胰岛β细胞功能障碍是2型糖尿病发生发展的核心因素，而胰岛素囊泡的转运和分泌障碍是胰岛β细胞功能损伤的重要环节。.我们前期研究发现：在原代胰岛及β细胞系中干扰钙/钙调蛋白依赖性丝氨酸蛋白激酶(CASK)表达可以显著降低高钾刺激的β细胞胰岛素释放(KSIS)，并与胰岛素囊泡在细胞膜上的锚定数减少有关；在高脂作用下，β细胞系中CASK表达显著下降、KSIS功能也显著降低，过表达CASK则可以部分逆转脂肪酸诱导的胰岛素分泌障碍，提示：CASK可能与胰岛素囊泡转运和分泌密切相关，但具体机制尚待研究。.本研究拟：借助胰岛β细胞功能研究的各种方法，并通过构建转基因和基因敲除小鼠的手段，①进一步验证CASK参与胰岛素囊泡转运和分泌的作用及其调控机制；② 探讨影响CASK表达的上游调控机制（如：FoxO1转录因子等）。本研究将为阐明2型糖尿病胰岛β细胞功能障碍的机制提出新理论并为糖尿病治疗靶点提供新思路。

Pancreatic beta-cells dysfunction is one of the major causes of type 2 diabetes. Meanwhile, Insulin granules trafficking and secretion defect plays an important role in pancreatic beta-cells dysfunction..Based on our research thus far, we found that interference CASK expression in primary and islet β cell lines could significantly reduce the insulin secretion in an environment of high K + concentration（KSIS）, which is closely associated with the reduced number of insulin granules anchored on the cell membrane; meanwhile, in the high-fat state, expression of CASK and the function of KSIS is significantly decreased, and the overexpression of CASK can partially reverse insulin secretion disorder caused by fatty acid. One caveat of the research is that the calcium / calmodulin-dependent serine protein kinase CASK is closely associated with insulin granules trafficking and secretion, but the exact mechanism is unclear. .Purpose of the study: through studying the function of islet β cells using multiple methods and constructing transgenic and knockout mice, we propose to ①discuss and verify the mechanism of CASK regulation function of insulin granules trafficking and secretion; ②investigate the effect of upstream regulatory mechanisms on CASK expression (eg: FoxO1). This study could provide new experimental evidence, as wells as a new theory for elucidating the mechanism of islet β-cell dysfunction in type 2 diabetes. It would also offer new potential drug targets for the prevention and treatment of diabetes.