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Submitted on August 24, 2004
Accepted on October 4, 2004
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; Department of Medical Physiology, University of Copenhagen, DK-2200 Copenhagen, Denmark
* To whom correspondence should be addressed. E-mail: dburrin{at}bcm.tmc.edu.
GLP-2 is a gut hormone that stimulates mucosal growth in TPN-fed piglets, however the dose-dependent effects on apoptosis, cell proliferation and protein synthesis are unknown. We studied thirty-eight TPN-fed neonatal piglets infused intravenously with either saline, or GLP-2 at three rates (2.5, 5.0, and 10.0 nmol•kg-1) for 7 days. 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 only stimulated 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 PKB and GSK-3 phosphorylation, yet the expression PI3-kinase was unaffected by GLP-2. Intestinal eNOS 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 physiologic GLP-2 concentrations; however, induction of cell proliferation and protein synthesis is a pharmacologic response. Moreover, we show that GLP-2 stimulates intestinal cell survival and proliferation in association with induction of PKB and GSK-3 phosphorylation and Bcl-2 expression.
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