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Glucagon-Like Peptide 2 Dose-Dependently Activates Intestinal Cell Survival and Proliferation in Neonatal Piglets

United States Department of Agriculture, Agricultural Research Service, Children’s Nutrition Research Center (D.G.B., B.S., X.G., L.C., X.C.), Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; and Department of Medical Physiology (J.J.H.), University of Copenhagen, DK-2200 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Douglas G. Burrin, Ph.D., Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030. E-mail: dburrin{at}bcm.tmc.edu.

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.

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