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Endocrinology. 2014 Feb;155(2):370-9. doi: 10.1210/en.2013-1871. Epub 2013 Nov 21.

The intestinal epithelial insulin-like growth factor-1 receptor links glucagon-like peptide-2 action to gut barrier function.

Author information

1
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.

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.

PMID:
24265452
DOI:
10.1210/en.2013-1871
[Indexed for MEDLINE]

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