Role of inflammation in diabetic neuropathy

Abstract

Diabetic peripheral neuropathy is one of the most common complications of diabetes mellitus and represents an important cause of neuropathic pain, loss of protective sensation, diabetic foot ulceration, and impaired quality of life. Its pathophysiology is complex and has traditionally been associated with chronic hyperglycemia, oxidative stress, mitochondrial dysfunction, metabolic abnormalities, and microvascular damage. However, recent evidence identifies inflammation and neuroinflammation as relevant mechanisms involved in the initiation, maintenance, and progression of neural injury.

Persistent exposure to hyperglycemia and lipotoxicity promotes the accumulation of advanced glycation end products, reactive oxygen species, and cellular danger signals. These stimuli activate inflammatory receptors and pathways, including RAGE, Toll-like receptors, NF-κB, and the NLRP3 inflammasome, promoting the release of mediators such as TNF-α, IL-1β, IL-6, and other cytokines and chemokines. This inflammatory response may directly affect axons, neurons, and Schwann cells, impairing myelination, neuronal function, and repair mechanisms.

The involvement of the central nervous system adds an important neuroimmune dimension to the disease. Microglial activation, together with interactions among microglia, neurons, and astrocytes, may sustain a persistent inflammatory state and promote central sensitization. Activation of pathways such as RAGE/TLR4/NLRP3 and the release of IL-1β and BDNF may contribute particularly to the development and maintenance of neuropathic pain. Thus, diabetic neuropathy can be understood as the result of a dynamic interaction between metabolic abnormalities, peripheral inflammation, and central neuroimmune mechanisms.

This emerging perspective suggests that inflammation may act not only as a consequence of nerve injury but also as an amplifier of diabetic neural damage. Identifying patients with a predominantly inflammatory phenotype and biomarkers capable of reflecting this activity could improve risk stratification. Furthermore, targeting inflammatory and neuroimmune pathways represents a potential therapeutic strategy that could complement metabolic control and symptomatic treatment.