Development of new therapy for type 2 diabetes targeting sphingolipid receptor on pancreatic beta cell

为了评价鞘脂信号在胰腺β细胞中的功能，使用Cre-Lox P系统产生β细胞特异性S1 P1敲除小鼠。β S1 P1 KO在体内无明显表型。与对照组相比，Forskolin能促进β S1 P1 KO胰岛细胞胰岛素分泌。在完整的胰岛斑块中，即使在500 nM S1 P下，也可在β S1 P1 KO胰岛中观察到Forskolin刺激的Ca^<2+>的高振荡。在胰岛移植实验中，β S1 P1 KO胰岛边缘数（100个）在STZ诱导的1型糖尿病模型小鼠中持续降低血糖水平，而对照胰岛无此作用。总的来说，抑制β细胞中的S1 P1信号传导可以导致针对β细胞损伤的保护，并导致糖尿病中的新型β细胞疗法。

To evaluate the function of sphingolipid signaling in pancreatic β cells, β cell specific S1P1 knocked out mouse was generated using Cre-Lox P system. βS1P1KO showed no apparent phenotype in vivo. Forskolin potentiated insulin secretion was promoted in isolated islet of βS1P1KO compared to control. In whole islet patch clump, forskolin stimulated hyper-oscillation of Ca^<2+> was observed inβS1P1KO islet even under 500nM S1P. In islet transplantation experiment, marginal number of βS1P1KO islets (100) successively lowered glucose level in STZ induced type 1 diabetic model mouse, but not of control islets. Collectively, inhibition of S1P1 signaling in β cells can lead to protection against β cell injury and lead to a new type of β cell therapy in diabetes.