The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist.

Research output: Contribution to journalJournal articleResearchpeer-review

Jesper Thulesen, Lotte Bjerre Knudsen, Bolette Hartmann, Sven Hastrup, Hannelouise Kissow, Palle Bekker Jeppesen, Cathrine Ørskov, Jens Juul Holst, Steen Seier Poulsen

The therapeutic potential of the intestinotrophic mediator glucagon-like peptide-2 (1-33) [GLP-2 (1-33)] has increased interest in the pharmacokinetics of the peptide. This study was undertaken to investigate whether the primary degradation product GLP-2 (3-33) interacts with the GLP-2 receptor. Functional (cAMP) and binding in vitro studies were carried out in cells expressing the transfected human GLP-2 receptor. Furthermore, a biologic response of GLP-2 (3-33) was tested in vivo. Mice were allocated to groups treated for 10 days (twice daily) with: (1) 5 microg GLP-2 (1-33), (2) 25 microg GLP-2 (3-33), (3) 5 microg GLP-2 (1-33)+100 microg GLP-2 (3-33), or (4) 5 microg GLP-2 (1-33)+500 microg GLP-2 (3-33). The intestine was investigated for growth changes. GLP-2 (3-33) bound to the GLP-2 receptor with a binding affinity of 7.5% of that of GLP-2 (1-33). cAMP accumulation was stimulated with an efficacy of 15% and a potency more than two orders of magnitude lower than that of GLP-2 (1-33). Increasing doses of GLP-2 (3-33) (10(-7)-10(-5) M) caused a shift to the right in the dose-response curve of GLP-2 (1-33). Treatment of mice with either GLP-2 (1-33) or (3-33) induced significant growth responses in both the small and large intestines, but the response induced by GLP-2 (3-33) was much smaller. Co-administration of 500 microg of GLP-2 (3-33) and 5 microg GLP-2 (1-33) resulted in a growth response that was smaller than that of 5 microg GLP-2 (1-33) alone. Consistent with the observed in vivo activities, our functional studies and binding data indicate that GLP-2 (3-33) acts as a partial agonist with potential competitive antagonistic properties on the GLP-2 receptor.
Original languageEnglish
JournalRegulatory Peptides
Issue number1
Pages (from-to)9-15
Number of pages6
Publication statusPublished - 2002

Bibliographical note

Keywords: Animals; Body Weight; Cell Line; Cricetinae; Cyclic AMP; Drug Administration Schedule; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Image Processing, Computer-Assisted; Injections, Subcutaneous; Intestine, Large; Intestine, Small; Mice; Mice, Inbred C57BL; Organ Size; Peptide Fragments; Protein Binding; Random Allocation; Receptors, Glucagon; Recombinant Proteins; Transfection

ID: 8418400