Feature-Based Molecular Networking Facilitates the Comprehensive Identification of Differential Metabolites in Diabetic Cognitive Dysfunction Rats

Cognitive dysfunction is a frequent complication of type 2 diabetes mellitus (T2DM), usually accompanied by metabolic disorders. However, the metabolic changes in diabetic cognitive dysfunction (DCD) patients, especially compared to T2DM groups, are not fully understood. Due to the subtle differences in metabolic alterations between DCD groups and T2DM groups, the comprehensive detection of the untargeted metabolic profiles of hippocampus and urine samples of rats was conducted by LC–MS, considering the different ionization modes and polarities of the examined compounds, and feature-based molecular networking (FBMN) was performed to help identify differential metabolites from a comprehensive perspective in this study. In addition, an association analysis of the differential metabolites in hippocampus and urine was conducted by the O2PLS model. Finally, a total of 71 hippocampal tissue differential metabolites and 179 urine differential metabolites were identified. The pathway enrichment results showed that glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism, glycerol phospholipid metabolism, TCA cycle, and arginine biosynthesis in the hippocampus of DCD animals were changed. Seven metabolites (AUC > 0.9) in urine appeared as key differential metabolites that might reflect metabolic changes in the target tissue of DCD rats. This study showed that FBMN facilitated the comprehensive identification of differential metabolites in DCD rats. The differential metabolites may suggest an underlying DCD and be considered as potential biomarkers for DCD. Large samples and clinical experiments are needed for the subsequent elucidation of the possible mechanisms leading to these alterations and the verification of potential biomarkers.