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

  • Douglas G. Burrin
    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
  • Barbara Stoll
    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
  • Xinfu Guan
    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
  • Liwei Cui
    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
  • Xiaoyan Chang
    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
  • Jens J. Holst
    Department of Medical Physiology (J.J.H.), University of Copenhagen, DK-2200 Copenhagen, Denmark

抄録

<jats:p>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.</jats:p>

収録刊行物

  • Endocrinology

    Endocrinology 146 (1), 22-32, 2005-01-01

    The Endocrine Society

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