In vivo functional profiling and structural characterisation of the human Glp1r A316T variant

El Eid, L.; Deane-Alder, K.; Rujan, R.-M.; Mariam, Z.; Oqua, A. I.; Manchanda, Y.; Belousoff, M. J.; Bernardino de la Serna, J.; Sloop, K. W.; Rutter, G. A.; Montoya, A.; Withers, D. J.; Millership, S.; Bouzakri, K.; Jones, B.; Reynolds, C. A.; Sexton, P. M.; Wootten, D.; Deganutti, G.; Tomas, A.

doi:10.1101/2024.10.19.619191

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bioRxiv · 10.1101/2024.10.19.619191

In vivo functional profiling and structural characterisation of the human Glp1r A316T variant

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable. Variation in the human Glp1r gene might be directly linked to therapeutic responses. A naturally occurring missense variant, A316T, protects against T2D and cardiovascular disease. Here, we have 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, and exhibited alterations in islet cytoarchitecture and /{beta}-cell identity under a high-fat, high-sucrose diet. This was however associated with blunted responses to GLP-1RAs in vivo. Further investigations in rodent and human {beta}-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. TeaserThe Glp1r A316T missense variant displays improved glucose tolerance but impaired pharmacological incretin responses in vivo.

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El Eid, L., Deane-Alder, K., Rujan, R.-M., Mariam, Z., Oqua, A. I., Manchanda, Y., Belousoff, M. J., Bernardino de la Serna, J., Sloop, K. W., Rutter, G. A., Montoya, A., Withers, D. J., Millership, S., Bouzakri, K., Jones, B., Reynolds, C. A., Sexton, P. M., Wootten, D., Deganutti, G., Tomas, A.. 2024-10-21. In vivo functional profiling and structural characterisation of the human Glp1r A316T variant. https://doi.org/10.1101/2024.10.19.619191

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