Nutrient-dependent action of glucagon and GLP-1 in glucose metabolism and insulin secretion

胰高血糖素和 GLP-1 在葡萄糖代谢和胰岛素分泌中的营养依赖性作用

• 批准号: 10005025
• 负责人: Sarah Marie Gray
• 金额: $ 2.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005025
• 关键词: Address; Agonist; Alpha Cell; Amino Acids; Attenuated; Beta Cell; Biology; Blood Glucose; Cell Communication; Cell physiology; Cells; Clinic; Clinical; Communication; Complex; Conceptions; Data; Diabetes Mellitus; Disease; Dose; Excision; Fasting; Foundations; Gastric Inhibitory Polypeptide; Generations; Glucagon; Glucagon Receptor; Glucose; Goals; Hepatic; High Fat Diet; Hormones; Human; Hyperglycemia; Hypoglycemia; Insulin; Intake; Islet Cell; Islets of Langerhans; Literature; Liver; Measurement; Mediating; Metabolic stress; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional status; Peptides; Pharmaceutical Preparations; Physiological; Physiology; Pre-Clinical Model; Proprotein Convertase 1; Proprotein Convertase 2; Proteins; Regulation; Reporting; Rodent; Role; Specificity; Structure of alpha Cell of islet; Structure of beta Cell of islet; Technology; Testing; Time; Training; Translational Research; Work; blood glucose regulation; clinical investigation; clinically relevant; conditional knockout; counterregulation; design; fasting glucose; gene product; glucagon-like peptide 1; glucose metabolism; glucose output; glucose production; glucose tolerance; glycemic control; healthy volunteer; improved; in vivo; insight; insulin secretion; islet; liquid chromatography mass spectrometry; novel; novel therapeutic intervention; novel therapeutics; paracrine; peptide hormone; pre-clinical; prevent; primary outcome; proglucagon; receptor; response; stem; translational approach

Project Summary/Abstract Glucagon and glucagon-like peptide 1 (GLP-1) are proglucagon gene products that regulate blood glucose levels through insulin-dependent and insulin–independent mechanisms. Canonically, glucagon and GLP-1 are believed to have opposing effects on pancreatic β-cell function, with glucagon from pancreatic α-cells functioning as a counterregulatory hormone to increase blood glucose during fasting and GLP-1 augmenting glucose-stimulated insulin secretion in the fed state to lower blood glucose. Glucagon receptor antagonism, which should decrease hepatic glucose production, has been explored as a means to lower blood glucose during diabetes. However, this has not translated to the clinic. More recently, drugs incorporating glucagon receptor agonism actually improved glycemia—highlighting that glucagon’s physiological role in regulating glycemia is likely more complex. Our preclinical data suggest that glucagon action depends on ambient glycemia, i.e., at fasting glucose concentrations, glucagon acts canonically at the liver to maintain hepatic glucose output, while at elevated (e.g., postprandial) glucose concentrations, glucagon acts in an incretin manner to directly stimulate insulin secretion from pancreatic β-cells. We hypothesize that this is also true in humans. Moreover, there appears to be intra-islet interplay between glucagon, GLP-1, and their respective receptors depending on nutrient intake and metabolic stress. We further hypothesize that α-cell glucagon and GLP-1—not gut-derived GLP-1— regulate nutrient-stimulated insulin secretion. To address these hypotheses, we will test whether glucagon’s ability to increase insulin secretion is dependent on glycemia in humans (aim 1) and the relative contributions of islet GLP-1 and glucagon toward facilitating insulin secretion in preclinical models of normal physiology and metabolic stress (aim 2). This translational approach offers insight into novel paracrine relationships between α- and β-cells, which has the potential to profoundly revolutionize our understanding of islet biology and offer new treatment approaches for diabetes.

项目总结/摘要 胰高血糖素和胰高血糖素样肽1（GLP-1）是胰高血糖素原基因产物，调节血液 通过胰岛素依赖性和胰岛素非依赖性机制调节葡萄糖水平。典型地，胰高血糖素和 GLP-1被认为对胰腺β细胞功能具有相反的作用，胰高血糖素来自胰腺α细胞 作为一种反调节激素，在空腹和GLP-1增强期间增加血糖 在进食状态下葡萄糖刺激的胰岛素分泌以降低血糖。胰高血糖素受体拮抗作用， 其应该减少肝葡萄糖的产生，已经被探索作为降低血糖的手段， 糖尿病然而，这并没有转化为诊所。最近，结合胰高血糖素受体的药物 激动剂实际上改善了糖尿病，突出了胰高血糖素在调节血糖中的生理作用。 可能更复杂。我们的临床前数据表明，胰高血糖素的作用取决于环境温度，即，在 空腹血糖浓度，胰高血糖素在肝脏起典型作用以维持肝葡萄糖输出，而 在升高的（例如，餐后）葡萄糖浓度，胰高血糖素以肠促胰岛素的方式直接刺激 胰腺β细胞分泌胰岛素。我们假设这在人类中也是如此。而且 胰高血糖素、GLP-1及其各自受体之间的胰岛内相互作用取决于营养素 摄入和代谢应激。我们进一步假设α-细胞胰高血糖素和GLP-1-而非肠源性GLP-1-可能与α-细胞胰高血糖素和GLP-1-有关。 调节营养素刺激的胰岛素分泌。为了解决这些假设，我们将测试胰高血糖素是否 增加胰岛素分泌的能力依赖于人类的胰岛素水平（目的1）， 胰岛GLP-1和胰高血糖素促进正常生理学临床前模型中的胰岛素分泌， 代谢应激（目标2）。这种翻译的方法提供了深入了解新的旁分泌之间的关系α- 和β细胞，这有可能深刻地改变我们对胰岛生物学的理解，并提供新的 糖尿病的治疗方法。