Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia

项目总结 低血糖是外源性胰岛素治疗1型糖尿病(T1D)的危险并发症 通过外源性的胰升糖素分泌。然而，使用外源性胰高血糖素有其自身的副作用，可以 在紧急情况下很难管理。作为另一种选择，刺激导致强健的内源性 分泌胰高血糖素可能有效对抗严重低血糖。促胰高血糖素分泌可通过 氨基酸，如丙氨酸和精氨酸，以及葡萄糖依赖的促胰岛素肽(GIP)。 值得注意的是，我们发现，虽然丙氨酸或GIP单独导致胰高血糖素分泌略有增加，但 丙氨酸和GIP联合应用协同增加人和小鼠胰高血糖素分泌 胰岛，以及体内的小鼠。更好地了解这种胰高血糖素的生理机制 它的释放需要确定刺激内源性胰高血糖素是否可以治疗T1D的低血糖。我们 假设内源性细胞刺激物，如GIP丙氨酸，可以对抗胰岛素诱导的低血糖。 这个项目的目的是阐明细胞刺激是否可以缓解严重的低血糖，如何 -细胞刺激作用在T1D时发生改变，丙氨酸刺激- 分泌胰升糖素的细胞。该项目的成功完成将增进我们对-CELL和 为低血糖或胰岛素联合治疗的基础提供洞察力。此外，AIMS将 拓宽应聘者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.