Abstract

Background: Diabetic Peripheral Neuropathy (DPN) is one of the most common and debilitating complications of diabetes, characterized by progressive damage to peripheral nerves. Among the earliest pathological changes is the degeneration of small unmyelinated C-fibers and thinly myelinated Aδ-fibers, which are crucial for pain and temperature perception. Small fiber degeneration plays a central role in the transition from metabolic disturbances to clinical neuropathic pain.
Objective: This review aims to explore the underlying mechanisms contributing to small fiber degeneration in DPN and their role in the pathogenesis of neuropathic pain. Methods: Relevant literature was reviewed from experimental, clinical and translational studies focusing on small fiber pathology, metabolic dysfunction and pain mechanisms in diabetic neuropathy.
Result: Multiple interrelated mechanisms contribute to small fiber degeneration. Chronic hyperglycemia induces oxidative stress, Advanced Glycation End-Product (AGE) accumulation and mitochondrial dysfunction, leading to axonal injury. Vascular insufficiency and impaired neurotrophic support further exacerbate fiber loss. Additionally, low-grade inflammation and immune-mediated processes sensitize nociceptors, promoting spontaneous firing and hyperexcitability. Structural changes such as reduced Intraepidermal Nerve Fiber Density (IENFD), altered ion channel expression and impaired axonal transport are strongly associated with pain phenotypes in DPN. These mechanisms collectively disrupt nociceptive signal processing, resulting in allodynia, hyperalgesia and spontaneous pain.
Conclusion: Small fiber degeneration represents a pivotal mechanism in the pathophysiology of painful DPN. Understanding the interplay between metabolic, vascular, inflammatory and neurotrophic factors provides critical insights into disease progression and pain generation. Targeting small fiber preservation and regeneration may open new therapeutic avenues for managing neuropathic pain in diabetes.

Keywords:Diabetic peripheral neuropathy; Small fiber neuropathy; Neuropathic pain; Intraepidermal nerve fiber density; Oxidative stress; Hyper excitability