Secreted PDZD2 exerts an insulinotropic effect on INS-1E cells by a PKA-dependent mechanism

Secreted PDZD2 (sPDZD2) is a signaling molecule generated upon proteolytic processing of the multi-PDZ-containing protein PDZD2. Previous analysis of gene-trap mice deficient in the synthesis of full-length PDZD2, but not the secreted form, revealed a role of PDZD2 in the regulation of glucose-stimulated insulin secretion. Here, using the pancreatic INS-1E β cells as in vitro model, we showed that depletion of PDZD2/sPDZD2 by RNA interference suppressed the expression of β-cell genes Ins1, Glut2 and MafA whereas treatment with recombinant sPDZD2 rescued the suppressive effect. Similar to GLP-1, sPDZD2 stimulated intracellular cAMP levels, activated β-cell gene expression in a PKA-dependent manner and induced the phosphorylation and nuclear localization of PDX1. Depletion of PDX1 inhibited the sPDZD2 insulinotropic effect, which could also be demonstrated in mouse islets. In summary, our findings are consistent with sPDZD2 serving a signaling function in regulating β-cell gene expression. •PDZD2/sPDZD2 depletion suppresses pancreatic β cell gene expression.•Recombinant sPDZD2 rescues the suppressive effect.•sPDZD2 acts via a PKA-dependent mechanism to stimulate gene transcription.•sPDZD2 induces the phosphorylation and nuclear translocation of PDX1.•sPDZD2 enhances the insulinotropic effect of GLP-1.