Glucagon and insulin act cooperatively in the regulation of prandial hepatic glycogen metabolism

项目摘要 胰高血糖素和胰岛素是胰腺激素，控制血糖对禁食和进食的反应。 典型地，胰高血糖素在禁食状态下分泌，其中它刺激肝糖原分解， 为了提高产量，相反，胰岛素的分泌是对血糖升高的反应 以刺激外周组织中的葡萄糖摄取。胰高血糖素和胰岛素的这些典型的、相反的作用， 肝脏忽视了长期以来的理解，即混合营养物喂养中的氨基酸刺激胰岛A细胞， 分泌胰高血糖素。此外，我们最近的工作表明胰高血糖素刺激胰岛素分泌的重要性 维持葡萄糖耐量因此，对生理混合营养餐的预期反应是 胰高血糖素和胰岛素共同分泌到门静脉循环中。本文提供的初步数据支持 胰高血糖素和胰岛素协同而非拮抗地控制餐时葡萄糖代谢的观点。 我们假设胰高血糖素和胰岛素共同分泌控制肝脏葡萄糖代谢，使葡萄糖 在储存在肝脏之前到达外周。这个项目的成功完成将改变我们的 对肝葡萄糖代谢的基本了解和我对新的治疗靶点的了解 用于治疗代谢性疾病。重要的是，完成拟议目标将支持几个新的 技术和概念的发展，这将为作为一个独立的调查员的职业生涯奠定基础。

Project Summary Glucagon and insulin are pancreatic hormones that control the glycemic response to fasting and feeding. Canonically, glucagon is secreted in the fasted state where it stimulates hepatic glycogenolysis and gluconeogenesis in order to raise glycemia. Conversely, insulin is secreted in response to elevated blood glucose to stimulate glucose uptake in peripheral tissues. These canonical, opposing effects of glucagon and insulin on the liver overlook the long understanding that amino acids in mixed nutrient feeding stimulate the islet a-cell to secrete glucagon. Moreover, our recent work has shown the importance of glucagon-stimulated insulin secretion to maintaining glucose tolerance. Therefore, the expected response to a physiologic mixed nutrient meal is the co-secretion of glucagon and insulin into portal circulation. The preliminary data presented herein support the notion that glucagon and insulin work cooperatively, not antagonistically, to control prandial glucose metabolism. We hypothesize that glucagon and insulin co-secretion controls hepatic glucose metabolism to allow glucose to reach the periphery before being stored in the liver. Successful completion of this project will alter our fundamental understanding of hepatic glucose metabolism and my provide insight for novel therapeutic targets for the treatment of metabolic disease. Importantly, completion of the proposed aims will support several new technical and conceptual developments that will provide a foundation for a career as an independent investigator.