Diabetic impact on the neuroaxis: from peripheral neuropathy to central neurodegeneration

Background Diabetic neuropathy has typically been viewed as a peripheral nerve disorder, most commonly presenting as distal symmetrical polyneuropathy (DSPN). However, accumulating evidence suggests that diabetes affects not only peripheral somatic and autonomic fibers but also the central nervous system, indicating more widespread neurodegenerative processes. Aim This narrative review aims to synthesize current knowledge on how diabetes affects the nervous system across the neuroaxis, integrating peripheral, autonomic, and central mechanisms, and to provide an overview of clinical manifestations, diagnostic approaches, and management strategies. Results Chronic hyperglycemia induces a range of metabolic and vascular disturbances, including oxidative stress, inflammation, and microvascular dysfunction, which contribute to peripheral nerve injury. These changes affect both small and large fibers, leading to sensory loss, neuropathic pain, and motor impairment. Autonomic involvement is common and manifests as cardiovascular, gastrointestinal, sudomotor, urogenital, and ocular dysfunction. Importantly, diabetes-related neural injury extends beyond the peripheral nervous system. Structural and functional alterations have been demonstrated in the spinal cord, brainstem and brain, including changes in white matter integrity, cortical organization, and functional connectivity. Peripheral and central mechanisms interact bidirectionally, contributing to altered sensory processing and pain modulation. Conclusion Diabetic neuropathy should be understood as a disorder of the entire neuroaxis. Integrating peripheral and central aspects is essential to gain a holistic view of diabetic neuropathy and to support the development of more targeted diagnostic and therapeutic strategies.