The effect of endogenous GLP-1 secretion on islet function in vivo

内源性 GLP-1 分泌对体内胰岛功能的影响

• 批准号: 10439778
• 负责人: Adrian Vella
• 金额: $ 51.06万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439778
• 关键词: Alpha Cell; Arginine; Beta Cell; Blood Circulation; Bolus Infusion; Cell Communication; Cell physiology; Cells; Cellular Stress; Data; Diabetes Mellitus; Dose; Enteroendocrine Cell; Enzymes; Exhibits; Exposure to; Fasting; Functional disorder; GLP-I receptor; Gastric Bypass; Genetic; Genetic Variation; Genotype; Glucagon; Glucose; Glutamine; Human; Hyperglycemia; Impairment; Ingestion; Insulin; Intravenous; Islet Cell; Islets of Langerhans; Mediating; Metabolic; Metabolic stress; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Pancreas; Pathway interactions; Peptide Hydrolases; Persons; Physiological; Physiology; Production; Prohormone Convertase; Role; Series; Signal Transduction; Single Nucleotide Polymorphism; Site; Stimulus; Therapeutic Agents; Variant; antagonist; base; experimental study; exposed human population; fasting glucose; glucagon-like peptide 1; in vivo; inhibitor; insulin secretion; islet; non-diabetic; novel; paracrine; peptide hormone; proglucagon; response; stressor

The overall aim of this application is to better understand the role of endogenous Glucagon-Like Peptide-1(GLP-1) signaling, primarily in the fasting state, to influence α-cell and β-cell function both during the fasting state and in response to subsequent meal challenges. This has been an ignored aspect of GLP-1 physiology, given its primarily post-prandial effects. However, therapeutic agents that harness the GLP-1 pathway lower both fasting and postprandial glucose concentrations. In addition, a non-synonymous Single Nucleotide Polymorphism in the GLP-1 receptor, rs3765467, previously shown by us to enhance response to hyperglycemia and to GLP-1, lowers fasting glucose and protects from type 2 diabetes (T2DM). GLP-1 arises by post-translational processing of proglucagon by a specific prohormone convertase enzyme (PC-1/3). There is evidence that this enzyme can be expressed within the islet enabling local production of GLP-1. This may function in a paracrine fashion to augment glucose-stimulated insulin secretion and glucose mediated suppression of glucagon. Expression of PC-1/3 and GLP-1 is increased in T2DM and also by exposure to hyperglycemia and free fatty acids. An explanation of these observations is that GLP-1 may help islet adaptation to metabolic stressors at least early in the course of T2DM. Intriguingly, our preliminary data shows that the effect of antagonizing fasting endogenous GLP-1 secretion differs between people with and without T2DM. Another aspect of α-cell to β-cell communication is that intra-islet glucagon concentrations can act as stimulus to insulin secretion, signaling partially through the GLP-1 receptor. The importance of this in normal physiology and in T2DM is unknown. The proposed experiments will elucidate how rs3765467 alters islet function in the presence and absence of GLP-1 receptor blockade. In addition, we will examine the role of endogenous GLP-1 secretion in T2DM and compare responses to metabolic stress. The experimental conditions will also enable us to examine the role of GLP-1 signaling in the insulin secretory response to glucagon. Successful completion of these experiments will clarify the role of endogenous GLP-1 in vivo.

本申请的总体目的是更好地了解内源性胰高血糖素样肽-1（GLP-1）信号传导（主要在空腹状态下）在影响空腹状态下α细胞和β细胞功能以及响应后续进餐挑战中的作用。这是GLP-1生理学的一个被忽视的方面，因为它主要是餐后效应。然而，利用GLP-1途径的治疗剂降低空腹和餐后葡萄糖浓度。此外，GLP-1受体中的非同义单核苷酸多态性rs3765467，我们先前已证明可增强对高血糖和GLP-1的反应，降低空腹血糖并预防2型糖尿病（T2 DM）。GLP-1通过特定激素原转化酶（PC-1/3）对胰高血糖素原进行翻译后加工而产生。有证据表明，这种酶可以在胰岛内表达，从而能够局部产生GLP-1。这可能以旁分泌方式起作用，以增加葡萄糖刺激的胰岛素分泌和葡萄糖介导的胰高血糖素抑制。PC-1/3和GLP-1的表达在T2 DM中增加，并且暴露于高血糖和游离脂肪酸也增加。对这些观察结果的解释是，GLP-1可能有助于胰岛适应代谢应激源，至少在T2 DM病程的早期。有趣的是，我们的初步数据显示，拮抗空腹内源性GLP-1分泌的作用在患有和不患有T2 DM的人之间是不同的。α-细胞与β-细胞通讯的另一个方面是胰岛内胰高血糖素浓度可以刺激胰岛素分泌，部分通过GLP-1受体进行信号传导。这在正常生理学和T2 DM中的重要性尚不清楚。拟定实验将阐明rs3765467如何在存在和不存在GLP-1受体阻断剂的情况下改变胰岛功能。此外，我们将研究内源性GLP-1分泌在T2 DM中的作用，并比较对代谢应激的反应。实验条件也将使我们能够检查GLP-1信号传导在对胰高血糖素的胰岛素分泌反应中的作用。这些实验的成功完成将阐明内源性GLP-1在体内的作用。