Metabolic reprogramming in diabetic panvascular disease: Molecular mechanism and therapeutic strategies

Diabetes mellitus substantially increases the risk of cardiovascular, cerebrovascular, renal, retinal and peripheral vascular complications. These are collectively referred to as diabetic panvascular disease. A traditional approach that treats each complication separately is no longer sufficient. An emerging framework places metabolic reprogramming at its center. This review examines how the diabetic environment, including hyperglycemia, insulin resistance, and dyslipidemia, rewires core metabolic pathways in vascular cells. Major changes include the diversion of glucose through the polyol, hexosamine and AGE-PKC axes, lipotoxicity resulting from excessive fatty acids, disruption of amino acid networks such as BCAA and one-carbon metabolism, mitochondrial dysfunction with increased mtROS production, and epigenetic modifications that drive metabolic memory. These interconnected abnormalities promote oxidative stress and chronic inflammation, which in turn lead to endothelial dysfunction, atherosclerosis, microvascular rarefaction, and end-organ damage in the heart, brain, kidney, retina, and peripheral nerves. We also describe the current therapeutic landscape, ranging from established agents such as metformin, SGLT2 inhibitors, GLP-1 receptor agonists, RAAS blockers, and anti-VEGF therapies to emerging mechanism-based strategies including aldose reductase inhibitors, glucokinase activators, PKC, RAGE, NOX, and NLRP3 inhibitors, miRNA modulators, and exosome therapy. Finally, we highlight unmet needs and future directions. These may include multi-omics guided precision phenotyping, cross-organ causal inference, single-cell metabolic flux technologies, and adaptive clinical trial designs. By shifting from a glucose-centric to a metabolic reprogramming-centric paradigm, this review aims to provide a roadmap for developing more targeted therapies for diabetic panvascular disease.