Glial Triad in Diabetic Neuropathy: Central Players in Neuropathic Pain Pathogenesis and Disease-Modifying...

Painful diabetic neuropathy (PDN) is a prevalent and debilitating complication of diabetes, characterized by persistent neuropathic pain that severely impairs quality of life. Current management strategies predominantly target peripheral nerve dysfunction and offer only symptomatic relief, with no disease-modifying therapies available. Emerging evidence now underscores the critical role of central nervous system (CNS) glial cells-microglia, astrocytes, and oligodendrocytes, collectively termed the "glial triad"-in driving PDN pathogenesis. This review synthesizes recent advances elucidating how these glial cells contribute to neuroinflammation, metabolic dysregulation, and central sensitization. We detail specific mechanisms including microglial NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation and metabolic reprogramming, astrocytic aquaporin-4 (AQP4) polarity disruption impairing glymphatic function, and oligodendrocyte myelination deficits via Mammalian Target of Rapamycin (mTOR) signaling. Furthermore, we discuss the translational potential of glia-derived biomarkers (e.g., Translocator Protein (TSPO), Glial Fibrillary Acidic Protein (GFAP), myelin basic protein (MBP)) for early diagnosis and patient stratification. Finally, we highlight promising therapeutic avenues that target glial pathways, such as interleukin-35 (IL-35), β-hydroxybutyrate, and metformin, which aim to shift the treatment paradigm from symptomatic control to disease modification. By integrating preclinical and clinical insights, this review proposes the glial triad as a central player in PDN and suggests that targeted glial interventions may represent a promising frontier for future disease-modifying strategies.