胰岛α细胞功能失调导致胰高血糖素过量分泌是促进糖尿病发生发展的重要因素，如何纠正α细胞功能失调成为糖尿病防治中的研究热点。糖毒性造成氧化应激是导致α细胞功能失调的重要机制。前期研究发现，SCD1在糖尿病小鼠db/db胰岛α细胞中表达下降，α细胞过表达SCD1能够抑制糖毒性造成的氧化应激和胰高血糖素过度分泌；高脂喂养条件下，α细胞特异性敲入SCD1小鼠的葡萄糖耐量和胰岛素敏感性明显改善，这可能与SCD1催化产物-单不饱和脂肪酸(MUFAs)的增加和后者的抗氧化作用有关，但机制不清。该项目将借助α细胞特异性SCD1敲入/敲除小鼠，结合糖尿病造模和表型分析，在动物水平进行生化机制研究，特别是α细胞和胰岛内MUFAs浓度的测定；借助染色质免疫共沉淀和RNA-Seq等实验，在原代胰岛和细胞水平进行分子机制的研究。本研究将有助于阐明糖尿病胰岛α细胞功能失调的发生机制，并为糖尿病的防治提供实验依据。

The dysfunction of pancreatic α-cell can cause hypersecretion of glucagon, which contributes to pathogenesis of diabetes. How to correct pancreatic α-cell dysfunction is important for the prevention and treatment of diabetes. Chronic hyperglycemia, commonly called “glucotoxicity”, directly induces excessive glucagon secretion by the activation of oxidative stress. Our previous study showed that SCD1 expression was significantly decreased in pancreatic α-cells from db/db mice compared to control mice. SCD1 over-expression can inhibit the activation of oxidative stress and excessive glucagon secretion in α-cells exposed to chronic hyperglycemia. Alpha cell-specific SCD1 knock-in mice improved glucose tolerance and insulin sensitivity after high-fat-diet feeding, which may be caused by the increase of monounsaturated fatty acids (MUFAs) generated by SCD1 and MUFAs had the antioxidant effects. However, the exact mechanism remains unclear. In this study, we aim to investigate the biochemical mechanism especially the determination of MUFAs concentrations in alpha cells and islets via α-cell-specific SCD1 knock-in/knockout mice, combined with diabetic modeling and phenotypic analysis, and to figure out the underlying molecular mechanisms, using primary islets and cell lines through molecular biological technologies (ChIP etc.) and RNA-Seq. This study will not only elucidate the mechanism of pancreatic α-cell dysfunction in diabetes, but also provide experimental evidence for the prevention and treatment of diabetes.