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

Soona Shin, John Le Lay, Logan J. Everett, Rana K Gupta, Kiran Rafiq, Klaus H. Kaestner

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 CrebloxP/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.

Original languageEnglish (US)
Pages (from-to)803-812
Number of pages10
JournalMolecular Metabolism
Volume3
Issue number8
DOIs
StatePublished - Nov 1 2014

Keywords

  • Apoptosis
  • CAMP signaling
  • CREB
  • Conditional gene ablation
  • Leucine zipper transcription factor
  • P21

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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