Involvement of cellular and enzymatic aspects in the complexity of diabetic neuropathy

Diabetic neuropathy (DN) is a multifaceted and progressive complication of diabetes mellitus, characterized by functional and structural damage to peripheral, autonomic, and sensory nerves. Despite its high prevalence and debilitating consequences, current therapeutic approaches remain largely symptomatic, with limited disease-modifying strategies available. The pathogenesis of DN is driven by a complex network of molecular, cellular, and enzymatic interactions, primarily instigated by chronic hyperglycemia. This review unravels the intricate molecular and cellular crosstalk underlying DN, emphasizing the roles of specific cellular and enzymatic mediators in disease progression. Key cellular players, including neurons, Schwann cells, satellite glial cells, macrophages, and bone marrow-derived cells, orchestrate and respond to pathogenic stimuli, contributing to neuroinflammation, demyelination, and axonal degeneration. Chronic hyperglycemia activates several enzymatic pathways that exacerbate oxidative stress, mitochondrial dysfunction, and vascular impairment. Among the pivotal enzymes involved is aldose reductase, which drives the polyol pathway and sorbitol accumulation; diacylglycerol (DAG)-mediated protein kinase C (PKC), linked to vascular dysfunction; poly(ADP-ribose) polymerase (PARP), which amplifies DNA damage responses; and endogenous antioxidants, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, whose dysregulation further fuels oxidative injury. Additionally, growth factors (e.g. NGF, IGF-1, and VEGF), along with metabolic regulators (like AMPK), play pivotal roles in maintaining neuronal growth, survival, and function by modulating cellular energy homeostasis, oxidative balance, and inflammatory responses. By examining these interconnected molecular mechanisms, this review highlights potential therapeutic targets and proposes future directions for mechanism-based interventions aimed at halting or reversing the progression of diabetic neuropathy.