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.

项目概要/摘要 2 型糖尿病 (T2D) 的发病机制主要与 β 细胞缺陷有关，但也有证据表明 指出胰高血糖素和α细胞功能在这种疾病中的主要贡献。小鼠累积数据 模型和人类表明，多种氨基酸 (AA)，包括支链氨基酸 (BCAA) 和 据报道，芳香族氨基酸与 T2D 风险相关。这些 AA 的增加是 与人类群体中胰岛素分泌减少、胰岛素抵抗和血糖有关。在一起，这个 有证据表明支链氨基酸的升高可以提供肥胖/胰岛素抵抗之间的机制联系 以及β和α细胞适应性反应。然而，AA 如何作用于代谢活跃的组织以增加 糖尿病风险尚不完全清楚。而AAs对胰岛素和胰岛素的代谢耦合机制 胰高血糖素分泌已被探索，但对细胞内 AA 传感机制的理解存在差距 机制控制餐后或胰岛素抵抗中 AA 诱导的 β 和 α 细胞反应。这 该项目的长期目标是揭示 AA 传感机制在正常情况下的 β 和 α 细胞中的作用 和病理状况。实验数据已确定亮氨酸传感器Sestrin和精氨酸传感器 Castor 聚集在 GATOR2 复合体中，诱导 mTORC1 信号传导的 Rag 依赖性激活。使用鼠标 通过删除 β 和 α 中的 Wdr24（该复合物的组成部分）来破坏 GATOR2 复合物 细胞表明 GATOR2 在 β 和 α 细胞稳态中发挥关键作用，并调节胰岛素和 胰高血糖素分泌。这表明体内 GATOR2 通路介导的 AA 传感机制是 对于协调 β 和 α 细胞中的 AA 反应至关重要。该应用程序的目标是建立在这些基础上 观察并确定 AA 传感依赖性通路如何在生理学中调节 β 和 α 细胞 和病理状态。我们假设 AA 对体内 β 和 α 细胞质量和功能的影响 主要由 GATOR2 介导。为了验证这一假设，我们将确定 AA 传感机制如何 使用体内遗传方法以及离体研究调节 β 和 α 细胞质量和功能 小鼠和人类的胰岛。在这些研究结束时，我们将更好地了解 AA 的可用性如何 调节 β 和 α 细胞质量和功能并确定 GATOR2 功能的程度 专门作为体内亮氨酸和精氨酸传感机制。这些研究还将确定新颖的 高血糖或高氨基酸血症状态下适应营养过剩的机制。最后， 目前的工作将更好地了解 AA（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。