Nardilysin is required for maintaining pancreatic β-cell function

Abstract

Type 2 diabetes (T2D) is associated with pancreatic β-Cell dysfunction, manifested by reduced glucosestimulated insulin secretion (GSIS). Several transcription factors enriched in β-Cells, such as MafA, control β-Cell function by organizing genes involved in GSIS. Here we demonstrate that nardilysin (N-arginine dibasic convertase; Nrd1 and NRDc) critically regulates β-Cell function through MafA. Nrd1-/-mice showed glucose intolerance and severely decreased GSIS. Islets isolated from Nrd1-/- mice exhibited reduced insulin content and impaired GSIS in vitro. Moreover, β-Cell-specific NRDcdeficient (Nrd1delb) mice showed a diabetic phenotype with markedly reduced GSIS. MafA was specifically downregulated in islets from Nrd1delb mice, whereas overexpression of NRDc upregulated MafA and insulin expression in INS832/13 cells. Chromatin immunoprecipitation assay revealed that NRDc is associated with Islet-1 in the enhancer region of MafA, where NRDc controls the recruitment of Islet-1 and MafA transcription. Our findings demonstrate that NRDc controls β-Cell function via regulation of the Islet-1-MafA pathway.