Abstract

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia, which exerts profound 
effects on multiple organ systems, including the nervous system. Neurotoxicity in diabetes is increasingly 
recognized as a consequence of mitochondrial dysfunction and activation of redox-sensitive signalling pathways. 
Persistent hyperglycemia induces excessive production of reactive oxygen species (ROS) and reactive nitrogen 
species (RNS), leading to oxidative stress, mitochondrial damage, and dysregulated cellular signalling. These 
alterations compromise neuronal bioenergetics, promote inflammation, and precipitate axonal degeneration and 
synaptic dysfunction. Redox-sensitive transcription factors, including NF-kB, Nrf2, and AP-1, mediate 
inflammatory and antioxidant responses, while mitochondrial permeability transition, calcium dysregulation, and 
apoptotic signalling contribute to neuronal death. This review integrates current understanding of the mechanisms 
underlying diabetic neurotoxicity, highlighting the interplay between mitochondrial impairment and oxidative 
stress-mediated signalling pathways. Therapeutic strategies targeting mitochondrial function, redox balance, and 
downstream signalling are discussed, emphasizing their potential to prevent or mitigate diabetic neuropathy and 
cognitive dysfunction.