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

TY - JOUR

T1 - Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets

AU - Burrin, Douglas G

AU - Stoll, Barbara

AU - Guan, Xinfu

AU - Cui, Liwei

AU - Chang, Xiaoyan

AU - Holst, Jens Juul

PY - 2005/1

Y1 - 2005/1

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Newborn

KW - Apoptosis

KW - Caspase 3

KW - Caspase 6

KW - Caspase Inhibitors

KW - Caspases

KW - Cell Count

KW - Cell Division

KW - Cell Survival

KW - Dose-Response Relationship, Drug

KW - Enzyme Precursors

KW - Glucagon-Like Peptide 2

KW - Glucagon-Like Peptides

KW - Glycogen Synthase Kinase 3

KW - Intestines

KW - Parenteral Nutrition, Total

KW - Peptides

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins c-akt

KW - Proto-Oncogene Proteins c-bcl-2

KW - Swine

U2 - 10.1210/en.2004-1119

DO - 10.1210/en.2004-1119

M3 - Journal article

C2 - 15486229

SN - 0013-7227

VL - 146

SP - 22

EP - 32

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

ER -