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)的发病机制主要与β细胞缺陷有关，但有证据表明 指出了胰升糖素和阿尔法细胞功能在这种疾病中的主要作用。鼠标中的累积数据 模型和人类表明，几种氨基酸(AAs)，包括支链氨基酸(BCAA)和 芳香族氨基酸，已被报道与T2D的风险有关。这些高级行政许可的增加是 与人类队列中的胰岛素分泌减少、胰岛素抵抗和血糖有关。总而言之，这 有证据表明，支链氨基酸水平的升高可能会在肥胖和胰岛素抵抗之间提供机械联系 以及β细胞和阿尔法细胞的适应性反应。然而，AAs如何作用于代谢活跃的组织以增加 糖尿病的风险还没有完全了解。而AAs对胰岛素和胰岛素的代谢偶联机制 胰升糖素的分泌已经被探索过了，对于细胞内AA是如何感知的还存在一个空白 机制控制餐后或胰岛素抵抗时由AAs引起的β细胞和α细胞反应。这个 这个项目的长期目标是解开AA感知机制在正常的β细胞和α细胞中的作用。 以及病态的情况。实验数据表明，亮氨酸传感器、七叶皂苷传感器和精氨酸传感器 Castor聚集在GATOR2复合体中，诱导依赖RAG的mTORC1信号的激活。使用小鼠 通过删除β和α中的Wdr24(该复合体的组成部分)来破坏GATOR2复合体 细胞证明GATOR2在β细胞和α细胞内稳态中起关键作用，并调节胰岛素和 胰高血糖素分泌。这表明，体内GATOR2通路介导的AA感知机制是 对于协调β细胞和阿尔法细胞中的AA反应至关重要。本应用程序目标是在这些基础上构建 观察并确定AA感觉依赖通路如何在生理学上调节β细胞和α细胞 以及病态。我们假设AAs对体内β和α细胞质量和功能的影响 主要由GATOR2介导。为了检验这一假设，我们将确定AA感知机制 在体内和体外研究中使用遗传方法调节β和α细胞的质量和功能 老鼠和人类的小岛。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细胞的质量和功能，并确定GATOR2的功能程度 在体内仅作为一种亮氨酸和精氨酸的感知机制。这些研究还将确定小说 高血糖或高氨基酸血症状态下对营养过剩的适应机制。最后， 目前的工作将为更好地了解氨基酸，特别是支链氨基酸如何增加糖尿病风险提供更好的见解。 了解β细胞和α细胞中AA感知的分子基础将对 并提供可用于扩大糖尿病药物开发机会的信息。