Causal Links of Type 2 Diabetes and Its Complications With Cortical Modification: A Mendelian Randomization and...

Type 2 diabetes (T2D) and its complications are linked to cognitive decline over time, accompanied by cortical abnormalities. The causality between T2D and cortical modifications, however, remains elusive.

Applying two-sample Mendelian randomization (MR), we probed causal relationships between T2D and its complications and cortical modifications. Genetic associations were elucidated via linkage disequilibrium score regression and Bayesian colocalization. An instrumental variable-guided protein-protein interaction (PPI) network was constructed and subjected to clustering and pathway analysis. Moreover, a two-step MR strategy was used to identify immune mediators in the causal relationship.

The results showed that T2D (p = 0.005), T2D with ophthalmic (T2D_OPTH, p = 0.004), or peripheral circulatory (T2D_PERIPH, p = 0.005) complications had a significant impact on reducing isthmus cingulate thickness. T2D_PERIPH led to an increase in the anterior cingulate surface areas, including both the caudal (p = 0.008) and rostral (p = 0.002) regions. Suggested colocalization was exclusive to T2D_OPTH and isthmus thickness, without additional genetic associations. PPI network clustering revealed causal pathway associations beyond conventional diabetes mechanisms, implicating roles in infection, addiction, and neurodegeneration. IL20RA, IgD- CD38dim B cells, HLA DR+ CD4+ T cells, and CD3 on effector memory CD4+ T cells emerged as candidate mediators of the observed causal links.

Our study uncovers causal associations between T2D and its complications with cortical structure, highlighting the cingulate's particular vulnerability. Immuno-metabolic dysregulation emerges as a mediator in the causal pathway connecting them, underlining inflammation control's critical importance in diabetes management.