Amino acid sensing mechanisms in beta and alpha cells

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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.