临床数据显示HCV感染及其所致的慢性肝病与2型糖尿病存在明显相关性。已有的研究结果初步证实HCV感染可以削弱胰岛素信号通路，引起肝脏胰岛素抵抗，然而HCV感染是否会损伤胰岛β细胞并最终导致2型糖尿病的发生尚不清晰。我们的前期结果显示HCV感染能导致胰岛β细胞胰岛素分泌障碍。本项目将首先分析HCV对β细胞胰岛素合成和分泌过程的影响确定HCV感染导致胰岛素分泌障碍的环节；进一步研究HCV病毒蛋白以及复制中间体dsRNA对β细胞胰岛素分泌的影响确定HCV感染导致胰岛素分泌障碍的病毒因子；基于HCV感染能诱导宿主细胞产生NO以及NO能够损伤胰岛β细胞功能的已有结论，深入挖掘HCV如何通过NO这个重要分子引起β细胞胰岛素分泌障碍。研究将最终获得HCV感染导致胰岛β细胞胰岛素分泌障碍的分子机制，为HCV感染所致的2型糖尿病的预防控制提供理论依据和新的思路。

Epidemiological and clinical studies have suggested that HCV infection is associated with the development of type 2 diabetes. Pancreatic beta cell failure is central to the progression of type 2 diabetes. Several experimental studies have supported that, in hepatic cells, HCV infection may induce insulin resistance by interfering with insulin signaling. However, potential effects of HCV infection on beta cells which promote type 2 diabetes remain unknown. Recently, our experiments have indicated that HCV infection represents a risk factor in the inhibition of glucose-stimulated insulin secretion in pancreatic beta cells. In this project, we will first analysis the key step, from insulin biosynthesis to insulin exocytosis, which is impaired in HCV infected-beta cells, resulting in the loss of β-cell function. Secondly, the experiments will be designed to ensure the virus factor, HCV protein or double-stranded RNA, which induces the inhibition of insulin secretion. Based on the known facts that HCV infection could activate nitric oxide synthase in hepatic cells and nitric oxide could induce islet damage, we will further explore the mechanism that HCV infection inhibits beta cell function by stimulating beta cell production of nitric oxide. Our study will obtain the biological mechanism underlying which provides a rationale to investigate hepatitis C itself as a potential therapeutic target for treatment of HCV-associated type 2 diabetes.