Role And Mechanism Of IGF1R In Estrogen Protection Of Pancreatic ?-cell-function And Survival

Estrogen(E2)can act directly on the islet beta cells to promote insulin secretion and prevent beta cell apoptosis caused by many factors,thus plays an important pro-tective effect on islet beta cell survival and function,and may be of great significance in the treatment and prevention of diabetes.But at the moment,the mechanisms of E2 proteciton of islet function and survival remains unclear.Similar to E2,insulin growth factor(IGF1)also plays a protective role in islet beta cell function and survival,and a close interaction of its receptor(IGF1R)and estrogen receptor(ER,mainly ERa)was frequently reported in nerve,blood vessel,breast,uterine and other organizations.OBJECTIVE—To explore the role of IGF1R in E2 protection of pancreatic beta cell function and survival.RESEARCH DESIGN AND METHODS—Using pancreatic beta cell line Min6 cells,we investigated the E2 actions in beta cell survival under hypoxic condition.One percent oxygen was adopted to induce hypoxic damage,CCK8 was used to de-tect cell proliferation,jc-1 reagents was used to detect mitochondrial membrane po-tential,and Tunel was used to detect apoptosis.Protein expression and phosphorylaton was measured by Western Blot.Pancreatic beta cell specific IGF1R knockout mouse model was generated by cre-loxp strategy.RESULTS—Under the condition of hypoxia,E2 increased Min6 cell proliferation,reduced the apoptosis,which was blocked by IGF1R inhibitors JB-1.E2 quickly acti-vated phosphorylation of Akt and ERK,which was abolished by IGF1R inhibition.The protective effects of E2 on pancreatic beta cell survival disappeared in the pres-ence of PI3K inhibitor LY294002,and ERK inhibitor PD58059.E2 ameliorated hy-poxia-induced damage of mitochondrial membrane potential,which was blocked by IGF1R inhibitor JB-1.Conclusion—E2 plays important protective roles in pancreatic beta cell survival under hypoxic condition,in which IGF1R and its two key downstream signaling pathway-PI3K and ERK exert indispensable roles.