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

Background and PurposeSpecific, 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.Experimental ApproachTransiently transfected COS‐7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using 125I‐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.Key ResultsHuman (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (E max) 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 and ImplicationsWhen 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.

N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor

“…On the human GIP receptor, we observed GIP(6-30)NH 2 to have the lowest affinity of the truncated GIP (1-30)NH 2 variants and poor antagonistic properties. This is not in line with previous studies, but the pharmacological differences between rodent and human GIP systems are not yet clarified (Sparre-Ulrich et al, 2015). In contrast to the findings for GIP(6-30)NH 2 , our results of the human GIP(7-30)NH 2 are in line with previous studies using the porcine GIP(7-30)NH 2 on the rat GIP receptor (Tseng et al, 1996;Gelling et al, 1997;Tseng et al, 1999;Hinke et al, 2001).…”

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

“…Such a scenario is highly unlikely, however, as our data shows that the GLP-1R-overexpressing SH-hGLP-1R#9 cell line dramatically enhances the neurotrophic and neuroprotective effects of twincretin. Additionally, although one recent publication suggests that human (Pro3)GIP may actually be a full agonist of the human GIPR, rather than an antagonist (Sparre-Ulrich et al, 2016), several results obtained in the current study (data not shown), in addition to the results displayed in Fig. 1c, suggest that (Pro3)GIP is in fact an antagonist of the human GIPR.…”

A novel GIP analogue, ZP4165, enhances glucagon‐like peptide‐1‐induced body weight loss and improves glycaemic control in rodents

“…Similarly to the present study, a statistically significant difference was only found vs mono‐GIP receptor agonist treatment. It is not yet clear whether this presumably enhanced effect of combined GIP receptor and GLP‐1 receptor activation can be translated to human diabetes, particularly because of species differences in GIP sensitivity and species differences at the GIP receptor level . An additive insulinotropic effect has been demonstrated in an infusion study in healthy participants, but not in patients with T2DM .…”