Amino acid regulation of pancreatic islet alpha cell proliferation and function

项目摘要 高胰高血糖素血症导致2型糖尿病（T2 D）的高血糖症。因此， 胰高血糖素作用作为T2 D的治疗干预具有很大的前景。然而，中断胰高血糖素 多种途径的信号传导导致α-细胞增殖和增生。采用多学科 我们最近发现，当胰高血糖素信号在肝脏中被中断时，血液中的积聚 氨基酸（高氨基酸血症或AAHi），特别是谷氨酰胺和精氨酸，驱动α细胞增殖。这些 研究还揭示了一种以前未被认识和保守的（从鱼到人）肝胰岛α细胞轴， 肝胰高血糖素信号传导调节血清氨基酸水平和增加的AA，特别是谷氨酰胺（Q）， 调节胰高血糖素分泌以及α细胞增殖和质量。AAHi是引起细胞凋亡的必要和充分条件 以mTORC 1依赖的方式增殖。我们假设AAHi在α- 细胞，因为一组独特的AA转运蛋白和催化酶的高表达，导致 mTORC 1激活、胰高血糖素分泌和α细胞增殖。我将采取一种实验性的策略， 利用小鼠模型的优势，同时并行识别途径和定义机制， 将我的发现转化为初级人类胰岛。另外，我将利用一种新的体外胰岛α- 细胞增殖，以补充移植人胰岛的小鼠体内研究。这些研究将 扩大我们对控制α细胞生物学，功能，增殖和 质量，并提供了对胰岛细胞质量的受控和安全扩增途径的深入了解。这些研究 还应该为正常α细胞功能以及T2 D中的α细胞功能障碍如何提供新的见解。 减轻。

Project Summary Hyperglucagonemia contributes to the hyperglycemia of type 2 diabetes (T2D). As such, antagonism of glucagon action has great promise as a therapeutic intervention for T2D. However, interrupted glucagon signaling by multiple approaches leads to α-cell proliferation and hyperplasia. Using a multidisciplinary approach we recently discovered when glucagon signaling is interrupted in the liver, the accumulation of blood amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, drive α-cell proliferation. These studies also revealed a previously unappreciated and conserved (fish to man) hepatic-islet α-cell axis where hepatic glucagon signaling regulates serum amino acid levels and increased AA, especially glutamine (Q), regulate glucagon secretion and α-cell proliferation and mass. AAHi is necessary and sufficient to cause -cell proliferation in an mTORC1-dependent manner. We hypothesize that AAHi exerts the effect specifically in α- cells because of the high expression of a unique set of AA transporters and catalytic enzymes, leading to mTORC1 activation, glucagon secretion and α-cell proliferation. I will pursue an experimental strategy that leverages the advantages of mouse models for identifying pathways and defining mechanisms while in parallel testing the translation my findings into primary human islets. Plus, I will utilize a new in vitro assay for islet α- cell proliferation to complement in vivo studies in mouse with transplanted human islets. These studies will expand our understanding of the molecular mechanisms controlling α-cell biology, function, proliferation, and mass and provide insight into pathways for controlled and safe expansion of islet cell mass. These studies should also provide new insights into normal α-cell function and how the α-cell dysfunction in T2D could be mitigated.