title: The intestinal epithelial insulin-like growth factor-1 receptor links glucagon-like peptide-2 action to gut barrier function.
abstract: Glucagon-like peptide-2 (GLP-2) is an intestinal growth-promoting hormone used to treat short bowel syndrome. GLP-2 promotes intestinal growth through a mechanism that involves both IGF-1 and the intestinal-epithelial IGF-1 receptor (IE-IGF-1R). GLP-2 also enhances intestinal barrier function, but through an unknown mechanism. We therefore hypothesized that GLP-2-enhanced barrier function requires the IE-IGF-1R and is mediated through alterations in expression and localization of tight junction proteins. Conditional IE-IGF-1R-null and control mice were treated with vehicle or degradation-resistant Gly(2)-GLP-2 for 10 days; some animals also received irinotecan to induce enteritis. Mice were then examined for gastrointestinal permeability to 4-kDa fluorescein isothiocyanate-dextran, jejunal resistance using Ussing chambers, tight junction structure by electron microscopy, and expression and localization of tight junction proteins by immunoblot and immunohistofluorescence, respectively. GLP-2 treatment decreased permeability to 4-kDa fluorescein isothiocyanate-dextran and increased jejunal resistance (P <.05-.01), effects that were lost in IE-IGF-1R-null mice. Electron microscopy did not reveal major structural changes in the tight junctions in any group of animals. However, the tight junctional proteins claudin-3 and -7 were upregulated by GLP-2 in control (P <.05-.01) but not null mice, whereas IE-IGF-1R deletion induced a shift in occludin localization from apical to intracellular domains; no changes were observed in expression or distribution of claudin-15 and zona occludins-1. Finally, in irinotecan-induced enteritis, GLP-2 normalized epithelial barrier function in control (P < .05) but not knockout animals. In conclusion, the effects of GLP-2 on intestinal barrier function are dependent on the IE-IGF-1R and involve modulation of key components of the tight junctional complex.
authors.affiliation: Departments of Physiology (C.X.D., W.Z., C.S., K.J.R., P.L.B.), Pediatrics (T.G.), and Medicine (P.L.B.), University of Toronto, Toronto, Ontario M5S 1A8 Canada; Department of Paediatric Laboratory Medicine (C.A.), and Physiology and Experimental Medicine, Research Institute (T.G.), The Hospital for Sick Children, Toronto M5G 1X8, Canada; Centre National de la Recherche Scientifique (S.R.), Institut Curie, Paris, 75248 France; and Inserm (M.H.), Hôpital St-Antoine, Paris, 75005 France.
authors.forename: Charlotte X
authors.initials: CX
authors.lastname: Dong
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.forename: Chloe
authors.initials: C
authors.lastname: Solomon
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Rowland
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Tanja
authors.initials: T
authors.lastname: Gonska
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D062465:Claudin-3 / Q000378:metabolism; D057167:Claudins / Q000378:metabolism; D004751:Enteritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D062465:Claudin-3; D057167:Claudins; C507360:Cldn7 protein, mouse; D053767:Glucagon-Like Peptide 2; D017526:Receptor, IGF Type 1