Molecular Mechanisms of Postnatal Islet alpha-cell Proliferation

出生后胰岛α细胞增殖的分子机制

• 批准号: 10339386
• 负责人: WENBIAO CHEN
• 金额: $ 55.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339386
• 关键词: Abbreviations; Agreement; Alpha Cell; Amino Acid Receptors; Amino Acid Transporter; Amino Acids; Animal Model; Arginine; Biology; Blood; Calcium-Sensing Receptors; Catabolism; Cations; Cell Count; Cell Proliferation; Cell membrane; Cell physiology; Cells; Cellular biology; Complement; Complex; Diabetes Mellitus; Endocrine; Enzymes; FRAP1 gene; Feedback; Fishes; Functional disorder; Genes; Glucagon; Glucagon Receptor; Glutaminase; Glutamine; Hepatic; Hepatic Mass; Homeostasis; Human; Hyperargininemia; Hyperglycemia; Hyperplasia; Impairment; Insulin-Dependent Diabetes Mellitus; Interruption; Knock-out; Liver; Mammalian Cell; Metabolism; Molecular; Mouse Protein; Mus; Neutral Amino Acid Transport Systems; Non-Insulin-Dependent Diabetes Mellitus; Orthologous Gene; Pancreas; Pathway interactions; Pharmacology; Physiological; Play; Publishing; Regulation; Reporting; Role; Serum; Signal Transduction; Testing; Therapeutic Intervention; Translations; Transplantation; Zebrafish; Zebrafish Proteins; antagonist; blood glucose regulation; cell type; clinical application; human model; hyperglucagonemia; in vitro Assay; in vivo; insight; interdisciplinary approach; interest; islet; knock-down; man; mouse model; postnatal; pre-clinical; receptor; sensor; synergism; transcriptome sequencing; uptake

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.

高胰高血糖素血症导致2型糖尿病（T2 D）的高血糖症。因此，胰高血糖素作用的拮抗作用作为T2 D的治疗干预具有很大的前景。然而，通过多种途径中断胰高血糖素信号传导（IGS）导致α-细胞增殖和增生。使用多学科方法，我们最近发现，由于肝脏中氨基酸催化剂的减少，血液氨基酸（高氨基酸血症或AAHi），特别是谷氨酰胺和精氨酸的积累会驱动α细胞增殖。这些研究还揭示了一种先前未被认识和保守的（鱼类到人类）肝-α细胞轴，其中肝胰高血糖素信号传导调节血清氨基酸水平，AA（尤其是谷氨酰胺（Q））增加调节胰高血糖素分泌和α细胞增殖和质量。AAHi是以mTORC 1依赖性方式引起α细胞增殖所必需且充分的。然而，单独的mTORC 1激活是不够的。我们假设，高氨基酸血症激活哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）和钙敏感受体（CaSR），导致α细胞特异性增殖，这是由于其高表达一组独特的AA转运蛋白和催化酶。在这个多PI提案的合作努力中，我们的团队将寻求一种实验策略，该策略利用斑马鱼和小鼠模型的优势，快速识别途径并定义机制，同时并行测试我们的发现在初级人类胰岛中的应用和翻译。此外，我们将利用一种新的胰岛α细胞增殖体外试验来补充鱼、小鼠和移植的人胰岛的体内研究。我们将在鱼、小鼠和人胰岛中检验以下假设：1）α细胞中特异性质膜AA转运蛋白的高表达通过允许有效的AA摄取来驱动mTORC 1活化; 2）高氨基酸血症通过精氨酸分解激活mTORC 1需要精氨酸酶; 3）高氨基酸血症也激活CaSR，CaSR与mTORC 1协同作用诱导α细胞增殖。此外，由于高氨基酸血症刺激α-细胞增殖和胰高血糖素分泌，这些研究也应该提供关于氨基酸如何调节胰高血糖素分泌的新信息。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，并深入了解如何减轻T2 D中的α细胞功能障碍。