Differential Network Analysis Integrates Pathway Mapping to Characterize Dynamic Metabolic Changes in the Progression of Diabetic Complications

Onset and progression of diseases are often characterized by dynamic changes in various metabolites. Monitoring these metabolic fluctuations is a central focus within the field of disease metabolomics. This study introduces an integrative analytical method that combines cross-comparative differential network analysis with network mapping to delineate the dynamic changes of diabetes rats in the fecal metabolome induced by a high-fat diet and streptozotocin. Our results indicate that the fecal metabolite networks are significantly associated with diabetes development. The network analysis identified 13 specific biomarkers linked to the progression of diabetic complications, highlighting that diabetes development is marked by an exacerbation of metabolic dysfunction. Interestingly, the networks analysis also uncovered age-related metabolites including BCAAs (leucine, isoleucine, valine), urocanate, tyrosine, lysine succinate, betaine, and cytosine, which may potentially promote the onset and progression of diabetes. Pathway analysis revealed disruptions in amino acid metabolism, ketone body synthesis and degradation, glycolysis/gluconeogenesis, galactose metabolism, nicotinamide metabolism, and purine metabolism, along with alterations in signaling pathways related to mineral absorption and neurotransmitter synaptic transmission. The cross-comparison network analysis in conjunction with network mapping analysis constitutes an effective method for exploring the dynamic metabolic networks implicated in diseases pathogenesis.