The Role And Mechanism Of MTORC1 In Regulation Of Pancreatic β Cell Proliferation

Background and objective Beta cell mass plays a great role in maintaining glucose homeostasis,which depends on beta cell size,proliferation,neogenesis and apoptosis.Beta cell mass is increased when the needs increase in maintaining glucose homeostasis.Failure to adapt to the increment of glucose metabolism leads to the development of chronically elevated blood glucose and even diabetes.The mechamism of beta cell proliferation has been well studied recently since the proliferation is a major way for increment of adult pancreatic beta cell mass.The regulatory factors involved in beta cell proliferation include insulin,glucose,IGF and other nutrients.mTORC1 which works as the nutrient sensor in the cells,plays a great role in the regulaion of beta cell proliferation.However,the role and mechanism of mTORC1 in regulaion of beta cell proliferation is still unclear.Material and methods 1)to develop the model of pancreatic beta cell proliferation induced by 60%pancreatectomy.2)to explore the role of mTORC1 signaling in the regulation of pancreatic beta cell.Adult c57BL/6J mice were allocated into four groups:（1）sham-operated plus vehicle（sham+vehicle）;（2）sham-operated plus rapamycin（0.5mg/kg.d）（sham+rapa）;（3）60%pancreatectomy plus vehicle（Px+vehicle）;（4）60%pancreatectomy plus rapamycin（0.5 mg/kg.d）（Px+rapa）.Body weight was measured pre and7 days after operation,and IPGTT,IRT and ITT was performed on the 6^th day after operation.To dctect the gene expression involved in cell proliferation,real-time PCR and immunohistochemistry were performed 3)to investigate the phenotypes in beta cell specific raptor KO mice.4)to observe beta cell proliferation in theβRic KO mice with 60%pancreatectomy 5)cell proliferation was analyzed in Rinm5f cells treated with rapamycin and with raptor siRNA,respectively.results 1)Insulin secretion and pancreatic insulin content were reduced in mice receiving 60%pancreatectomy and treated with rapamycin for 6 days,however,peripheral insulin resistance was not affected.2)The beta cell proliferation induced by 60%pancreatectomy was inhibited by rapamycin.3)Random blood glucose levels and fasting blood glucose levels were increased,and glucose tolerance impaired inβRap KO mice.4)However,glucose tolerance and beta cell proliferation were not changed inβRicKO mice receiving 60%pancreatectomy compare with Ric lox/lox mice receiving 60%pancreatectomy.5)The prolifetation was inhibited in Rinm5f cells treated with rapamycin and raptor siRNA.Cyclin D2 was dramatically reduced accordingly conclusion 1)mTORC1 plays a critical role in beta cell proliferation induced by 60%pancreatectomy.2)mTORC1 regulates cell proliferation possibly through upregulation of cyclin D2.