GLP-1R Regulation of Insulin Action

GLP-1R 胰岛素作用调节

• 批准号: 8977542
• 负责人: ZHENQI LIU
• 金额: $ 56.59万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8977542
• 关键词: Acute; Address; Affect; Angiotensin II Type 1 Receptor Blockers; Animals; Applications Grants; Area; Biopsy; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular Diseases; Cardiovascular system; Chronic; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Diagnostic; Diet; Endothelium; Equilibrium; Fatty acid glycerol esters; Forearm; Functional disorder; Future; Health; Human; Infusion procedures; Insulin; Insulin Resistance; Laboratory Animals; Light; Lipids; Mediating; Metabolic; Microbubbles; Microcirculation; Morbidity - disease rate; Muscle; Muscle Contraction; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Prediabetes syndrome; Rattus; Receptor Activation; Recruitment Activity; Regulation; Reporting; Skeletal Muscle; Surface; Techniques; Testing; Therapeutic Studies; Ultrasonography; Vascular Endothelium; Vasodilation; adiponectin; analog; angiogenesis; base; capillary; contrast enhanced; density; endothelial dysfunction; feeding; glucagon-like peptide; glucagon-like peptide 1; glucose disposal; glucose uptake; improved; insulin secretion; insulin sensitivity; interest; liraglutide; mortality; prevent; public health relevance; receptor; response; targeted treatment; therapy design

 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.

 描述（由申请人提供）：2 型糖尿病 (T2DM) 患者存在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，胰高血糖素样肽 1 (GLP-1) 会有效募集肌肉微血管并增加肌肉输送。胰岛素的作用，可能通过实验动物中的蛋白激酶 A 和一氧化氮依赖性途径进行。在拟议的研究中，我们将测试 GLP-1 受体持续激活的总体假设。 (GLP-1R) 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，从而增加肌肉胰岛素输送和糖尿病作用。我们将研究持续的 GLP-1R 激活是否会 1) 增加健康人的基础值。肌肉微血管灌注并在急性脂质诱导的胰岛素抵抗的情况下挽救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，改善肌肉毛细血管化并增强慢性胰岛素患者的肌肉胰岛素输送和作用；糖尿病前期或 T2DM 中出现的抵抗；3) 在高脂肪饮食 (HFD) 喂养的大鼠中预防微血管胰岛素抵抗，增强跨内皮胰岛素转运并通过 AMPK 介导的途径促进肌肉血管生成。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，量化持续 GLP-1R 激活对人体微血管和胰岛素代谢反应的影响有或没有胰岛素抵抗/糖尿病，并为未来的机制和/或治疗研究开辟新的途径，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。胰岛素抵抗并降低与糖尿病相关的心血管发病率和死亡率。