👤 Esther Karen Tordrup

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates bone remodeling postprandially. Species variations complicate the development of long-acting agonists with similar effects on rodent and human GIP receptors (GIPR). We created a series of long-acting molecules suitable for rat studies based on human GIP, stabilized with Aib insertion in position 2, lipidations in the middle region (compounds 1-4: positions 14/16/17/20) or the C-terminus (compound 5: position 40), and elongation with an exendin-4 tail in the C-terminus (Cex). The compounds were tested in vitro on the human and rat GIPR for cAMP accumulation, beta-arrestin recruitment and internalization. Pharmacokinetic profiling in rats was completed for two compounds, and one was selected for bone remodeling studies in rats (measurements of C-terminal telopeptide (CTX) and procollagen type 1 N-propeptide). All five compounds retained the potency and efficacy of native (human and rat) GIP in cAMP accumulation and arrestin recruitment on human and rat GIPR with no differences in relative activities from native GIP. Only compound 3 induced internalization like species-matched GIP on respective receptors and was chosen for in vivo assessments in rats. Mean T Show less

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus. The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta-arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C-terminal tails were studied in parallel. The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for G Desensitization of the human GIPR is dependent on the C-terminal tail. The species-dependent functionality of the C-terminal tail and the different species-dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR-targeting therapeutic compounds. This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc. Show less