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

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 μg GLP-2 (1–33), (2) 25 μg GLP-2 (3–33), (3) 5 μg GLP-2 (1–33)+100 μg GLP-2 (3–33), or (4) 5 μg GLP-2 (1–33)+500 μg 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 μg of GLP-2 (3–33) and 5 μg GLP-2 (1–33) resulted in a growth response that was smaller than that of 5 μg 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.