GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations.
Glucose-dependent insulinotropic polypeptide [GIP-(1-42)] is degraded by dipeptidyl peptidase IV (DPP IV), forming GIP-(3-42). In mice, high concentrations of synthetic GIP-(3-42) may function as a GIP receptor antagonist, but it is unclear whether this occurs at physiological concentrations. In COS-7 cells transiently transfected with the human GIP receptor, GIP-(1-42) and -(3-42) bind with affinities (IC(50)) of 5.2 and 22 nM, respectively. GIP-(1-42) was a potent agonist, stimulating cAMP accumulation (EC(50), 13.5 pM); GIP-(3-42) alone had no effect. When incubated together with native GIP, GIP-(3-42) behaved as a weak antagonist (IC(50), 92 and 731 nM for inhibition of cAMP accumulation elicited by 10 pM and 1 nM native GIP, respectively). In the isolated perfused rat pancreas, GIP-(3-42) alone had no effect on insulin output and only reduced the response to GIP (1 nM) when coinfused in >50-fold molar excess (IC(50), 138 nM). The ability of GIP-(3-42) to affect the antihyperglycemic or insulinotropic actions of GIP-(1-42) was examined in chloralose-anesthetized pigs given intravenous glucose. Endogenous DPP IV activity was inhibited to reduce degradation of the infused GIP-(1-42), which was infused alone and together with GIP-(3-42), at rates sufficient to mimic postprandial concentrations of each peptide. Glucose, insulin, and glucagon responses were identical irrespective of whether GIP-(1-42) was infused alone or together with GIP-(3-42). We conclude that, although GIP-(3-42) can weakly antagonize cAMP accumulation and insulin output in vitro, it does not behave as a physiological antagonist in vivo.
Deacon
Carolyn F
CF
Dept. of Medical Physiology, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. deacon@mfi.ku.dk
Plamboeck
Astrid
A
Rosenkilde
Mette M
MM
de Heer
Jocelyn
J
Holst
Jens J
JJ
D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010477:Perfusion; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D013552:Swine; D014633:Valine / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D010446:Peptide Fragments; D011758:Pyrroles; D011964:Receptors, Gastrointestinal Hormone; C112092:valine-pyrrolidide; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4; D014633:Valine