mTORC1 signaling and regulation of alpha-cell mass and function.

 描述（由申请人提供）： 糖尿病是世纪影响人类健康的最普遍疾病之一。大多数我们的努力，以了解发病机制和治疗的疾病集中在两个主要组成部分：胰岛素敏感性和胰岛素分泌。然而，目前的证据表明，高胰高血糖素血症在2型糖尿病高血糖症的发病机制中起主要作用，并对1型糖尿病的血糖波动和低血糖易感性有重要影响。目前的证据强调了胰岛素/IRS 2/Akt信号传导对调节α-细胞质量和胰高血糖素分泌的重要性。然而，Akt信号传导如何在体内调节α-细胞的功能和质量以及该过程对葡萄糖代谢调节的潜在贡献仍不清楚。Akt的下游，TSC 1/2（恶性硬化症复合体）和mTOR/Raptor（mTORC 1）成为这一过程中的主要候选者，因为它们整合了来自生长因子和营养素的信号。这些研究的长期目标是揭示胰岛素/Akt信号传导如何调节α细胞质量和胰高血糖素分泌。在初步的实验中，我们发现mTORC 1功能的丧失导致a细胞质量和胰高血糖素分泌的主要异常。这些研究的目的是建立在这些观察的基础上，以了解营养信号如何调节a细胞的功能和质量。我们推测胰岛素信号主要通过调节mTORC 1信号来调节α-细胞质量和胰高血糖素分泌。具体目标将确定mTORC 1功能的获得和丧失如何调节α-细胞质量、胰高血糖素分泌和对致糖尿病条件的适应。这一建议将提供重要的见解的分子机制，管理a-细胞质量扩增mTORC 1。这些信息可用于扩大糖尿病药物开发机会。

 DESCRIPTION (provided by applicant): 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.