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，主要是在禁食状态下，在禁食状态期间以及响应随后的进餐挑战时影响 α 细胞和 β 细胞功能。鉴于 GLP-1 主要在餐后产生影响，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。此外，GLP-1 受体 rs3765467 中的非同义单核苷酸多态性（rs3765467）先前被我们证明可以增强对高血糖和 GLP-1 的反应，降低空腹血糖并预防 2 型糖尿病 (T2DM)。 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抑制。 PC-1/3 和 GLP-1 的表达在 T2DM 中增加，并且暴露于高血糖和游离脂肪酸也会增加。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。有趣的是，我们的初步数据表明，拮抗空腹内源性 GLP-1 分泌的效果在患有和未患有 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 信号在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。