|Burrin, Douglas - Doug|
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/4/2004
Publication Date: 1/1/2005
Citation: Burrin, D.G., Stoll, B., Guan, X., Cui, L., Chang, X., Holst, J.J. 2005. Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets. Endocrinology. 146:22-32. Interpretive Summary: The growth and development of the gut is critically important for newborn infants, especially those born premature. These infants often cannot be fed by mouth and require intravenous nutrition, called total parenteral nutrition (TPN). Our previous studies showed that TPN causes impaired intestinal growth and development in neonatal piglets, which are used a model for human premature infants. In addition, we found that the poor intestinal growth during TPN is linked to reduced secretion of a key gut hormone called glucagon-like peptide 2 (GLP-2). Thus, in the current study, our aim was to determine whether exogenous infusion of GLP-2 at different dose could reverse the poor intestinal growth induced by TPN. We studied piglets given TPN or three dose of GLP-2 for seven days and then measured endpoints of intestinal growth. We found that intestinal growth was increased with increasing doses of GLP-2. However, we found that intestinal cell death was inhibited at all GLP-2 doses, but the growth of new cells was only increased at the highest GLP-2 dose. We also showed that GLP-2 inhibits intestinal cell death by stimulating key cell signals, protein kinase B and Bcl-2. This study provides important information regarding the dose of GLP-2 required to stimulate intestinal growth and may be useful for treatment of intestinal diseases in infants.
Technical Abstract: 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.