title: Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs.
abstract: BACKGROUND
  The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during the phase of rapid growth during infancy is required to guide the development of therapeutic applications. We studied the effects of GLP-2 in the neonatal pig to determine the potential effects of exogenous administration.
  
  
  METHODS
  Two day old newborn domestic piglets were treated with GLP-2 (1-33) at 40 μg/kg/day or control drug vehicle (saline), by subcutaneous injection, given in two doses per day, (n=6/group) for 42 days. Animals were weaned normally, over days 21-25. In the fifth week of life, they underwent neuro-developmental testing, and a pharmacokinetic study. On day 42, they were euthanized, and a complete necropsy performed, with histological assessment of tissues from all major organs.
  
  
  RESULTS
  GLP-2 treatment was well tolerated, one control animal died from unrelated causes. There were no effects of GLP-2 on weight gain, feed intake, or behavior. In the treated animals, GLP-2 levels were significantly elevated at 2400±600 pM while at necropsy, organ weights and histology were not affected except in the intestine, where the villus height in the small intestine and the crypt depth, throughout the small intestine and colon, were increased. Similarly, the rate of crypt cell proliferation (Ki-67 staining) was increased in the GLP-2 treated animals and the rate of apoptosis (Caspase-3) was decreased, the depth of the microvilli was increased and the expression of the mRNA for the GLP-2 receptor was decreased throughout the small and large intestine.
  
  
  CONCLUSIONS
  In these growing animals, exogenous GLP-2 at pharmacologic doses was well tolerated, with effects confined to the gastrointestinal tract.
authors.affiliation: Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada. Electronic address: sigalet@ucalgary.ca.
authors.forename: David L
authors.initials: DL
authors.lastname: Sigalet
authors.affiliation: Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: de Heuvel
authors.affiliation: Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Wallace
authors.affiliation: Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Estrella
authors.initials: E
authors.lastname: Bulloch
authors.affiliation: Dept of Pediatrics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Justine
authors.initials: J
authors.lastname: Turner
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wales
authors.affiliation: Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nation
authors.affiliation: Dept of Pediatrics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Wizzard
authors.affiliation: Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bollette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Meena
authors.initials: M
authors.lastname: Assad
authors.affiliation: Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004353:Drug Evaluation, Preclinical; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D053767:Glucagon-Like Peptide 2 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D034421:Sus scrofa; D014886:Weaning; D015430:Weight Gain / Q000187:drug effects
chemical_list: D005765:Gastrointestinal Agents; D053767:Glucagon-Like Peptide 2
keywords: Crypt cell proliferation; DPP-IV; Feeding behavior; Ki-67; Nutrient absorption