MicroRNA-203a regulates pancreatic ß cell proliferation and apoptosis by targeting IRS2.

ABSTRACT

The main pathogenesis of type 1 diabetes mellitus (T1DM) is autoimmune-mediated apoptosis of pancreatic islet ß cells. We sought to characterize the function of microRNA-203a (miR-203a) on pancreatic islet ß cell proliferation and apoptosis. In situ hybridization was used to detect the expression of miR-203a in islet ß cells in normal and hyperglycaemic non-obese diabetic (NOD) mice. Cell proliferation was measured by cell counting kit eight and cell apoptosis was detected using flow cytometry. Insulin receptor substrate 2 (IRS2/Irs2) was determined to be a direct target of miR-203a by Luciferase reporter assay. We detected the effects of miR-203a overexpression or inhibition on proliferation and apoptosis of IRS2-overexpressing or IRS2-knockdown MIN6 cells respectively, and preliminarily explored the downstream targets of the IRS2 pathway. NOD mice model was used to detect miR-203a inhibitor treatment for diabetes. Our experiment showed miR-203a was upregulated in pancreatic ß cells of hyperglycaemic NOD mice. Elevated miR-203a expression inhibited the proliferation and promoted the apoptosis of MIN6 cells. IRS2/Irs2 is a novel target gene directly regulated by miR-203a and miR-203a overexpression downregulated the expression of IRS2. Irs2 silencing reduced cell proliferation and increased apoptosis. Irs2 overexpression could abolish the pro-apoptotic and anti-proliferative effects of miR-203a on MIN6 cells. Hyperglycemia in newly hyperglycemic NOD mice was under control after treatment with miR-203a inhibitor. Our study suggests that miR-203a regulates pancreatic ß cell proliferation and apoptosis by targeting IRS2, treatment with miR-203a inhibitors and IRS2 might provide a new therapeutic strategy for T1DM.