GLP-1R Regulation of Insulin Action

 描述（由申请人提供）：2型糖尿病（T2 DM）患者存在微血管胰岛素抵抗和功能障碍;两者均导致代谢性胰岛素抵抗和心血管并发症。胰高血糖素样肽1（GLP-1）在实验室动物中可能通过蛋白激酶A和一氧化氮依赖性途径有效募集肌肉微血管并增加肌肉递送和胰岛素作用。在拟定的研究中，我们将检验一个总体假设，即GLP-1受体（GLP-1 R）的持续激活可增强肌肉微血管灌注，促进血管生成，并改善肌肉微血管对胰岛素的反应，从而导致糖尿病中肌肉胰岛素递送和作用增加。我们将检查持续的GLP-1 R激活是否会1）在健康人体中增加基础肌肉微血管灌注，并在急性脂质诱导的胰岛素抵抗背景下挽救肌肉微血管和代谢胰岛素反应; 2）在糖尿病前期或T2 DM中观察到的慢性胰岛素抵抗患者中恢复肌肉微血管胰岛素敏感性，改善肌肉毛细血管化，并增强肌肉胰岛素递送和作用;和3）在高脂饮食（HFD）喂养的大鼠中，通过AMPK介导的途径预防微血管胰岛素抵抗，增强跨内皮胰岛素转运并促进肌肉血管生成。我们将使用最先进的技术，对比增强超声，结合前臂动静脉平衡，肌肉活检和胰岛素钳夹，以量化持续GLP-1 R激活对有或无胰岛素抵抗/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/或治疗研究开辟新的途径。我们将进一步在动物实验中探讨其潜在机制。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疾病的发病率和死亡率。

 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.