Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia

项目摘要 低血糖是1型糖尿病（T1D）外源性胰岛素治疗的危险并发症， 通过外源性胰高血糖素分泌。然而，使用外源性胰高血糖素有其自身的副作用， 在紧急情况下很难管理。作为替代方案，刺激，导致强大的内源性 胰高血糖素分泌可以有效对抗严重的低血糖症。胰高血糖素分泌可以通过以下刺激： 氨基酸，如丙氨酸和精氨酸，以及葡萄糖依赖性促胰岛素肽（GIP）。 值得注意的是，我们发现，虽然丙氨酸或GIP单独诱导胰高血糖素分泌的适度增加， 丙氨酸和GIP的组合协同增加分离的小鼠和人中的胰高血糖素分泌 胰岛以及小鼠体内。更好地了解这种胰高血糖素的生理学和 需要其释放来确定刺激内源性胰高血糖素是否可以治疗T1D中的低血糖症。我们 假设内源性β细胞刺激物，如GIP +丙氨酸，可以对抗胰岛素诱导的低血糖。 本项目的目的是阐明β细胞刺激是否可以减轻严重的低血糖， T1D患者的β细胞刺激效应发生了变化，丙氨酸刺激β细胞的机制是什么？ 细胞分泌胰高血糖素。本项目的成功完成将加深我们对电池的理解， 为低血糖症或胰岛素联合治疗的治疗学基础提供见解。此外，目标将 拓宽候选人的技术专长，并发展对细胞生理学的概念性理解， 为独立调查员的职业生涯奠定基础。

PROJECT SUMMARY Hypoglycemia is a dangerous complication of exogenous insulin therapy in Type 1 Diabetes (T1D) that is treated by exogenous glucagon secretion. However, the use of exogenous glucagon has its own side effects and can be complicated to administer in an emergency situation. As an alternative, stimuli that lead to robust endogenous glucagon secretion could be effective to counter severe hypoglycemia. Glucagon secretion can be stimulated by amino acids, like alanine and arginine, as well as by glucose-dependent insulinotropic peptide (GIP). Remarkably, we found that while alanine or GIP alone induce modest increases in glucagon secretion, the combination of alanine and GIP synergistically increase glucagon secretion in both isolated mouse and human islets, as well as mice in vivo. A better understanding of the physiology of this glucagon and the mechanism of its release is needed to determine if stimulating endogenous glucagon can treat hypoglycemia in T1D. We hypothesize that endogenous -cell stimuli, such as GIP + alanine, can counter insulin-induced hypoglycemia. The aims of this project are designed to elucidate whether -cell stimuli can mitigate severe hypoglycemia, how the effects of -cell stimulation are changed in T1D, and what is the mechanism that alanine stimulates the - cell to secrete glucagon. Successful completion of this project will enhance our understanding of the -cell and provide insight for the basis of therapeutics for hypoglycemia or insulin co-therapies. In addition, the aims will broaden the Candidate’s technical expertise and develop conceptual understanding of -cell physiology that will provide a foundation for a career as an independent investigator.