Article Dans Une Revue Nature Metabolism Année : 2023

Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity

Erika Cecon
Panagiotis Katsonis
  • Fonction : Auteur
Zhiran Fan
  • Fonction : Auteur
Guofei Hou
  • Fonction : Auteur
Olivier Lichtarge
  • Fonction : Auteur
Julie Dam

Résumé

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity 1,2. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways. The defective insulin secretion of GLP1R LoF variants is rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200,000 participants from the UK Biobank show that impaired GLP1R cell surface expression contributes to poor glucose control and increased adiposity with increased glycated haemoglobin A1c and body mass index. This study defines impaired GLP1R cell surface expression as a risk factor for traits associated with type 2 diabetes and obesity and provides potential treatment options for GLP1R LoF variant carriers.

Fichier principal
Vignette du fichier
Gao_2023_submitted.pdf (3.12 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)
Licence

Dates et versions

hal-04233247 , version 1 (23-11-2023)

Licence

Identifiants

Citer

Wenwen Gao, Lei Liu, Eunna Huh, Florence Gbahou, Erika Cecon, et al.. Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity. Nature Metabolism, 2023, ⟨10.1038/s42255-023-00889-6⟩. ⟨hal-04233247⟩
226 Consultations
730 Téléchargements

Altmetric

Partager

  • More