title: Species-specific action of (Pro3)GIP - a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors.
abstract: OBJECTIVE
  Specific, high potency receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent, insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist, (Pro3)GIP, and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system.
  
  
  METHODS
  Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using (125) I-human GIP. Using isolated perfused pancreata both from wild type and GIP receptor-deficient rodents, insulin-releasing, glucagon-releasing and somatostatin-releasing properties in response to species-specific GIP and (Pro3)GIP analogues were evaluated.
  
  
  RESULTS
  Human (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (Emax ) for cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata in the presence of 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion, corresponding to the partial agonist activities observed in cAMP production.
  
  
  CONCLUSIONS
  When evaluating new compounds, it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models, human GIP is a comparatively weak partial agonist. Human (Pro3)GIP was not an antagonist at human GIP receptors, so there is still a need for a potent antagonist in order to elucidate the physiology of human GIP.
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.|NNF Center for Basic Metabolic Research, Copenhagen, Denmark.
authors.forename: A H
authors.initials: AH
authors.lastname: Sparre-Ulrich
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.|NNF Center for Basic Metabolic Research, Copenhagen, Denmark.|Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: L S
authors.initials: LS
authors.lastname: Hansen
authors.affiliation: NNF Center for Basic Metabolic Research, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Svendsen
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: F K
authors.initials: FK
authors.lastname: Knop
authors.affiliation: NNF Center for Basic Metabolic Research, Copenhagen, Denmark.|Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: NNF Center for Basic Metabolic Research, Copenhagen, Denmark.|Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M M
authors.initials: MM
authors.lastname: Rosenkilde
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000378:metabolism; D013045:Species Specificity
chemical_list: D007328:Insulin; D007457:Iodine Radioisotopes; D011964:Receptors, Gastrointestinal Hormone; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP