Effects of different sugar-lipid ratio diets on the occurrence of type 2 diabetes mellitus

Objective: Type 2 diabetes mellitus (T2DM) arises from sustained energy imbalance and macronutrient dysregulation. This study elucidates how distinct dietary sugar-to-lipid ratios modulate T2DM progression and delineates the underlying molecular mechanisms. Methods: Forty C57BL/6 mice were randomized into a control group (standard diet) and three high-energy cohorts with varying sugar-to-fat ratios (10% fat/70% carbohydrate; 45% fat/35% carbohydrate; 60% fat/20% carbohydrate). Body weight and fasting blood glucose were longitudinally monitored to assess obesity and T2DM onset. Following diagnosis, we analyzed serum metabolic profiles, insulin resistance, organ indices, and histopathology of the liver, pancreas, and white adipose tissue. Integrated proteomic and untargeted metabolomic analyses of liver tissue were employed to decode mechanistic pathways, with key targets validated via molecular assays. Results: Elevated dietary fat content dose-dependently accelerated obesity and T2DM onset, exacerbating glycolipid dysregulation, insulin resistance, hepatic steatosis, and adipose inflammation. Proteomic profiling revealed that differentially expressed proteins, primarily localized to the mitochondria, endoplasmic reticulum, and plasma membrane, were enriched in lipid, amino acid, and cofactor metabolism. Concurrently, metabolomics identified 4,276 hepatic metabolites with significant enrichment in glycerophospholipid and linoleic acid pathways. Integrated analysis demonstrated that high-fat diets disrupt systemic homeostasis by inducing coordinated perturbations in specific lipid metabolism networks. Validation confirmed that these diets suppressed mitochondrial markers (AMPK, PGC-1α, TFAM, NRF1) while dysregulating lipid regulators (upregulated PPAR-γ, downregulated PPAR-α). Conclusion: High-fat diets exert more severe metabolic detriment than other macronutrient configurations. This progression is driven by a dual interaction network involving mitochondrial dysfunction and lipid metabolic reprogramming, which collectively dismantle systemic metabolic homeostasis.