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  • Kizilkaya, Hüsün S.University of Copenhagen (author)

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • 2024
  • 14 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:21b7dcd9-415b-4175-865d-eb3b1a6aeed4
  • https://lup.lub.lu.se/record/21b7dcd9-415b-4175-865d-eb3b1a6aeed4URI
  • https://doi.org/10.1038/s42255-024-01061-4DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:238871982URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:158501173URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Sørensen, Kimmie V.Novo Nordisk Foundation Centre for Basic Metabolic Research (author)
  • Madsen, Jakob S.University of Copenhagen (author)
  • Lindquist, PeterUniversity of Copenhagen (author)
  • Douros, Jonathan D.Novo Nordisk, Inc., US (author)
  • Bork-Jensen, JetteNovo Nordisk Foundation Centre for Basic Metabolic Research (author)
  • Berghella, AlessandroUniversity of Copenhagen (author)
  • Gerlach, Peter A.University of Copenhagen (author)
  • Gasbjerg, Lærke S.University of Copenhagen (author)
  • Mokrosiński, JacekNovo Nordisk, Inc., US (author)
  • Mowery, Stephanie A.Novo Nordisk, Inc., US (author)
  • Knerr, Patrick J.Novo Nordisk, Inc., US (author)
  • Finan, BrianNovo Nordisk, Inc., US,Eli Lilly and Company (author)
  • Campbell, Jonathan E.Duke University (author)
  • D’Alessio, David A.Duke University (author)
  • Perez-Tilve, DiegoUniversity of Cincinnati College of Medicine (author)
  • Faas, FelixUniversity of Copenhagen (author)
  • Mathiasen, SigneUniversity of Copenhagen (author)
  • Rungby, JørgenUniversity of Copenhagen,Steno Diabetes Center Copenhagen (author)
  • Sørensen, Henrik T.Aarhus University,Boston University (author)
  • Vaag, AllanLund University,Lunds universitet,Translationell diabetesforskning,Forskargrupper vid Lunds universitet,Translational Diabetes Research,Lund University Research Groups,Steno Diabetes Center Copenhagen(Swepub:lu)med-ava (author)
  • Nielsen, Jens S.University of Southern Denmark,Odense University Hospital (author)
  • Holm, Jens ChristianUniversity of Copenhagen,Novo Nordisk Foundation Centre for Basic Metabolic Research,Holbæk Hospital (author)
  • Lauenborg, JeannetGentofte Hospital (author)
  • Damm, PeterCopenhagen University Hospital,University of Copenhagen (author)
  • Pedersen, OlufGentofte Hospital,Novo Nordisk Foundation Centre for Basic Metabolic Research,University of Copenhagen (author)
  • Linneberg, AllanUniversity of Copenhagen,Copenhagen University Hospital (author)
  • Hartmann, BoletteUniversity of Copenhagen (author)
  • Holst, Jens J.Novo Nordisk Foundation Centre for Basic Metabolic Research,University of Copenhagen (author)
  • Hansen, TorbenNovo Nordisk Foundation Centre for Basic Metabolic Research (author)
  • Wright, Shane C.Karolinska Institutet,Karolinska Institute (author)
  • Lauschke, Volker M.Karolinska Institutet,Karolinska Institute,Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology,University of Tübingen (author)
  • Grarup, NielsNovo Nordisk Foundation Centre for Basic Metabolic Research (author)
  • Hauser, Alexander S.University of Copenhagen (author)
  • Rosenkilde, Mette M.University of Copenhagen (author)
  • University of CopenhagenNovo Nordisk Foundation Centre for Basic Metabolic Research (creator_code:org_t)

Related titles

  • In:Nature Metabolism6:7, s. 1268-12812522-5812

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