The intricacies of advanced glycation end products (AGEs) in diabetic neuropathy

Advanced glycation end products (AGEs) are key molecular mediators implicated in diabetic neuropathy (DN), although their exact mechanisms and therapeutic implications remain unclear. This review systematically integrates current evidence on AGE formation, AGE-RAGE signaling, oxidative stress, and emerging interventions in DN. A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar, in accordance with the PRISMA guidelines. Studies addressing biochemical, molecular, and clinical aspects of AGEs in DN were identified, screened, and qualitatively analyzed. Evidence consistently shows that AGEs promote neuronal and vascular injury through both receptor-dependent (AGE-RAGE-NF-κB/oxidative stress) and receptor-independent (protein crosslinking and matrix stiffening) mechanisms. Clinical data reveal significant associations between elevated AGE levels and DN severity, although differences in assay methods and diagnostic criteria limit direct comparisons. Antiglycation and antioxidant therapies, including aminoguanidine, carbonyl scavengers, and RAGE antagonists, have demonstrated neuroprotective potential in preclinical studies but have yielded variable results in human trials. AGEs play a central yet multifactorial role in DN by coupling metabolic stress with neuroinflammation and structural damage. Standardization of AGE detection techniques, longitudinal human studies, and rigorously designed translational trials are essential to advance their diagnostic and therapeutic potential.