Study Of Islet Precursors Differentiation And Regulation Of Insulin Secretion By FXR-CaV1.2

Type 2 diabetes mellitus is a kind of metabolic diseases which is characterized by long term hyperglycemia and serious insulin resistance.Pancreatic ?-cell is the only cell secreting insulin,therefore,the quantity and function of pancreatic ?-cell play a crucial role in glucose homeostasis.In this study we explored: 1)Ca V1.2 mediates the regulatory effect of FXR on insulin secretion;2)The effect of HIP on the differentiation of islet precursors into functional ?-cell.1.The mechanism of HIP in regulating islet precursors differentiationIslet transplantation is an effective therapy for type 2 diabetes.But there are many problems in this method,such as the shortage of donated cells and immunological rejection.One of the solutions of the problems is to establish in vitro inducible system of functional pancreatic ?-cell.Researches have shown that HIP could increase the quantity of ?-cell,but the mechanism remains unclear.Our study found that HIP inhibited the expression of FOXO1 and Menin in mature ?-cells and islet precursors.Furture study shows the phosphorylation level of FOXO1 and AKT is increased after treated with HIP in islet precursors,while this phenomenon is diminished after treatment of Wortmanin,which is an inhibitor of PI3 K.The results showed that HIP induces differentiation of islet precursor via PI3K-AKT-FOXO1-Menin pathway.Our study provides new evidence for elucidating the mechanism of HIP regualting islet precursor differentiation.2.FXR regulates insulin secretion through CaV1.2FXR,as bile acid receptor,is implicated in glucolipid metabolism.Recently,it is reported that FXR could regulate insulin secretion in pancreatic ?-cells,but the underlying mechanism remains unclear.Ca V1.2,one of the L-type calcium channel,plays an important role in the process of insulin secretion.However,if there is any correlation between FXR and Ca V1.2 in regulating insulin secretion is unknown.In the present study,we found that the effects of agonist and antagonist of Ca V1.2 on insulin secretion were decreased in FXR knockout mouse islets.Moreover,GW4064,the FXR agonist,promoted the m RNA and protein expression of Ca V1.2 in ?-cells.By contrast,silence or knockout of FXR inhibited the m RNA and protein expression of Ca V1.2.Further studies showed that activation of FXR promotes itself binding to the promoter of Ca V1.2 in ?-cells,thereby recruiting the histone acetylase SRC1 to the promoter of Ca V1.2 and resulting in the increase of acetylation of histone H3.On the contrary,knockdown of FXR decreased the occupation of FXR and SRC1 on the promoter of Ca V1.2 and the acetylation level of Ca V1.2 promoter,suggesting that Ca V1.2 is one of targets epigenetically regulated by FXR.These data will provide new evidence to elucidate the mechanism of FXR regulating insulin secretion of ?-cells.