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: 10197125
• 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/10197125
• 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; Physiological; Physiology; Production; Prohormone Convertase; Role; Series; Signal Transduction; Single Nucleotide Polymorphism; Site; Stimulus; Therapeutic Agents; Variant; base; experimental study; exposed human population; fasting glucose; glucagon-like peptide 1; in vivo; inhibitor/antagonist; 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.

本申请的总体目标是更好地了解内源性胰高血糖素样肽-1 (GLP-1) 信号传导的作用（主要在禁食状态下），以影响禁食状态下和正常情况下的 α 细胞和 β 细胞功能。鉴于 GLP-1 主要在餐后发挥作用，这一直是 GLP-1 生理学中被忽视的一个方面。然而，利用 GLP-1 途径的治疗药物可降低空腹和餐后血糖浓度。 GLP-1 受体 rs3765467 中的非同义单核苷酸多态性，我们之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由 GLP-1 引起的 2 型糖尿病 (T2DM)。由特定的激素原转化酶 (PC-1/3) 进行的胰高血糖素原翻译加工 有证据表明该酶可以在体内表达。胰岛能够局部产生 GLP-1，这可能以旁分泌方式发挥作用，增强葡萄糖刺激的胰岛素分泌，并且葡萄糖介导的胰高血糖素抑制在 T2DM 中以及暴露于暴露于高血糖素的情况下也会增加。高血糖和游离脂肪酸对这些观察结果的解释是，GLP-1 至少在 T2DM 病程的早期可能有助于胰岛适应代谢应激源。拮抗空腹内源性 GLP-1 分泌在患有和未患有 T2DM 的人之间存在差异，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 受体发出信号。这在正常生理学和 T2DM 中的重要性尚不清楚。拟议的实验将阐明 rs3765467 在存在和不存在 GLP-1 受体阻断的情况下如何改变胰岛功能。此外，我们将检查内源性 GLP-1 分泌在 T2DM 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 信号传导在胰高血糖素的胰岛素分泌反应中的作用。这些实验将阐明内源性 GLP-1 在体内的作用。