title: Mucosal adaptation to enteral nutrients is dependent on the physiologic actions of glucagon-like peptide-2 in mice.
abstract: OBJECTIVE
  Our understanding of the intestinotropic actions of glucagon-like peptide-2 (GLP-2)(1-33) is based on pharmacologic studies involving exogenous administration. However, the physiologic role of GLP-2 in mucosal growth and adaptation to nutritional stimulation remains poorly understood.
  
  
  METHODS
  The properties of GLP-2(3-33), a GLP-2(1-33) metabolite, were determined in baby-hamster kidney cells transfected with the mouse GLP-2 receptor complementary DNA and in isolated murine intestinal muscle strips. To investigate the role of endogenous GLP-2(1-33) in gut adaptation, GLP-2(3-33) was administered to mice that were re-fed for 24 hours after 24 hours of fasting, and the small intestine was analyzed. GLP-2(3-33) also was injected into rats for analysis of circulating GLP-2(1-33) levels.
  
  
  RESULTS
  GLP-2(3-33) antagonized the actions of GLP-2(1-33) in vitro and ex vivo. Fasting mice exhibited small intestinal atrophy (37% +/- 1% decrease in small intestinal weight, 19% +/- 2% decrease in crypt-villus height, and 99% +/- 35% increase in villus apoptosis, P < .05-.01). Adaptive growth in re-fed mice restored all these parameters, as well as crypt-cell proliferation, to normal control levels (P < .05 vs. fasting); these adaptive changes were prevented partially or completely by co-administration of GLP-2(3-33) to refeeding mice (by 32% +/- 19% to 103% +/- 15%, P < .05-.01 vs re-fed mice). Exogenous GLP-2(3-33) did not affect endogenous GLP-2(1-33) levels.
  
  
  CONCLUSIONS
  These data show that endogenous GLP-2 regulates the intestinotropic response in re-fed mice through modulation of crypt-cell proliferation and villus apoptosis. GLP-2 is therefore a physiologic regulator of the dynamic adaptation of the gut mucosal epithelium in response to luminal nutrients.
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Shin
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: Angelo
authors.initials: A
authors.lastname: Izzo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001835:Body Weight; D002455:Cell Division / Q000502:physiology; D003001:Cloning, Molecular; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D005934:Glucagon / Q000235:genetics; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D007421:Intestine, Small / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009929:Organ Size; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D052336:Proglucagon; D011498:Protein Precursors / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; C451520:glucagon-like peptide-2 (3-33); D052336:Proglucagon; D004763:Glucagon-Like Peptides; D005934:Glucagon