Metabolic reprogramming in diabetic complications: mechanisms, pathologies, and molecular evidence from multi-organ studies.

Metabolic reprogramming is a critical link between systemic metabolic dysregulation and organ-specific, persistent injury in diabetic complications. Previous reviews have largely focused on individual organs or isolated metabolic pathways, leaving unresolved how common diabetic metabolic reprogramming is translated into divergent tissue injury across different organs and cell types. Addressing this gap is important because it connects fragmented pathway-level evidence with tissue-specific disease mechanisms and may help prioritize more precise therapeutic strategies for diabetic complications. This review summarizes alterations in glucose, lipid, and amino acid metabolism, mitochondrial function, immunometabolism, and epigenetic regulation in diabetic kidney disease, diabetic retinopathy, diabetic foot ulcers, diabetic peripheral neuropathy, and diabetic cardiovascular complications. Current evidence indicates that hypoxia-inducible factor 1α (HIF-1α)-driven glycolysis, ferroptosis-associated oxidative stress, mitochondrial dysfunction, dysregulated nutrient sensing, and inflammatory metabolic remodeling are shared across multiple diabetic complications. However, their downstream consequences are highly dependent on tissue-specific microenvironments and resident-cell composition. For example, HIF-1α-related glycolytic remodeling promotes macrophage-driven inflammation and fibrosis in diabetic kidney disease but contributes to Müller-cell-derived VEGF/ANGPTL4 expression and pathological angiogenesis in diabetic retinopathy. Similarly, ferroptosis-associated lipid injury causes endothelial repair failure in diabetic foot ulcers but cardiomyocyte injury and cardiac remodeling in diabetic cardiovascular complications. These examples suggest that local oxygen status, metabolic demand, immune-cell composition, intercellular metabolic crosstalk, and tissue repair capacity reshape shared metabolic programs into organ-specific pathological outcomes, including filtration-barrier injury, vascular leakage, impaired wound healing, neuropathic injury, and cardiac dysfunction. Moreover, hyperglycemia-induced oxidative stress, inflammatory metabolic remodeling, and epigenetic alterations may persist after glycemic improvement and contribute to metabolic memory. By integrating evidence across organs and cell types, this review provides a new perspective for understanding why shared metabolic reprogramming in diabetes produces tissue-specific pathological outcomes. Therapeutic strategies should therefore combine glycemic control with interventions targeting both shared metabolic pathways and organ- or cell-specific pathogenic mechanisms.