WileyJan 22 2025
Glucagon-like peptide 1 receptor agonists (GLP1RA)-medications for type 2 diabetes and obesity that have recently been making headlines due to a rise in popularity as weight loss agents-have been linked with behavioral side effects. A large population-based analysis in Diabetes, Obesity and Metabolism assessed whether certain genetic variants might help explain these effects.
GLP1RA mimic the GLP-1 hormone in the body that helps control insulin and blood glucose levels and promotes feelings of satiety. GLP-1 binds to GLP1R on cells in the brain and pancreas.
For the analysis, investigators examined common genetic variants in the GLP1R gene in 408,774 white British, 50,314 white European, 7,667 South Asian, 10,437 multiple ancestry, and 7,641 African-Caribbean individuals.
Variants in the GLP1R gene had consistent associations with cardiometabolic traits (body mass index, blood pressure, and type 2 diabetes) across ancestries. GLP1R variants were also linked with risk-taking behavior, mood instability, chronic pain, and anxiety in most ancestries, but the results were less consistent. The genetic variants influencing cardiometabolic traits were separate from those influencing behavioral changes and separate from those influencing expression levels of the GLP1R gene.
The findings suggest that any observed behavioral changes with GLP1RA are likely not acting directly through GLP1R.
Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioral changes are unlikely to be a direct result of the GLPRAs. Exactly how these indirect effects are occurring is currently unclear."
Rona J. Strawbridge, PhD, corresponding author of the University of Glasgow, UK
Wiley
Journal reference:
Hayman, M. M. E., et al. (2025) Association of GLP1R locus with mental ill-health endophenotypes and cardiometabolic traits: A trans-ancestry study in UK Biobank. Diabetes Obesity and Metabolism. doi.org/10.1111/dom.16178.