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 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.
Thulesen
Jesper
J
Department of Medical Anatomy, Section B, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 N, Copenhagen, Denmark. J.Thulesen@mai.ku.dk
Knudsen
Lotte Bjerre
LB
Hartmann
Bolette
B
Hastrup
Sven
S
Kissow
Hannelouise
H
Jeppesen
Palle Bekker
PB
Ørskov
Cathrine
C
Holst
Jens Juul
JJ
Poulsen
Steen Seier
SS
D000818:Animals; D001835:Body Weight; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007279:Injections, Subcutaneous; D007420:Intestine, Large / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014162:Transfection
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; C451520:glucagon-like peptide-2 (3-33); D004763:Glucagon-Like Peptides; D000242:Cyclic AMP