Signaling complexity in diabetic neuropathy: a multitargeted perspective on pathogenesis and therapy

Diabetic neuropathy (DN), a prevalent and disabling complication of diabetes mellitus is characterized by chronic pain, sensory loss, and motor impairment arising from multifaceted metabolic, inflammatory, and oxidative mechanisms triggered by chronic hyperglycemia. Among the metabolic contributors, polyol pathway, AGE, PKC pathway, and hexosamine biosynthetic pathway are key players. These are closely intertwined with inflammatory mediators and pathways, including NF-κB, MAPK, the NLRP3 inflammasome, cytokine/chemokine signaling, and emerging inflammatory circuits. Mitochondrial dysfunction and oxidative stress, exacerbated by the impairment of AMPK/SIRT/PGC-1α and Nrf2 signaling, contribute to cellular damage and bioenergetic failure. Additionally, disruptions in insulin signaling, specifically involving Akt and RAC1 pathways, worsen neuronal survival, cytoskeletal function, and glucose metabolism. The interplay between these pathways establishes a self-propagating cycle of metabolic stress, inflammation, and neurodegeneration. Recent research has focused on targeting these specific mechanisms, including aldose reductase inhibitors, RAGE antagonists, PKC inhibitors, AMPK activators, and Nrf2 inducers. While many have shown promise in preclinical models, clinical translation remains limited. Understanding the intricate crosstalk between these pathways is essential for developing more effective, multi-targeted interventions aimed at halting or reversing the progression of DN. This review explores the multifaceted pathways underlying DN, including metabolic, inflammatory, mitochondrial dysfunction, and insulin signaling pathways. It highlights the intricate interlinks between these mechanisms and discusses recent advancements in targeted therapeutic approaches.