Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets

Endocrinology. 2005 Jan;146(1):22-32. doi: 10.1210/en.2004-1119. Epub 2004 Oct 14.

Abstract

Glucagon-like peptide 2 (GLP-2) is a gut hormone that stimulates mucosal growth in total parenteral nutrition (TPN)-fed piglets; however, the dose-dependent effects on apoptosis, cell proliferation, and protein synthesis are unknown. We studied 38 TPN-fed neonatal piglets infused iv with either saline or GLP-2 at three rates (2.5, 5.0, and 10.0 nmol.kg(-1).d(-1)) for 7 d. Plasma GLP-2 concentrations ranged from 177 +/- 27 to 692 +/- 85 pM in the low- and high-infusion groups, respectively. GLP-2 infusion dose-dependently increased small intestinal weight, DNA and protein content, and villus height; however, stomach protein synthesis was decreased by GLP-2. Intestinal crypt and villus apoptosis decreased and crypt cell number increased linearly with GLP-2 infusion rates, whereas cell proliferation and protein synthesis were stimulated only at the high GLP-2 dose. The intestinal activities of caspase-3 and -6 and active caspase-3 abundance decreased, yet procaspase-3 abundance increased markedly with increasing infusion rate and plasma concentration of GLP-2. The GLP-2-dose-dependent suppression of intestinal apoptosis and caspase-3 activity was associated with increased protein kinase B and glycogen-synthase kinase-3 phosphorylation, yet the expression phosphatidylinositol 3-kinase was unaffected by GLP-2. Intestinal endothelial nitric oxide synthase mRNA and protein expression was increased, but only at the high GLP-2 dose. We conclude that the stimulation of intestinal epithelial survival is concentration dependent at physiological GLP-2 concentrations; however, induction of cell proliferation and protein synthesis is a pharmacological response. Moreover, we show that GLP-2 stimulates intestinal cell survival and proliferation in association with induction of protein kinase B and glycogen-synthase kinase-3 phosphorylation and Bcl-2 expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Caspase 3
  • Caspase 6
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Count
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Precursors / metabolism
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptides
  • Glycogen Synthase Kinase 3 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Intestines / drug effects
  • Intestines / physiology*
  • Parenteral Nutrition, Total
  • Peptides / administration & dosage*
  • Peptides / blood
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Swine

Substances

  • Caspase Inhibitors
  • Enzyme Precursors
  • Glucagon-Like Peptide 2
  • Peptides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Glucagon-Like Peptides
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Caspase 3
  • Caspase 6
  • Caspases