CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis

FASEB J. 2018 Mar;32(3):1566-1578. doi: 10.1096/fj.201700845R. Epub 2018 Jan 3.


Glucagon-like peptide 1 (GLP-1) is a major incretin that controls glucose homeostasis. The secretion of mature GLP-1 is regulated via GPCRs, including bile acid receptor G protein-coupled bile acid receptor 1, which uses cAMP signaling to enhance the exocytosis of GLP-1-containing vesicles. However, the role of cAMP-mediated transcription has not been clearly demonstrated to date. In this study, we explored the role of cAMP response element-binding protein/CREB-regulated transcription coactivator 2 (CREB/CRTC2)-dependent transcription on GLP-1 secretion in the L cells. We found that the reduced CREB/CRTC2 activity impaired the cAMP-dependent increase in GLP-1 secretion, whereas expression of constitutively active CRTC2 increased GLP-1 exocytosis from the L cells. Close investigation revealed that expression of not only proglucagon but also PC1/3, an endopeptidase for GLP-1 maturation, is transcriptionally regulated by CREB/CRTC2. Furthermore, expression of peroxisome proliferator-activating receptor coactivator 1 α is also reduced upon depletion of CRTC2, leading to the decreased expression of oxidative phosphorylation (OxPhos) genes, reduced ATP levels, and calcium concentrations in the L cells. Finally, we observed that intestine-specific CRTC2 knockout mice displayed reduced GLP-1 expression, leading to the lower plasma GLP-1 levels, impaired glucose tolerance, and decreased insulin-containing β cells in pancreatic islets. Our data show that the CREB/CRTC2-dependent transcriptional pathway is critical for regulating glucose homeostasis by controlling production of GLP-1 from the L cells at the level of transcription, maturation, and exocytosis.-Lee, J.-H., Wen, X., Cho, H., Koo, S.-H. CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis.

Keywords: cAMP signaling; glucose metabolism; intestinal L cells; transcriptional activator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Cell Line
  • Enteroendocrine Cells / metabolism*
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / genetics
  • Glucose / metabolism*
  • Homeostasis / physiology*
  • Mice
  • Mice, Knockout
  • Oxidative Phosphorylation
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology


  • Crtc2 protein, mouse
  • Transcription Factors
  • Glucagon-Like Peptide 1
  • Glucose
  • Calcium