前胰岛素原(PPI)从细胞浆向内质网的跨膜转位是胰岛素生物合成的起始步骤，PPI的低效转位可导致人类糖尿病，但具体机制不明。我们的前期工作提示，有多种蛋白机器参与的PPI跨膜转位可受多种因素的影响。本课题的研究假设是，PPI和β细胞的一些自身生物学特性使PPI具有潜在低效转位的风险，某些病理情况（如β细胞内质网应激或过负荷时的“预清除质控”、与2型糖尿病易感性相关的信号序列受体1 功能不足及信号肽突变等），可以进一步增加上述低效转位的风险，致使未转位的PPI增多，当超过β细胞蛋白降解阈值时，PPI在细胞浆中异常堆积，导致β细胞蛋白稳态失衡及功能衰竭。本课题在研究PPI转位方式、效率及其影响因素的基础上，深入理解β细胞对低效转位PPI的信号反应及未转位PPI在细胞内的降解过程，明确PPI低效转位在1型和2型糖尿病中的作用，及由此所致糖尿病的分子机制，为糖尿病的个体化靶向治疗提供重要的基础。

In pancreatic beta cells, insulin biosynthesis begins with its precursor, preproinsulin (PPI), in the cytosol. To enter the secretory pathway, newly synthesized PPI, led by its signal peptide and assisted by translocation machineries, must undergo multiple translocation processes across the membrane of endoplasmic reticulum (ER). These earliest events are critical to insulin biosynthesis, but they are largely unexplored in the 4 decades since PPI was discovered in the late 1970s. Yet the question of how PPI translocation, what factors affect its translocation efficiency, and what cellular responses and consequences of inefficient PPI translocation, has never had more pathophysiological significance than it does now. Over the past years, two new PPI signal peptide mutations have been reported to cause diabetes in humans, indicating serious adverse consequences when these early processes are not properly executed. Our preliminary results suggest that the efficiency of PPI translocation can be affected by several factors. The hypothesis of this project is that PPI is predisposed to inefficient translocation due to some biological characters of PPI and beta cells. Under certain pathological conditions, including signal peptide mutations, beta cell ER overload or ER stress, and inefficient function of signal sequence receptor 1 (SSR1) or other translocation machineries, untranslocated PPI increases in the cytosol. When the amount of the untranslocated PPI reaches to the “threshold” that beta cells can efficiently degrade abnormal proteins, the PPI accumulates in the cells, leading to beta cell toxicity, failure, and diabetes. By applying cellular and molecular approaches both in vitro and in vivo, this study aims to: 1). To better understand molecular mechanisms of beta cell failure and diabetes caused by inefficient PPI translocation. 2). To examine the role of inefficient PPI translocation in type 1 and type 2 diabetes. 3). To deepen our understanding of degradation pathway involved in clearance of untranslocated PPI in beta cells. This study will not only extend our knowledge of beta cell biology, but also shed light on developing new targets for preventing and treating diabetes.