In vivo functional profiling and structural characterization of the human GLP1R A316T variant
- Liliane El Eid
- Yusman Manchanda
- Gregory Austin
- Kieran Deane-Alder
- Roxana-Maria Rujan
- Zamara Mariam
- Affiong I. Oqua
- Matthew J. Belousoff
- Jorge Bernardino de la Serna
- Kyle W. Sloop
- Guy A. Rutter
- Alex Montoya
- Dominic J. Withers
- Steven J. Millership
- Karim Bouzakri
- Ben Jones
- Christopher A. Reynolds
- Patrick M. Sexton
- Denise Wootten
- Giuseppe Deganutti
- Alejandra Tomas
2026-02-04
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.