The Glucagon Receptor Is Expressed in the Frontal Cortex and Impaired Signaling Associates With Cognitive Decline

Sasha AS Kjeldsen, Jonas Folke, Maud E Ottenheijm, Marie Winther-Sørensen, Jónvá Hentze, Pia Nyeng, Sara L Garcia, Agata Casado-Sainz, Sanne Simone Kaalund, Reidar Albrechtsen, Karina Banasik, Søren Brunak, Nina L Hansen, Jens Juul Holst, Mette M Rosenkilde, Jørgen Rungby, Majken K Jensen, Birgitte Georg, Jens Hannibal, Tomasz Brudek, Susana Aznar, Nicolai J Wewer Albrechtsen
Journal of the Endocrine Society, Volume 9, Issue 6, June 2025, bvaf056
https://doi.org/10.1210/jendso/bvaf056

Abstract

Individuals with type 2 diabetes (T2D) have an elevated risk of cognitive decline, yet the mechanisms connecting these pathologies remain unclear. Altered glucagon and insulin signaling contribute to T2D, and insulin resistance may also be associated with cognitive decline. The role of glucagon in this context is unknown. Here we aimed to characterize glucagon receptor (GCGR) expression in brain tissue and investigate the potential impact of altered GCGR signaling on dementia prevalence and cognitive function. We investigated GCGR protein expression in various human brain regions and cell types in postmortem brain samples. To explore the potential link between GCGR signaling and cognitive function, individuals with specific GCGR mutations with known or predicted impaired GCGR signaling were examined in connection to the prevalence of dementia defined by International Classification of Diseases, Tenth Revision coding and by cognitive function using population-scale cognitive tests in the UK Biobank. GCGR mRNA and protein were expressed specifically in neurons of the frontal cortex. Varying degrees of expression were observed across brain regions and with higher expression in the parietal cortex and thalamus by antibody-dependent analyses. GCGR variant carriers did not have a significantly higher prevalence of dementia, but 1 cognitive test was significantly impaired in individuals with a GCGR cAMP loss-of-function variant compared to sex- and age-matched nonvariant carrier controls. Our findings indicate GCGR expression in the human brain, particularly in neurons of the frontal cortex, and altered glucagon signaling may be associated with lower cognitive function. Further research is needed to elucidate mechanisms underlying the potential link between altered GCGR signaling and cognitive decline.

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