GLP-1R Regulation of Insulin Action

 描述(申请人提供)：2型糖尿病(T2 DM)患者有微血管胰岛素抵抗和功能障碍；两者都会导致代谢性胰岛素抵抗和心血管并发症。在实验动物中，胰高血糖素样肽1(GLP-1)可能通过蛋白激酶A和一氧化氮依赖的途径，有效地招募肌肉微血管，增加肌肉输送和胰岛素的作用。在拟议的研究中，我们将检验一个重要的假设，即GLP-1受体(GLP-1R)的持续激活增强了肌肉微血管灌流，促进了血管生成，并改善了肌肉微血管对胰岛素的反应，从而导致糖尿病患者肌肉胰岛素供应和作用的增加。我们将研究持续的GLP-1R激活是否将1)增加健康人的基础肌肉微血管灌注量，挽救急性脂溢性胰岛素抵抗时的肌肉微血管和代谢胰岛素反应；2)恢复肌肉微血管胰岛素敏感性，改善肌肉毛细血管形成，增加肌肉胰岛素的供应和作用，如糖尿病前期或T2 DM患者；以及3)防止微血管胰岛素抵抗，加强胰岛素的跨内皮转运，促进肌肉血管生成，通过AMPK介导的途径，在高脂饮食(HFD)的大鼠。我们将使用最先进的超声造影技术，结合前臂动静脉平衡、肌肉活检和胰岛素钳夹技术，量化持续激活GLP-1R对患有或不患有胰岛素抵抗/糖尿病的人的微血管和胰岛素代谢反应的影响，并为未来的机制和/或治疗研究开辟一条新的途径。我们将在动物研究中进一步探索潜在的机制。通过了解肌肉微循环的调节，有可能纠正血管和改善代谢性胰岛素抵抗，降低与糖尿病相关的心血管发病率和死亡率。

 DESCRIPTION (provided by applicant): Patients with Type 2 diabetes (T2DM) have microvascular insulin resistance and dysfunction; both contribute to metabolic insulin resistance and cardiovascular complications. Glucagon-like peptide 1 (GLP-1) potently recruits muscle microvasculature and increases muscle delivery and action of insulin, likely via a protein kinase A and nitric oxide dependent pathway in laboratory animals. In the proposed studies, we will test an overarching hypothesis that sustained activation of the GLP-1 receptor (GLP-1R) enhances muscle microvascular perfusion, promotes angiogenesis, and improves the muscle microvascular response to insulin which leads to increased muscle insulin delivery and action in diabetes. We will examine whether sustained GLP- 1R activation will 1) in healthy humans increase basal muscle microvascular perfusion and rescues muscle microvascular and metabolic insulin responses in the setting of acute lipid-induced insulin resistance; 2) restore muscle microvascular insulin sensitivity, improve muscle capillarization and enhance muscle insulin delivery and action in patients with chronic insulin resistance as seen in pre-diabetes or T2DM; and 3) prevent microvascular insulin resistance, enhance trans-endothelial insulin transport and promotes muscle angiogenesis via an AMPK-mediated pathway in high fat diet (HFD) fed rats. We will use a state-of-the-art technique, contrast-enhanced ultrasound, in combination with forearm arteriovenous balance, muscle biopsy and insulin clamp to quantify the effects of sustained GLP-1R activation on microvascular and metabolic responses to insulin in humans with or without insulin resistance/diabetes and open a new avenue for future mechanistic and/or therapeutic studies. We will further in animal studies explore the underlying mechanisms. By understanding the regulation of muscle microcirculation, it may be possible to correct vascular and ameliorate metabolic insulin resistance and decrease the cardiovascular morbidity and mortality associated with diabetes.