Dietary Responses in the Diabetic Brain: Transcriptomic Convergence and Comparison with an Alzheimer’s Disease Model

Dietary interventions alter brain gene expression in diabetes, but the extent to which their responses agree across experiments and reduce differences from controls remains unclear. Five public transcriptomic datasets were reanalyzed, spanning human cortical fractions, rat brain regions, diabetic mouse hippocampus with intermittent fasting (IF), diabetic whole brain with ketogenic diet, and APP/PS1 and wild-type hippocampus with IF. Gene and pathway comparisons assessed agreement across experiments. Statistical tests distinguished opposing disease and dietary effects from reductions in the remaining distance from controls. IF and ketogenic diet identified 6569 and 999 genes, respectively, in diabetic mice. Their effects showed modest agreement (Pearson r = 0.205), with 447 genes significant in both experiments, including 359 with matching directions. They shared 59 pathways with a matching direction at a fixed intergene correlation of 0.01; these overlaps were not supported when correlations were estimated from the data. IF responses in diabetic and APP/PS1 hippocampus agreed poorly (r = −0.056). No human genes met a per-contrast false discovery rate < 0.05. Thirteen diabetic genes showed significant opposition of disease and IF effects; neither primary fasting experiment demonstrated contraction toward controls. The results support limited agreement between the diabetic dietary experiments and little agreement in IF responses across the examined disease contexts. They do not establish transcriptomic restoration.