David L Sigalet1, Elaine de Heuvel2, Laurie Wallace2, Estrella Bulloch2, Justine Turner3, Paul W Wales4, Patrick Nation5, Pamela R Wizzard3, Bollette Hartmann6, Meena Assad2, Jens J Holst6. 1. 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. 2. Gastrointestinal Research Group, Snyder Institute of Infection, Immunity and Inflammation, Dept of Surgery, Faculty of Medicine, University of Calgary, Calgary, AB, Canada. 3. Dept of Pediatrics, University of Alberta, Edmonton, AB, Canada. 4. Department of Surgery, University of Toronto, Toronto, Canada. 5. Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada. 6. Panum Institute, University of Copenhagen, Copenhagen, Denmark.
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.
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: Sen Lin; Barbara Stoll; Jason Robinson; Jose J Pastor; Juan C Marini; Ignacio R Ipharraguerre; Bolette Hartmann; Jens J Holst; Stephanie Cruz; Patricio Lau; Oluyinka Olutoye; Zhengfeng Fang; Douglas G Burrin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2019-03-28 Impact factor: 4.052
Authors: Per T Sangild; Denise M Ney; David L Sigalet; Andreas Vegge; Douglas Burrin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2014-10-23 Impact factor: 4.052
Authors: Nuria de Diego-Cabero; Alessandro Mereu; David Menoyo; Jens J Holst; Ignacio R Ipharraguerre Journal: BMC Vet Res Date: 2015-05-14 Impact factor: 2.741