Diabetes mellitus is one of the most prevalent conditions affecting human health in the 21st century. Most of the focus of our efforts to understand the pathogenesis and therapy of the disease has focused on two major components: insulin sensitivity and insulin secretion. However, the current evidence suggests that hyperglucagonemia play major roles in the pathogenesis of hyperglycemia in type 2 diabetes and has a major impact in the glycemic volatility and susceptibility to hypoglycemia in type 1 diabetes. The current evidence underscores the importance of the insulin/IRS2/Akt signaling on regulation of a-cell mass and glucagon secretion. However, how Akt signaling regulates the function and mass of a-cells in vivo and the potential contribution of this process to the regulation of glucose metabolism remain unclear. Downstream of Akt, TSC1/2 (Tuberous Sclerosis Complex) and mTOR/Raptor (mTORC1) emerge as prime candidates in this process, because they integrate signals from growth factors and nutrients. The long-term goal of these studies is to uncover how insulin/Akt signaling regulates a-cell mass and glucagon secretion. In preliminary experiments, we showed that loss of mTORC1 function in a-cells results in major abnormalities in a-cell mass and glucagon secretion. The objective of these studies is to build on these observations to understand how nutrient signaling regulates a-cell function and mass. We hypothesize that insulin signaling regulates a-cell mass and glucagon secretion mainly by modulation of mTORC1 signaling.
The specific aims will determine how gain and loss of mTORC1 function modulates a-cell mass, glucagon secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern a-cell mass expansion by mTORC1. This information can be used to expand drug development opportunities for diabetes.
Type 2 Diabetes (T2D) is characterized by defective adaptation of -cells to insulin resistance. Most of the research effort has focused on elucidating the physiological, molecular, and genetic components that regulate -cell mass and insulin secretion, presenting diabetes as a unihormonal disorder. Contrary to this current approach, clinical data and animal experiments have shown that increased glucagon secretion by a-cells play a role in the pathogenesis of hyperglycemia in diabetes. The goal of this application is to understand how nutrient signaling regulates glucagon secretion and a-cell mass in an effort to develop novel therapies for diabetes. These agents could be used in translational experiments to treat diabetes by controlling glucagon secretion.
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