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The following is a summary of “Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment,” published in the January 2025 issue of Endocrinology by Huang et al. 

Insulin resistance is closely linked to cognitive function, but the causal relationship between the 2 remains unresolved and is a subject of ongoing debate.  

Researchers conducted a retrospective study to determine the causal relationship and direction between insulin resistance and cognition while also quantifying the mediating role of brain cortical structure in this association.  

They used publicly available data from meta-analyses of glucose and insulin-related traits consortium (MAGIC), enhancing neuroimaging genetics through meta-analysis (ENIGMA), and UK Biobank datasets to investigate insulin resistance (fasting insulin, homeostasis model assessment beta-cell function, homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time). A bidirectional 2-sample Mendelian randomization (MR) analysis was conducted to examine the influence of insulin resistance on cognitive traits. Additionally, a 2-step MR assessed the mediating effect of cortical surface area and thickness on the insulin resistance-cognition pathway. Inverse-variance weighted analysis, along with robust sensitivity checks, was used to confirm findings. Reverse MR was performed to assess cognition’s causal impact on insulin resistance and brain cortical structure.  

The results showed that genetically elevated proinsulin levels were associated with increased reaction time (beta=0.03, 95% CI =0.01 to 0.05, P =0.005) and reduced rostral middle frontal surface area (beta=-49.28, 95%CI=-86.30 to -12.27, P =0.009). The rostral middle frontal surface area accounted for 20.97% (95%CI=1.44% to 40.49%) of the effect of proinsulin on reaction time. No heterogeneity, pleiotropy, or reverse causality was detected.  

Investigators concluded an association between elevated insulin resistance and impaired cognition, mediated in part by alterations in brain cortical structure. 

Source: frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1443301/full