Study The Role And Mechanism Of COX6A2 In The Process Of Exendin-4 Protects Apoptotic ?-cell In Type 2 Diabetes

Insulin secreted by pancreatic ?-cells is the only hypoglycemic hormone in the body.?-cell apoptosis plays an important role in the onset and development and type 2 diabetes(T2DM).Exendin-4,an analogue of GLP-1,has been proved to inhibit ?-cell apoptosis and restore normal glucose level by improving insulin secretion.However,the underlying mechanisms remain largely unknown.Cytochrome c Oxidase ? A2(COX6A2),as one of the 13 subunits of Cytochrome c Oxidase,regulates mitochondrion function,and then affects cell survival.Farnesoid X receptor(FXR),a nuclear receptor,improves insulin secretion and insulin sensitivity through many pathways,but its effect on ?-cell apoptosis remains unclear.In the present study we explored: 1)Exendin-4 protects pancreatic ?-cells from apoptosis via inhibition of COX6A2 expression in T2 DM.2)FXR protects pancreatic ?-cell apoptosis induced by high glucose.Part I : Exendin-4 protects pancreatic ?-cells from apoptosis via inhibition of COX6A2 expression in T2 DM.We,for the first time,found that COX6A2 expresses in pancreatic ?-cells,and its expression is increased in pancreatic islets of diabetic Goto-Kakizak(GK)rats.Similarly,its expression is also induced in ?-cells exposed to chronic high glucose in vitro.It is noteworthy that overexpression of COX6A2 promoted ?-cell apoptosis.By contrast,knockdown of COX6A2 inhibited ?-cell apoptosis caused by exposure to high glucose,suggesting that COX6A2 is implicated in regulation of diabetic ?-cell apoptosis.Our further studies showed that carbohydrate response element binding protein(ChREBP),as a transcription factor,is implicated in the regulation of COX6A2 expression in ?-cells :overexpression of ChREBP promoted the expression of COX6A2 in ?-cells,on the contrary,knockdown of ChREBP curtailed COX6A2 expression of ?-cells,indicating that COX6A2 is one of the target genes regulated by ChREBP.Moreover,we also found that exendin-4decreases the increase of COX6A2 expression of ?-cells induced by high glucose,which is attributed to its inhibitory effect on the activation of ChREBP induced by high glucose.These results will shed light on revealing the cellular mechanisms of ?-cell apoptosis in T2 DM,as well as the mechanisms of exendin-4 inhibiting ?-cell apoptosis.Part ?: FXR protects pancreatic ?-cells from apoptosis caused by high glucose.It is unclear that the effect of FXR on pancreatic ?-cell apoptosis.We generated FXR overexpression and knockdown ?-cells,respectively.Then we investigated the role of FXR in the process of ?-cell apoptosis caused by exposure to high glucose.We found that overexpression of FXR could restrain INS-1E cell apoptosis induced by high glucose.By contrast,knockdown of FXR exacerbates INS-1E cell apoptosis,indicating that FXR plays an important role in the process of ?-cell apoptosis.Moreover,we also found that overexpression of FXR inhibits the expression of COX6A2 in ?-cells,by contrast,knockdown of FXR promotes COX6A2 expression of ?-cells.Similarly,COX6A2 expression is increased in FXR knockout mouse islets,suggesting that COX6A2 expression is regulated by FXR.These data provide new evidences for exploring the anti-apoptosis effect of FXR.