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

项目摘要/摘要 胰高血糖素和胰升糖素样肽1(GLP-1)是具有调节血液功能的胰高血糖素原基因产物 血糖水平通过胰岛素依赖和胰岛素非依赖机制。通常情况下，高血糖素和 GLP-1被认为对胰腺β细胞的功能具有相反的作用，而来自胰腺α细胞的胰高血糖素 作为一种反调节激素，在空腹和GLP-1增加期间升高血糖 葡萄糖刺激进食状态下的胰岛素分泌，以降低血糖。胰升糖素受体拮抗剂， 它应该减少肝脏葡萄糖的产生，已经被探索作为一种降低血糖的方法 糖尿病。然而，这并没有转化为临床。最近，含有胰高血糖素受体的药物 激动剂实际上改善了血糖--强调了胰高血糖素在调节血糖方面的生理作用 可能会更复杂。我们的临床前数据表明，胰升糖素的作用依赖于环境血糖，即 空腹血糖浓度，胰高血糖素在肝脏正常作用，以维持肝脏葡萄糖输出，而 当血糖浓度升高时(例如，餐后)，胰高血糖素以一种内分泌的方式直接刺激 胰腺β细胞的胰岛素分泌。我们假设，这在人类身上也是如此。此外，还有 似乎是胰岛内高血糖素、GLP-1和它们各自的受体之间的相互作用，取决于营养 摄入和代谢压力。我们进一步假设α细胞的胰高血糖素和GLP-1不是肠源性的GLP-1- 调节营养刺激的胰岛素分泌。为了解决这些假设，我们将测试胰高血糖素 增加胰岛素分泌的能力取决于人类的血糖水平(目标1)和 胰岛GLP-1和胰升糖素促进正常生理和临床前模型胰岛素分泌的研究 代谢应激(目标2)。这种翻译方法提供了对α-之间新的旁分泌关系的洞察- 和β细胞，它有可能深刻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。

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.