Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets
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Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets. / Burrin, Douglas G; Stoll, Barbara; Guan, Xinfu; Cui, Liwei; Chang, Xiaoyan; Holst, Jens Juul.
In: Endocrinology, Vol. 146, No. 1, 01.2005, p. 22-32.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 146
SP - 22
EP - 32
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0013-7227
IS - 1
ER -
ID: 132054108