title: Agonism and antagonism at the insulin receptor.
abstract: Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1-10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints ((3)H-thymidine incorporation), and not on metabolic endpoints ((14)C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity ((3)H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B'29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.
authors.affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. lsek@novonordisk.com
authors.forename: Louise
authors.initials: L
authors.lastname: Knudsen
authors.forename: Bo Falck
authors.initials: BF
authors.lastname: Hansen
authors.forename: Pia
authors.initials: P
authors.lastname: Jensen
authors.forename: Thomas Åskov
authors.initials: TÅ
authors.lastname: Pedersen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Vestergaard
authors.forename: Lauge
authors.initials: L
authors.lastname: Schäffer
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.forename: Martin B
authors.initials: MB
authors.lastname: Oleksiewicz
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Kiselyov
authors.forename: Pierre
authors.initials: P
authors.lastname: De Meyts
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D010455:Peptides; C532752:S961 peptide; C034329:insulin dimers; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose