GIP(3-30)NH is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release.

Alternative processing of the precursor protein pro-GIP results in endogenously produced GIP(1-30)NH, that by DPP-4 cleavage in vivo results in the metabolite GIP(3-30)NH. We showed previously that GIP(3-30)NH is a high affinity antagonist of the human GIPR in vitro. Here we determine whether it is suitable for studies of GIP physiology in rats since effects of GIP agonists and antagonists are strictly species-dependent. Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation or assayed in competition binding using human I-GIP(1-42) as radioligand. In isolated perfused rat pancreata, insulin, glucagon, and somatostatin-releasing properties were evaluated. Competition binding demonstrated that on the rat GIP receptor (GIPR), rat GIP(3-30)NH bound with high affinity (K of 17nM), in contrast to human GIP(3-30)NH (K of 250nM). In cAMP studies, rat GIP(3-30)NH inhibited GIP(1-42)-induced rat GIPR activation and schild-plot analysis showed competitive antagonism with a pA of 13nM and a slope of 0.9±0.09. Alone, rat GIP(3-30)NH displayed weak, low-potent partial agonistic properties (EC>1μM) with an efficacy of 9.4% at 0.32μM compared to GIP(1-42). In perfused rat pancreata, rat GIP(3-30)NH efficiently antagonized rat GIP(1-42)-induced insulin, somatostatin, and glucagon secretion. In summary, rat GIP(3-30)NH is a high affinity competitive GIPR antagonist and effectively antagonizes GIP-mediated G protein-signaling as well as pancreatic hormone release, while human GIP(3-30)NH, despite a difference of only one amino acid between the two (arginine in position 18 in rat GIP(3-30)NH; histidine in human), is unsuitable in the rat system. This underlines the importance of species differences in the GIP system, and the limitations of testing human peptides in rodent systems.