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

Regul Pept. 2002 Jan 15;103(1):9-15. doi: 10.1016/s0167-0115(01)00316-0.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Cell Line
  • Cricetinae
  • Cyclic AMP / metabolism
  • Drug Administration Schedule
  • Female
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides
  • Humans
  • Image Processing, Computer-Assisted
  • Injections, Subcutaneous
  • Intestine, Large / cytology
  • Intestine, Large / drug effects
  • Intestine, Large / growth & development*
  • Intestine, Small / cytology
  • Intestine, Small / drug effects
  • Intestine, Small / growth & development*
  • Mice
  • Mice, Inbred C57BL
  • Organ Size / drug effects
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Protein Binding
  • Random Allocation
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / metabolism
  • Transfection

Substances

  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Receptors, Glucagon
  • Recombinant Proteins
  • glucagon-like peptide-2 (3-33)
  • Glucagon-Like Peptides
  • Cyclic AMP