Publication Date

10-1-2023

Journal

Nature Metabolism

DOI

10.1038/s42255-023-00889-6

PMID

37709961

PMCID

PMC11610247

PubMedCentral® Posted Date

12-2-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Blood Glucose, Insulin, Diabetes Mellitus, Type 2, Adiposity, Obesity

Abstract

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in patients with type 2 diabetes (T2D) 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 performed a functional profiling of 60 GLP1R variants across four signaling pathways and revealed an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain- (GoF) and loss-of-functions (LoF). The defective insulin secretion of GLP1R LoF variants was rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200K participants from the UK Biobank show that impaired GLP1R cell surface expression contributes to poor glucose control and increased adiposity with increased HbA1c, BMI and diastolic blood pressure. This study defines impaired GLP1R cell surface expression as a risk factor for T2D- and obesity-associated traits and provides potential treatment options for GLP1R LoF variant carriers.

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