title: Loss of glucagon-like peptide-2-induced proliferation following intestinal epithelial insulin-like growth factor-1-receptor deletion.
abstract: OBJECTIVE
  Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes growth of the gastrointestinal tract. Although insulin-like growth factor (IGF)-1 and the IGF-1 receptor (IGF-1R) are required for GLP-2-induced proliferation of crypt cells, little is known about localization of the IGF-1R which mediates the intestinotropic actions of GLP-2.
  
  
  METHODS
  We examined intestinal growth and proliferative responses in mice with conditional deletion of IGF-1R from intestinal epithelial cells (IE-igf1rKO) after acute administration (30-90 min) of GLP-2, in response to 24-hour fasting and re-feeding (to induce GLP-2-dependent adaptation), and after chronic exposure (10 days) to GLP-2.
  
  
  RESULTS
  IE-igf1rKO mice had normal small intestinal weight, morphometric parameters, proliferative indices, and distribution of differentiated epithelial cell lineages. Acute administration of GLP-2 increased nuclear translocation of β-catenin in non-Paneth crypt cells and stimulated the crypt-cell proliferative marker c-Myc in control but not IE-igf1rKO mice. Small intestinal weight, crypt depth, villus height, and crypt-cell proliferation were decreased in control and IE-igf1rKO mice after 24-hour fasting. Although re-feeding control mice restored all of these parameters, re-fed IE-igf1rKO mice had reductions in adaptive regrowth of the villi and crypt-cell proliferation. Control mice that were given chronic GLP-2 had increases in small intestinal weight, mucosal cross-sectional area, crypt depth, villus height, and crypt-cell proliferation. However, the GLP-2-induced increase in crypt-cell proliferation was not observed in IE-igf1rKO mice, and growth of the crypt-villus axis was reduced.
  
  
  CONCLUSIONS
  The proliferative responses of the intestinal epithelium to exogenous GLP-2 administration and conditions of GLP-2-dependent adaptive re-growth require the intestinal epithelial IGF-1R.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Rowland
authors.forename: Shivangi
authors.initials: S
authors.lastname: Trivedi
authors.forename: Daiyoon
authors.initials: D
authors.lastname: Lee
authors.forename: Ken
authors.initials: K
authors.lastname: Wan
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D053767:Glucagon-Like Peptide 2; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1