Immunological mechanisms and therapeutic advances in diabetic neuropathy

Diabetic neuropathy (DN) is one of the most common and debilitating chronic complications of diabetes mellitus. It typically presents as a distal symmetric polyneuropathy (DSP), which is characterized by symmetric involvement of the distal extremities, manifesting as numbness, pain, paresthesia, and sensory loss. In addition to peripheral sensory involvement, patients may also experience autonomic neuropathy and focal nerve injuries. Persistent hyperglycemia can impair the structure and function of the nervous system through multiple interrelated mechanisms. Prolonged elevation of blood glucose levels induces non-enzymatic glycation reactions, leading to the excessive accumulation of advanced glycation end products (AGEs). These AGEs bind to their receptor RAGE, triggering a cascade of downstream signaling pathways, including ROS/NF-κB, JAK/STAT, and PKC, that promote oxidative stress and chronic inflammation. In addition, hyperglycemia exacerbates neural injury and impedes repair by disrupting microvascular integrity, altering immune cell function, disturbing ionic homeostasis within nerves, and inducing Schwann cells (SCs) apoptosis along with impaired production of neurotrophic factors. Currently, a variety of pharmacological agents are available for the treatment of DN, including gabapentin, pregabalin, methylcobalamin, α-lipoic acid, and aldose reductase inhibitors, either as monotherapy or in combination. These treatments can partially alleviate neurological dysfunction and neuropathic pain. This review summarizes the key mechanisms by which hyperglycemia induces nerve injury and highlights recent advances in pharmacological interventions. The aim is to provide a theoretical framework and therapeutic perspective to support both mechanistic research and clinical management of DN.