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

Journal Article (Journal Article)

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) plays a major role in pancreatic β-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 β-cell through inducible gene deletion. METHODS: We employed cell type-specific and inducible gene ablation to determine CREB function in pancreatic β-cells in mice. RESULTS: By ablating CREB acutely in mature β-cells in tamoxifen-treated Creb (loxP/loxP);Pdx1-CreERT2 mice, we show that CREB has little impact on β-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 (Cdkn1a) in β-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 β-cell function and mass. However, we reveal an important role for CREB in the β-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes.

Full Text

Duke Authors

Cited Authors

  • Shin, S; Le Lay, J; Everett, LJ; Gupta, R; Rafiq, K; Kaestner, KH

Published Date

  • November 2014

Published In

Volume / Issue

  • 3 / 8

Start / End Page

  • 803 - 812

PubMed ID

  • 25379405

Pubmed Central ID

  • PMC4216406

International Standard Serial Number (ISSN)

  • 2212-8778

Digital Object Identifier (DOI)

  • 10.1016/j.molmet.2014.08.001


  • eng

Conference Location

  • Germany