mTOR signaling and regulation of alpha-cell mass and function

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Diabetes mellitus is one of the most prevalent conditions affecting human health including veterans 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, dysregulation in glucagon secretion is a major component in diabetes. Hyperglucagonemia plays key 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. Our observations published during the current funding period suggest that downstream of insulin/Akt, the nutrient sensitive pathway (mTOR/Raptor or mTORC1) plays a major role in regulation of alpha cell mass and glucagon secretion. However, how mTORC1 acting on key downstream targets (4E-BPs and S6K) regulates the function and mass of alpha-cells in vivo and the potential contribution of these targets to the regulation of glucose metabolism remain unclear. The long-term goal of these studies is to uncover how the nutrient sensitive insulin/Akt/mTORC1 axis regulates α-cell mass and glucagon secretion in rodent models and humans. Our studies showed that loss of mTORC1 function in alpha-cells results in major abnormalities in alpha-cell mass and glucagon secretion. We also demonstrate that gain of mTORC1 results in chronic hyperglucagonemia and alpha cell mass expansion suggesting that this signaling pathway is critical for alpha cell mass and glucagon secretion. Based on these observations, we hypothesize that mTORC1 regulates alpha-cell mass mainly by a balance between S6K and 4E-BP signaling. The specific aims will assess the individual contribution of downstream targets of mTORC1 by establishing the role of mTORC1/4E-BP/eIF4E axis in regulation of alpha-cell mass, glucagon secretion and adaptation to diabetogenic conditions using novel alpha cell specific models. In addition, we will also identify the importance of mTORC1/S6K on the control of alpha-cell mass and glucagon secretion by generation of novel models with inducible gain of S6K function in alpha cells. Finally, how mTORC1 activation alters human alpha-cell responses will be determined using a model of human islet transplantation in the anterior chamber of the mouse eye. This proposal will provide important insights into the molecular mechanisms that govern alpha-cell mass expansion by mTORC1. This information can be used to uncover novel targets that can be used for treatment of diabetes and design interventions to rescue the defects in glucagon secretion in response to hypoglycemia in patients with diabetes.