| Title: |
In vivo functional profiling and structural characterization of the human GLP1R A316T variant |
| Authors: |
El Eid, Liliane; Manchanda, Yusman; Austin, Gregory; Deane-Alder, Kieran; Rujan, Roxana-Maria; Mariam, Zamara; Oqua, Affiong I.; Belousoff, Matthew J.; de la Serna, Jorge Bernardino; Sloop, Kyle W.; Rutter, Guy A.; Montoya, Alex; Withers, Dominic J.; Millership, Steven J.; Bouzakri, Karim; Jones, Ben; Reynolds, Christopher A.; Sexton, Patrick M.; Wootten, Denise; Deganutti, Giuseppe; Tomas, Alejandra |
| Contributors: |
Diabetes UK; Society for Endocrinology; MRC-PHE Centre for Environment and Health; BBSRC; MRC Programme Grant; NIH-NIDDK; National Health and Medical Research Council; NHMRC Ideas; Wellcome Trust ISSF Fellowship; Society for Endocrinology Early Career and Small Equipment Grants; Diabetes Research & Wellness Foundation; Wellcome Trust Discovery Award; MRC Clinician Scientist Fellowship; Wellcome Trust Investigator Award; CIHR-JDRF; CRCHUM start-up funds; Innovation Canada John R. Evans Leader Award |
| Source: |
Science Advances ; volume 12, issue 6 ; ISSN 2375-2548 |
| Publisher Information: |
American Association for the Advancement of Science (AAAS) |
| Publication Year: |
2026 |
| Description: |
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1R A316T/A316T 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 GLP1R 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1126/sciadv.adw0899 |
| Availability: |
https://doi.org/10.1126/sciadv.adw0899; https://www.science.org/doi/pdf/10.1126/sciadv.adw0899 |
| Accession Number: |
edsbas.E2C892BB |
| Database: |
BASE |