Nardilysin regulates Slc2a2 expression via an ISLET1-dependent enhancer mechanism in pancreatic β-cells.

Abstract

GLUT2 (Slc2a2) is a key glucose transporter in pancreatic β-cells, and its reduced expression is closely linked to defective glucose-stimulated insulin secretion (GSIS) and diabetes. We previously reported that pancreatic β-cell-specific nardilysin (NRDC)-deficient mice (BetaKO) exhibit a severe diabetic phenotype with defective GSIS and reduced Slc2a2 expression in islets. However, because BetaKO mice also showed reduced MafA, a key upstream regulator of Slc2a2, along with an increased α-cell/β-cell ratio and other secondary changes that could influence GLUT2 levels, the mechanism by which NRDC regulates Slc2a2 transcription remained unclear. Here, we demonstrate that NRDC controls Slc2a2 expression in a β-cell-autonomous and MafA-independent manner. By integrating publicly available ATAC-seq and ChIP-seq datasets, we identified four active enhancer regions around the murine Slc2a2 locus, two of which are evolutionarily conserved in human islets. Luciferase assays in MIN6 β-cells revealed that NRDC selectively controls the activity of a conserved enhancer located 39 kb downstream of the Slc2a2 transcription start site. Chromatin immunoprecipitation (ChIP) and re-ChIP assays further revealed that, in MIN6 cells, NRDC occupies this enhancer and is required for efficient recruitment of ISLET1, a transcription factor upstream of Slc2a2. These findings suggest that NRDC contributes to Slc2a2 regulation in addition to MafA, highlighting multifaceted roles of NRDC in pancreatic β-cell gene regulation.