Glucagon-like peptide-2 activates beta-catenin signaling in the mouse intestinal crypt: role of insulin-like growth factor-I

Endocrinology. 2008 Jan;149(1):291-301. doi: 10.1210/en.2007-0561. Epub 2007 Sep 20.


Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because beta-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly(2)-GLP-2 or LR(3)-IGF-I (positive control) for 0.5-4 h. Nuclear translocation of beta-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3beta and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased beta-catenin nuclear translocation in non-Paneth crypt cells by 72 +/- 17% (P < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 +/- 20 and 376 +/- 170%, respectively (P < 0.05-0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates beta-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in beta-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fasting / metabolism
  • Female
  • Glucagon-Like Peptide 2 / pharmacology*
  • High Mobility Group Proteins / metabolism
  • Insulin-Like Growth Factor I / analogs & derivatives
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / ultrastructure
  • Ki-67 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvilli
  • Models, Biological
  • Oncogene Protein v-akt / metabolism
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • SOX9 Transcription Factor
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • beta Catenin / metabolism*


  • Glucagon-Like Peptide 2
  • High Mobility Group Proteins
  • Ki-67 Antigen
  • LR(3)IGF-I
  • Mki67 protein, mouse
  • NVP-AEW541
  • Pyrimidines
  • Pyrroles
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Transcription Factors
  • beta Catenin
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Oncogene Protein v-akt