabolic actions are tightly coupled. To exert its action in muscle, insulin has to be first delivered to the microvasculature nourishing the muscle, and then be transported through the vascular endothelium into the muscle interstitium. Strong evidence has confirmed that altered muscle microvascular perfusion profoundly affects insulin delivery and action in muscle. As such, incretin-based therapy has emerged as a major treatment option for T2DM. Beyond enhancing insulin secretion, incretins have multiple extra-pancreatic actions. Glucagon-like peptide-1 (GLP-1), a major incretin, causes vasodilation, improves endothelial function, and stimulates muscle glucose uptake independent of insulin.We have recently proved that GLP-1, when given acutely, increases muscle glucose uptake by recruiting muscle microvasculature and increasing insulin delivery to muscle. Whether sustained GLP1R activation, using GLP-1 receptor agonist (GLP1RA), also improves muscle microvascular insulin responsiveness and thus metabolic actions of insulin in chronic insulin resistance status has not been studied. In the proposed study, we will examine the effects of sustained GLP1R activation on muscle microvascular blood volume and glucose uptake using a combined contrast-enhanced ultrasound (CEU) and insulin clamp approach in high fat diet (HFD) rats; and we will also examine the direct stimulatory effect of GLP1RA on NO production and cAMP/PKA/eNOS signaling pathway in cultured palmitate induced insulin resistant endothelial cells. These findings will significantly advance our understanding of the physiology and pathophysiology of GLP-1RA and the regulation of muscle microvasculature in chronic insulin resistance. It will also facilitate the design of future studies to prevent and/or treat insulin resistance related diseases .