@article{Tomas:2026,
author = {Tomas, Catala A},
journal = {Science Advances},
title = {In vivo functional profiling and structural characterisation of the human GLP1R A316T variant},
year = {2026}
}

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TY  - JOUR
AB  - 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 characterised a human GLP1R A316T mouse model. Human GLP1RA316T/A316T mice displayed lower fasting blood glucose versus wildtype 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 b-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.
AU  - Tomas,Catala A
PY  - 2026///
SN  - 2375-2548
TI  - In vivo functional profiling and structural characterisation of the human GLP1R A316T variant
T2  - Science Advances
ER  - 

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