胰岛β细胞数量和功能性代偿缺陷是2型糖尿病重要致病机制。我们前期研究首次证明Rictor/mTORC2活性是维持β细胞增殖的重要因子(Diabetes,2011.03)。我们还发现β细胞特异敲除Rictor后可显著抑制胰岛70%的葡萄糖刺激的胰岛素分泌（GSIS），提示Rictor/mTORC2在β细胞功能调节中亦十分重要。进一步研究发现敲除Rictor显著降低β细胞葡萄糖刺激的胞内钙离子浓度[Ca2+]i，Rictor主要下游底物AKT和PKC的表达和活性受抑。Rictor可能通过这两个信号通路调控β细胞葡萄糖感受，离子通道活性和胰岛素囊泡运动影响 [Ca2+]i及GSIS。因此本课题将采用β细胞特异敲除Rictor小鼠模型，分选纯化GFP标记活体β细胞；用离体灌流、细胞膜片钳和病毒转染等方法阐明Rictor调节β细胞GSIS的具体分子机制，希望找到促进β细胞增殖和功能的双重调节靶点。

Pancreatic islet β cell mass and function defects are the major pathophysiological mechanisms of Type 2 Diabetes. Our previous published study （Diabetes 2011.03）firstly demonstrated that the kinase for pAKTS473, mTORC2 is essential for maintaining β cell proliferation and mass. However, we simultaneously found that in in vitro islet perfusion, deletion Rictor also significantly inhibited GSIS to 30% of normal level which made us thought that Rictor might also play an important role in β cell function. Our preliminary data showed that glucose stimulated intracellular calcium concentration was dramatically decreased by knocking down Rictor and that AKT phosphorylation，PKC expression and intracellular localization were significantly changed in β cell lack of Rictor. PKC and AKT are the major downstream substrates of Rictor/mTORC2. They are reported to be involved in glucose sensing ,ion channels activities and insulin granules movement. Therefore, Rictor could also modulate glucose stimulated intracellular concentration to promote insulin secretion through controlling glucose sensing and insulin granules movement in addition to ion channel activities. In this project, we will take advantage of the mice with β cell specific knockout Rictor, mating them with R26GFP mice. Using purified β cell by FACs, we will employ the ex vivo perifusion, primary β cell membrane clamp and virus transduction, to investigate the underlying mechanism Rictor mediated by to regulate β cell GSIS in the hope to find the potential target for regulating both β cell function and proliferation.