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

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Douglas G Burrin, Barbara Stoll, Xinfu Guan, Liwei Cui, Xiaoyan Chang, Jens Juul Holst

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.

Original languageEnglish
JournalEndocrinology
Volume146
Issue number1
Pages (from-to)22-32
Number of pages11
ISSN0013-7227
DOIs
Publication statusPublished - Jan 2005

    Research areas

  • Animals, Animals, Newborn, Apoptosis, Caspase 3, Caspase 6, Caspase Inhibitors, Caspases, Cell Count, Cell Division, Cell Survival, Dose-Response Relationship, Drug, Enzyme Precursors, Glucagon-Like Peptide 2, Glucagon-Like Peptides, Glycogen Synthase Kinase 3, Intestines, Parenteral Nutrition, Total, Peptides, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Swine

ID: 132054108