PMID- 31299132
OWN - NLM
STAT- MEDLINE
DCOM- 20211004
LR  - 20211004
IS  - 1742-7843 (Electronic)
IS  - 1742-7835 (Print)
IS  - 1742-7835 (Linking)
VI  - 126 Suppl 6
IP  - Suppl 6
DP  - 2020 Jun
TI  - 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.
PG  - 122-132
LID - 10.1111/bcpt.13289 [doi]
AB  - In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of 
      the GIP system is desensitized, whereas this is not the case for the GLP-1 
      system. This has raised an interesting discussion of whether GIP agonists or 
      antagonists are most suitable for future treatment of T2DM together with 
      GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, 
      [E354Q], display lower bone mineral density, increased bone fracture risk and 
      slightly increased blood glucose. Here, we present an in-depth molecular 
      pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested 
      similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. 
      This was supported by homologous competition binding in COS-7 cells revealing 
      GIPR wt-like affinities of GIP(1-42) with K(d) values of ~2 nmol/L and wt-like 
      agonist association rates (K(on) ). In contrast, the dissociation rates (K(off) ) 
      were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. 
      Moreover, in G(alphas) 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 beta-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.
CI  - (c) 2019 The Authors. Basic & Clinical Pharmacology & Toxicology published by John 
      Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT 
      (former Nordic Pharmacological Society).
FAU - Gabe, Maria Buur Nordskov
AU  - Gabe MBN
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - van der Velden, Wijnand J C
AU  - van der Velden WJC
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Gadgaard, Sarina
AU  - Gadgaard S
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Smit, Florent Xavier
AU  - Smit FX
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Hartmann, Bolette
AU  - Hartmann B
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Brauner-Osborne, Hans
AU  - Brauner-Osborne H
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Rosenkilde, Mette Marie
AU  - Rosenkilde MM
AD  - Department of Biomedical Sciences, Faculty of Health and Medical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
LA  - eng
GR  - Carlsberg Foundation/
PT  - Journal Article
DEP - 20190819
PL  - England
TA  - Basic Clin Pharmacol Toxicol
JT  - Basic & clinical pharmacology & toxicology
JID - 101208422
RN  - 0 (beta-Arrestins)
RN  - 59392-49-3 (Gastric Inhibitory Polypeptide)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Gastric Inhibitory Polypeptide/agonists/chemistry/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Molecular Structure
MH  - Signal Transduction
MH  - beta-Arrestins
PMC - PMC7317972
OTO - NOTNLM
OT  - GIP receptor
OT  - GIPR-[E354Q]
OT  - internalization
OT  - signalling
COIS- MBNG, WJCvdV, SG, FXS, BH, HBO, and MMR declare that they have no conflict of 
      interest.
EDAT- 2019/07/13 06:00
MHDA- 2021/10/05 06:00
PMCR- 2020/06/26
CRDT- 2019/07/13 06:00
PHST- 2019/05/20 00:00 [received]
PHST- 2019/07/03 00:00 [accepted]
PHST- 2019/07/13 06:00 [pubmed]
PHST- 2021/10/05 06:00 [medline]
PHST- 2019/07/13 06:00 [entrez]
PHST- 2020/06/26 00:00 [pmc-release]
AID - BCPT13289 [pii]
AID - 10.1111/bcpt.13289 [doi]
PST - ppublish
SO  - Basic Clin Pharmacol Toxicol. 2020 Jun;126 Suppl 6(Suppl 6):122-132. doi: 
      10.1111/bcpt.13289. Epub 2019 Aug 19.