Amino acid sensing mechanisms in beta and alpha cells

β 和 α 细胞中的氨基酸传感机制

• 批准号: 10655636
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 38.32万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655636
• 关键词: Acute; Alpha Cell; Amino Acids; Arginine; Aromatic Amino Acids; B-Lymphocytes; Beta Cell; Branched-Chain Amino Acids; Cell physiology; Cells; Characteristics; Chronic; Circulation; Complex; Coupling; Cytoplasm; Data; Defect; Development; Diabetes Mellitus; Disease; Exhibits; Fasting; Functional disorder; Glucagon; Glucagon Receptor; Glucose; Glucose Intolerance; Goals; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Insulin; Insulin Resistance; Learning; Leucine; Link; Mediating; Metabolic; Molecular; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Pathogenesis; Pathologic; Pathway interactions; Physiological; Physiology; Play; Publishing; Reporting; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Structure of beta Cell of islet; Testing; Tissues; Work; antagonist; blood glucose regulation; cohort; detection of nutrient; diabetes pathogenesis; diabetes risk; diabetic; dietary; drug development; genetic approach; human data; in vivo; insight; insulin secretion; islet; mouse model; novel; response; sensor

Project Summary/Abstract The pathogenesis of type 2 diabetes (T2D) has been primarily linked to defects in beta-cells, but evidence also points to a major contribution of glucagon and alpha-cell function in this disease. Cumulative data in mouse models and humans show that several amino acids (AAs), including branched-chain amino acids (BCAAs) and aromatic amino acids, have been reported to be associated with the risk of T2D. The increase in these AAs is associated with reduced insulin secretion, insulin resistance, and glycemia in human cohorts. Together, this evidence suggests that elevation in BCAAs could provide a mechanistic link between obesity/insulin resistance and beta- and alpha- cell adaptive responses. However, how AAs act on metabolically active tissues to increase diabetes risk is not completely understood. While the metabolic coupling mechanisms of AAs on insulin and glucagon secretion have been explored, there is a gap in understanding of how intracellular AA sensing mechanisms control beta and alpha-cell responses induced by AAs after a meal or in insulin resistance. The long-term goal of this project is to unravel the role of AA sensing mechanisms in beta and alpha cells in normal and pathologic conditions. Experimental data have identified that the leucine sensor Sestrin and arginine sensor Castor converge in the GATOR2 complex to induce Rag-dependent activation of mTORC1 signaling. Using mice with disruption of GATOR2 complex by deletion of Wdr24 (integral component of this complex) in beta and alpha cell demonstrates that GATOR2 plays a key role in beta and alpha cell homeostasis and regulates insulin and glucagon secretion. This suggests that AA sensing mechanisms mediated by GATOR2 pathways in vivo are crucial for coordinating AA responses in beta and alpha cells. The objective of this application is to build on these observations and determine how AA sensing dependent pathways regulate beta and alpha cells in physiology and pathological states. We hypothesize that the effects of AAs on beta and alpha cell mass and function in vivo are mediated mainly by GATOR2. To test this hypothesis, we will determine how AA sensing mechanisms regulate beta and alpha-cell mass and function using genetic approaches in vivo as well as ex vivo studies in mouse and human islets. At the end of these studies we will have a better understanding of how AA availability regulates beta and alpha cell mass and function and determine the extent to which GATOR2 functions exclusively as a leucine and arginine sensing mechanism in vivo. These studies will also identify novel mechanisms of adaptation to nutrient excess in states of hyperglycemia or hyper aminoacidemia. Finally, the current work will provide better insights into how AAs and in particular BCAAs increase diabetic risk. Understanding the molecular basis for AA sensing in beta and alpha cells will have a fundamental impact in diabetes and provide information that can be used to expand drug development opportunities for diabetes.

项目摘要/摘要 2型糖尿病（T2D）的发病机理主要与β细胞的缺陷有关，但也证据 指出胰高血糖素和α细胞功能在该疾病中的主要贡献。鼠标中的累积数据 模型和人类表明，几种氨基酸（AA），包括分支链氨基酸（BCAA）和 据报道，芳香族氨基酸与T2D风险有关。这些AA的增加是 与人类人群中胰岛素分泌减少，胰岛素抵抗和糖症有关。一起，这个 有证据表明，BCAA的抬高可以在肥胖/胰岛素抵抗之间提供机械联系 以及β-和α-细胞自适应反应。但是，AA如何作用于代谢活性组织增加 糖尿病风险尚不完全了解。而AAS在胰岛素上的代谢耦合机制和 已经探索了胰高血糖素的分泌，了解细胞内AA感应的差距 机制控制餐后AAS引起的β和α细胞反应，或者在胰岛素抵抗后。这 该项目的长期目标是揭示AA感应机制在β和α细胞中的作用 和病理状况。实验数据已经确定亮氨酸传感器sestrin和精氨酸传感器 Castor在Gator2复合物中收敛，以诱导MTORC1信号传导的RAG依赖性激活。使用小鼠 通过删除beta和alpha中的WDR24（该复合物的积分组成部分）对Gator2复合物的破坏 细胞表明，Gator2在β和α细胞稳态中起关键作用，并调节胰岛素和 胰高血糖素分泌。这表明由Gator2途径在体内介导的AA感应机制是 对于在β和α细胞中协调AA响应至关重要。该应用程序的目的是建立在这些基础上 观察并确定AA感应依赖性途径如何调节生理学的β和α细胞 和病理状态。我们假设AAS对β和α细胞质量的影响以及体内功能 主要由Gator2介导。为了检验这一假设，我们将确定AA感应机制 使用体内的遗传方法调节β和α细胞质量以及功能 小鼠和人类胰岛。在这些研究结束时，我们将更好地了解AA的可用性 调节β和α细胞质量和功能，并确定Gator2功能的程度 在体内仅作为亮氨酸和精氨酸感测机制。这些研究还将确定新颖 高血糖或氨基酸血症状态的适应营养过量的机制。最后， 当前的工作将提供更好的见解，了解AAS，尤其是BCAA如何增加糖尿病风险。 了解β和α细胞中AA传感的分子基础将对 糖尿病并提供可用于扩大糖尿病药物开发机会的信息。