Molecular Mechanisms of Postnatal Islet alpha-cell Proliferation

高血糖导致2型糖尿病(T2D)的高血糖。因此，胰高血糖素的拮抗作用作为T2D的一种治疗干预具有很大的前景。然而，通过多种途径阻断胰高血糖素信号会导致α-细胞的增殖和增殖。利用多学科的方法，我们最近发现，由于肝脏氨基酸分解代谢降低，血液中氨基酸(高氨基酸血症或AAHi)，特别是谷氨酰胺和精氨酸的积累，推动了α细胞的增殖。这些研究还揭示了一个先前未被认识和保守的(鱼到人)肝-α细胞轴，其中肝高血糖素信号调节血清氨基酸水平，并增加AA，特别是谷氨酰胺(Q)，调节高血糖素分泌和α-细胞的增殖和质量。AAHi是导致α细胞以mTORC1依赖的方式增殖的必要条件和充分条件。然而，仅激活mTORC1是不够的。我们推测，高氨基酸血症通过高表达一组独特的AA转运蛋白和催化酶，激活哺乳动物雷帕霉素复合体1靶点(MTORC1)和钙敏感受体(CaSR)，导致α细胞特异性增殖。在这项多PI提案的协作努力中，我们的团队将采用一种实验策略，利用斑马鱼和老鼠模型的优势快速确定途径和定义机制，同时并行测试我们的发现在人类原生胰岛中的应用和转换。此外，我们将利用一种新的胰岛α细胞体外增殖试验来补充在鱼、小鼠和移植的人胰岛上的体内研究。我们将在鱼类、小鼠和人类胰岛中验证以下假设：1)特定质膜AA转运体在α细胞中的高表达通过允许有效的AA摄取来驱动mTORC1a的激活；2)谷氨酰胺酶是高氨基酸血症通过谷氨酰胺分解激活mTORc1所必需的；以及3)高氨基酸血症还激活CaSR，后者与mTORc1协同作用诱导α-细胞增殖。此外，由于高氨基酸血症同时刺激α细胞的增殖和胰升糖素的分泌，这些研究也应该提供有关氨基酸如何调节胰升糖素分泌的新信息。这些研究将扩大我们对控制α细胞生物学、功能、增殖和质量的分子机制的理解，并为如何缓解T2D的α细胞功能障碍提供洞察力。

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 (IGS) by multiple approaches leads to α-cell proliferation and hyperplasia. Using a multidisciplinary approach, we recently discovered that the accumulation of blood amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, due to decreased amino acid catabolism in the liver drives α-cell proliferation. These studies also revealed a previously unappreciated and conserved (fish to man) hepatic-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 α-cell proliferation in an mTORC1-dependent manner. However, mTORC1 activation alone is insufficient. We hypothesize that hyperaminoacidemia activates both mammalian target of rapamycin complex 1 (mTORC1) and Calcium Sensing Receptor (CaSR) to cause α-cell specific proliferation due to its high expression of a unique set of AA transporters and catalytic enzymes. In collaborative efforts in this multi-PI proposal, our groups will pursue an experimental strategy that leverages the advantages of zebrafish and mouse models for rapidly identifying pathways and defining mechanisms while in parallel testing the application and translation of our findings into primary human islets. Plus, we will utilize a new in vitro assay for islet α-cell proliferation to complement in vivo studies in fish, mouse, and transplanted human islets. We will test the hypotheses in fish, mouse, and human islets that 1) high expression of specific plasma membrane AA transporters in α cells drives mTORC1 activation by allowing efficient AA uptake; 2) glutaminase is required for hyperaminoacidemia activation of mTORC1 through glutaminolysis; and 3) hyperaminoacidemia also activates CaSR, which synergizes with mTORC1 to induce α-cell proliferation. Furthermore, since hyperaminoacidemia stimulates both α-cell proliferation and glucagon secretion, these studies should also provide new information about how amino acids regulate glucagon secretion. These studies will expand our understanding of the molecular mechanisms controlling α-cell biology, function, proliferation and mass and provide insight into how the α-cell dysfunction in T2D could be mitigated.