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.

该应用的总体目的是更好地了解禁食状态下主要的内源性胰高血糖素样肽-1（GLP-1）信号传导的作用，以影响禁食状态下的α细胞和β细胞功能，并响应随后的进餐挑战。鉴于其主要的餐后作用，这是GLP-1生理学的一个忽略方面。但是，利用GLP-1途径的治疗剂降低了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为RS3765467，以前是我们以前显示的，以增强对高血糖和GLP-1的反应，可降低空腹葡萄糖并保护2型糖尿病（T2DM）。 GLP-1是通过特异性激素转化酶（PC-1/3）对Proglucagon的翻译后加工产生的。有证据表明，该酶可以在胰岛中表达，从而使GLP-1的局部产生。这可能会以旁分泌的方式发挥作用，以增强葡萄糖刺激的胰岛素分泌和葡萄糖介导的胰高血糖素的抑制。 T2DM中PC-1/3和GLP-1的表达也会增加，并且通过暴露于高血糖和游离脂肪酸。这些观察结果的解释是，GLP-1至少在T2DM过程中至少有助于对代谢胁迫的胰岛适应。有趣的是，我们的初步数据表明，拮抗空腹内源性GLP-1分泌的作用在患有和没有T2DM的人之间有所不同。 α细胞到β细胞通信的另一个方面是，胰岛内胰高血糖素的浓度可以作为胰岛素分泌的刺激，部分通过GLP-1受体发出信号。这在正常生理和T2DM中的重要性尚不清楚。提出的实验将阐明RS3765467在存在和不存在GLP-1受体阻滞的情况下如何改变胰岛功能。此外，我们将研究内源性GLP-1分泌在T2DM中的作用，并比较对代谢应激的反应。实验条件还将使我们能够检查GLP-1信号传导在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体内的作用。