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

 描述(由申请人提供)： 糖尿病是21世纪影响人类健康的最常见疾病之一。我们努力了解该病的发病机制和治疗的大部分焦点都集中在两个主要组成部分上：胰岛素敏感性和胰岛素分泌。然而，目前的证据表明，高血糖在2型糖尿病高血糖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/IRS2/Akt信号在调节α细胞质量和胰升糖素分泌方面的重要性。然而，Akt信号如何在体内调节a细胞的功能和质量，以及这一过程对糖代谢调节的潜在贡献仍不清楚。在Akt下游，TSC1/2(结节性硬化症复合体)和mTOR/Raptor(MTORC1)是这一过程中的主要候选基因，因为它们整合了生长因子和营养物质的信号。这些研究的长期目标是揭示胰岛素/Akt信号如何调节α细胞质量和胰升糖素的分泌。在初步实验中，我们发现a细胞中mTORC1功能的丧失会导致a细胞质量和胰升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mTORC1信号来调节α细胞质量和胰升糖素的分泌。具体的目标将决定mTORC1功能的获得和丧失如何调节α细胞质量、胰升糖素分泌和对糖尿病发生条件的适应。这一提议将为mTORC1控制a-细胞质量扩张的分子机制提供重要的见解。这些信息可以用来扩大糖尿病的药物开发机会。

 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.