Researchers from the Hospital del Mar Research Institute and the Institut Cochin in Paris have developed a new method that improves the prediction of the effects of variants in the GLP-1 receptor, which are associated with diabetes and obesity.
The GLP-1 receptor is a protein that responds to GLP-1, a naturally occurring hormone that regulates blood sugar levels and the feeling of satiety. For this reason, it is a target of some of the most advanced and widely used treatments for type 2 diabetes and obesity, such as Ozempic. Understanding how the function of this receptor may vary as a result of genetic changes is therefore particularly important.
Naturally, each person may carry different genetic variants of the GLP-1 receptor, known as GLP1R variants. An individual’s risk of developing type 2 diabetes, as well as their response to treatments, may vary depending on the presence of one of these variants. Until now, determining whether a specific variant actually altered receptor function required complex laboratory studies.
This situation could change thanks to the work of a team from the Hospital del Mar Research Institute (HMRIB) and the Institut Cochin (CNRS/Inserm) in Paris. The researchers have developed a new computational method that can be applied to precision medicine and improves the ability to predict these effects. The method, known as GPCR^VP, is described in a study published in the journal Diabetologia.
The new method combines existing artificial intelligence-based predictors, including AlphaMissense and REVEL, with information about the receptor’s three-dimensional structure, membrane characteristics, and molecular dynamics. During its evaluation, GPCR^VP showed greater agreement with laboratory measurements and reduced false-positive predictions by approximately 78% in the validation datasets compared with AlphaMissense.
At the same time, the researchers successfully used the new tool to predict the functional impact of 174 additional human GLP1R variants.
As Dr. Jana Selent, coordinator of the GPCR Drug Discovery Research Group at HMRIB, explains: “These results suggest that incorporating the specific biological characteristics of this family of G protein-coupled receptors can improve the interpretation of human genetic variation.”
Marta López Balastegui, the study’s first author, adds: “Approaches such as GPCR^VP could help researchers and clinical professionals better understand how each person’s genetic variation may influence GLP-1 receptor function and potentially contribute to more personalized strategies for managing diabetes and obesity.”
Although the tool was initially validated using the GLP-1 receptor, the methodological framework developed by the researchers can be applied to the entire family of these receptors, as well as to other membrane proteins involved in human diseases.
Reference article
Lopez-Balastegui, M., Lian, S., Gao, W. et al. The GPCR^VP score reliably predicts the impact of GLP1R human variants on receptor function. Diabetologia (2026).