Study On The Regulation Of Pancreatic β Cell Function By Orphan Nuclear Receptor Nur77

In recent years,with the improvement of living standards,diabetes has become a global public health problem,and its occurrence and development are often accompanied by a decrease in the number of functional pancreatic β cells.Orphan nuclear receptor Nur77 is an important drug target,which has been proved to play an important role in regulating glucose metabolism.However,the mechanism of Nur77 in diabetes,especially the function of pancreatic β cells,is still unclear.As a model organism,zebrafish has been well applied to the study of metabolic diseases.The purpose of this study is to explore the role of Nur77 in pancreatic β cell development and function using zebrafish,cells and mouse model.We generated mutant zebrafish with global knockout of Nur77 gene,transgenic zebrafish with overexpression of Nur77 gene in pancreatic β cells,zebrafish strains with β cell specific supplement of Nur77 and other transgenic zebrafish with fluorescent tags.We found that the number of pancreatic β cells in Nur77-/-zebrafish decreased during the embryonic stages,accompanied by increasing of free blood glucose,decreasing of insulin expression and the impairment of insulin secretion function.The down-regulation of insulin insb gene expression may be the reason for the decrease of insulin expression.After supplementing Nur77 to pancreatic islet β cells,the number of β cells and insulin content returned to normal.To further explore the mechanism ofβ cells decrease in Nur77-/-,we found that Nur77-/-had no significant effect on the proliferation and apoptosis of pancreatic β cells in juvenile fish;and there is no transdifferentiation phenomenon in Nur77-/-zebrafish pancreatic β cells.We found that Nur77 may play an important regulatory role in the differentiation of progenitor cells into β cells.Knockout of Nur77 inhibits the differentiation process of Pdx1+ progenitor cells into β cells.Subsequently,we tested the expression of Pdx1 in the INS1 832/13 cell line of Nur77 knockout and pancreatic β cells of Nur77 knockout mice,and the levels of Pdx1 decreased.To sum up,it was found that Nur77 played an important role in the maintenance of pancreatic β cell number and function at animal and cellular level,and the possible mechanism of islet β cell regulation by Nur77 was analyzed,and the role of Nur77 in βcell differentiation was preliminarily determined.The further study of this subject will clarify the molecular mechanism of Nur77 regulating pancreatic β cells and provide new ideas and strategies for the development of targeted Nur77 drugs for diabetes.