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Characterization of...
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes
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- Kizilkaya, Hüsün S. (author)
- University of Copenhagen
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- Sørensen, Kimmie V. (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Madsen, Jakob S. (author)
- University of Copenhagen
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- Lindquist, Peter (author)
- University of Copenhagen
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- Douros, Jonathan D. (author)
- Novo Nordisk, Inc., US
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- Bork-Jensen, Jette (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Berghella, Alessandro (author)
- University of Copenhagen
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- Gerlach, Peter A. (author)
- University of Copenhagen
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- Gasbjerg, Lærke S. (author)
- University of Copenhagen
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- Mokrosiński, Jacek (author)
- Novo Nordisk, Inc., US
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- Mowery, Stephanie A. (author)
- Novo Nordisk, Inc., US
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- Knerr, Patrick J. (author)
- Novo Nordisk, Inc., US
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- Finan, Brian (author)
- Novo Nordisk, Inc., US,Eli Lilly and Company
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- Campbell, Jonathan E. (author)
- Duke University
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- D’Alessio, David A. (author)
- Duke University
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- Perez-Tilve, Diego (author)
- University of Cincinnati College of Medicine
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- Faas, Felix (author)
- University of Copenhagen
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- Mathiasen, Signe (author)
- University of Copenhagen
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- Rungby, Jørgen (author)
- University of Copenhagen,Steno Diabetes Center Copenhagen
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- Sørensen, Henrik T. (author)
- Aarhus University,Boston University
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- Vaag, Allan (author)
- Lund University,Lunds universitet,Translationell diabetesforskning,Forskargrupper vid Lunds universitet,Translational Diabetes Research,Lund University Research Groups,Steno Diabetes Center Copenhagen
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- Nielsen, Jens S. (author)
- University of Southern Denmark,Odense University Hospital
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- Holm, Jens Christian (author)
- University of Copenhagen,Novo Nordisk Foundation Centre for Basic Metabolic Research,Holbæk Hospital
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- Lauenborg, Jeannet (author)
- Gentofte Hospital
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- Damm, Peter (author)
- Copenhagen University Hospital,University of Copenhagen
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- Pedersen, Oluf (author)
- Gentofte Hospital,Novo Nordisk Foundation Centre for Basic Metabolic Research,University of Copenhagen
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- Linneberg, Allan (author)
- University of Copenhagen,Copenhagen University Hospital
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- Hartmann, Bolette (author)
- University of Copenhagen
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- Holst, Jens J. (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research,University of Copenhagen
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- Hansen, Torben (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Wright, Shane C. (author)
- Karolinska Institutet,Karolinska Institute
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- Lauschke, Volker M. (author)
- Karolinska Institutet,Karolinska Institute,Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology,University of Tübingen
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- Grarup, Niels (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Hauser, Alexander S. (author)
- University of Copenhagen
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- Rosenkilde, Mette M. (author)
- University of Copenhagen
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(creator_code:org_t)
- 2024
- 2024
- English 14 s.
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In: Nature Metabolism. - 2522-5812. ; 6:7, s. 1268-1281
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Abstract
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- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Kizilkaya, Hüsün ...
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Sørensen, Kimmie ...
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Madsen, Jakob S.
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Lindquist, Peter
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Douros, Jonathan ...
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Bork-Jensen, Jet ...
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show more...
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Berghella, Aless ...
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Gerlach, Peter A ...
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Gasbjerg, Lærke ...
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Mokrosiński, Jac ...
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Mowery, Stephani ...
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Knerr, Patrick J ...
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Finan, Brian
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Campbell, Jonath ...
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D’Alessio, David ...
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Perez-Tilve, Die ...
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Faas, Felix
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Mathiasen, Signe
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Rungby, Jørgen
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Sørensen, Henrik ...
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Vaag, Allan
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Nielsen, Jens S.
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Holm, Jens Chris ...
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Lauenborg, Jeann ...
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Damm, Peter
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Pedersen, Oluf
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Linneberg, Allan
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Hartmann, Bolett ...
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Holst, Jens J.
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Hansen, Torben
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Wright, Shane C.
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Lauschke, Volker ...
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Grarup, Niels
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Hauser, Alexande ...
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Rosenkilde, Mett ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Nature Metabolis ...
- By the university
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Lund University
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Karolinska Institutet