Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant E354Q facilitate receptor desensitization and long‐term impairment of the GIP system

signalling (cAMP production) GIP(1-42) was ~2-fold more potent and more efficacious on GIPR-E354Q compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of β-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for E354Q. Together with the previously described impaired recycling of E354Q, our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for E354Q carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.