In vivo functional profiling and structural characterization of the human <i>GLP1R</i> A316T variant
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with <i>GLP1R</i> gene variation potentially linked to therapeutic outcomes. A <i>GLP1R</i> natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human <i>GLP1R</i> A316T mouse model. Human <i>GLP1R</i><sup>A316T/A316T</sup> mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human <i>GLP1R</i> A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.
Authors
- Christopher A. Reynolds (ORCID: https://orcid.org/0000-0001-9267-5141)
- Dominic J. Withers (ORCID: https://orcid.org/0000-0002-8009-7521)
- Zamara Mariam (ORCID: https://orcid.org/0000-0002-4563-9559)
- Karim Bouzakri (ORCID: https://orcid.org/0000-0002-0703-5105)
- Liliane El Eid (ORCID: https://orcid.org/0000-0002-6511-6210)
- Steven J. Millership (ORCID: https://orcid.org/0000-0001-6947-7059)
- Kieran Deane-Alder (ORCID: https://orcid.org/0000-0003-2762-2240)
- Giuseppe Deganutti (ORCID: https://orcid.org/0000-0001-8780-2986)
- Matthew J. Belousoff (ORCID: https://orcid.org/0000-0002-3229-474X)
- Denise Wootten (ORCID: https://orcid.org/0000-0003-4563-1642)
- Affiong I Oqua (ORCID: https://orcid.org/0000-0002-0584-120X)
- Roxana-Maria Rujan
- Alejandra Tomas
- Gregory Austin
- Ben Jones
- Alex Montoya
- Guy A. Rutter
- Patrick M. Sexton
- Kyle W. Sloop
- Jorge Bernardino de la Serna
- Yusman Manchanda
Institutions
- University of Essex (GB)
- Eli Lilly (United States) (US)
- Nanyang Technological University (SG)
- McGill University Health Centre (CA)
- Sociétés, Acteurs, Gouvernement en Europe (FR)
- Centre Hospitalier de l’Université de Montréal (CA)
- Imperial College London (GB)
- Monash University (AU)
- Université de Montréal (CA)
- Coventry University (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2026-02-04
- DOI
- https://doi.org/10.1126/sciadv.adw0899
- Primary Topic
- Diabetes Treatment and Management
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Eli Lilly and Company
- Wellcome Trust
- Diabetes UK
- Society for Endocrinology
- Imperial College London
- University of Oxford
- Coventry University
- University of California, Irvine
- Medical Research Council
- National Health and Medical Research Council