CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse β-cells

Objective: Glucagon-like peptide-1 (GLP-1) plays a major role in pancreatic beta-cell function and survival by increasing cytoplasmic cAMP levels, which are thought to affect transcription through activation of the basic leucine zipper (bZIP) transcription factor CREB. Here, we test CREB function in the adult beta-cell through inducible gene deletion. Methods: We employed cell type-specific and inducible gene ablation to determine CREB function in pancreatic beta-cells in mice. Results: By ablating CREB acutely in mature beta-cells in tamoxifen-treated Cred(loxP/loxP);Pdx1-CreERT2 mice, we show that CREB has little impact on beta-cell turnover, in contrast to what had been postulated previously. Rather, CREB is required for GLP-1 to elicit its full effects on stimulating glucose-induced insulin secretion and protection from cytokine-induced apoptosis. Mechanistically, we find that CREB regulates expression of the pro-apoptotic gene p21 (Cdknla) in beta-cells, thus demonstrating that CREB is essential to mediating this critical aspect of GLP-1 receptor signaling. Conclusions: In sum, our studies using conditional gene deletion put into question current notions about the importance of CREB in regulating beta-cell function and mass. However, we reveal an important role for CREB in the beta-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes. (C) 2014 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license