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Ontogeny of the Glucagon-Like Peptide-2 Receptor Axis in the Developing Rat Intestine¹

Departments of Physiology (I.I., A.M., L.D., P.L.B.) and Medicine (J.L., B.Y., P.L.B., D.J.D.), Toronto General Hospital, Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. Daniel J. Drucker, Toronto General Hospital, 101 College Street, CCRW3–838, Toronto, Ontario, Canada M5G2C4. E-mail: d.drucker{at}utoronto.ca

Glucagon-like peptide-2 (GLP-2) is secreted by enteroendocrine cells in the small and large intestines and exerts intestinotropic effects in the gastrointestinal mucosal epithelium of the adult rodent. The actions of GLP-2 are mediated by the GLP-2 receptor, a new member of the G protein-coupled receptor superfamily. To ascertain whether the GLP-2/GLP-2 receptor axis is expressed and functional in the developing intestine, we have studied the synthesis of GLP-2 and the expression of the GLP-2 receptor (GLP-2R) in the fetal and neonatal rat gut. GLP-2 immunoreactivity (GLP-2-IR) was detected in the fetal rat intestine, and fetal rat intestinal cell cultures secreted correctly processed GLP-2^1–33 into the medium. High levels of GLP-2^1–33 were also detected in the circulation of 13-day-old neonatal rats (P < 0.001 vs. adult). Analysis of GLP-2 receptor expression by RT-PCR demonstrated GLP-2R messenger RNA transcripts in fetal intestine and in neonatal stomach, jejunum, ileum, and colon. The levels of GLP-2R messenger RNA transcripts were comparatively higher in the fetal and neonatal intestine (P < 0.05–001 vs. adult) and declined to adult levels by postnatal day 21. Subcutaneous administration of a degradation-resistant GLP-2 analog, h[Gly2]-GLP-2 once daily for 10 days increased stomach (0.009 ± 0.0003 vs. 0.007 ± 0.002 g/g body mass, h[Gly2]-GLP-2-treated vs. controls; P < 0.05) and small bowel weight (0.043 ± 0.0037 vs. 0.031 ± 0.0030 g/g body mass; P < 0.05). h[Gly2]-GLP-2 also increased both small (2.4 ± 0.05 vs. 1.8 ± 0.17 cm/g body mass; P < 0.05) and large bowel length (0.32 ± 0.01 vs. 0.25 ± 0.02 cm/g body mass, h[Gly2]-GLP-2-treated vs. saline-treated controls, respectively; P < 0.05) in neonatal rats. These findings demonstrate that both components of the GLP-2/GLP-2 receptor axis are expressed in the fetal and neonatal intestine. The ontogenic regulation and functional integrity of this axis raises the possibility that GLP-2 may play a role in the development and/or maturation of the developing rat intestine.

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