Diabetes and the Nervous System: Linking Peripheral Neuropathy to Central Neurodegeneration

Diabetes mellitus casts a long shadow over the nervous system, driving a spectrum of complications that extend far beyond glycemic control. Diabetic peripheral neuropathy and diabetes-associated cognitive decline—long viewed as separate clinical entities—are now recognized as intertwined expressions of a multi-organ, multi-pathway disease process. At the molecular core, hyperglycemia, oxidative stress, mitochondrial injury, immune activation, and vascular dysfunction con-verge with insulin resistance to erode neuronal and glial integrity. These events are amplified by gut dysbiosis, which reshapes immune tone, dis-rupts neurovascular homeostasis, and fuels neurodegeneration via the gut–brain–nerve axis. Recent advances reveal that neuroinflammation, microvascular rare-faction, metabolic inflexibility, and lipid-mediated toxicity act not in isolation but as a self-reinforcing network linking peripheral and central injury. Yet, progress toward disease-modifying therapy remains slow, hindered by knowledge gaps in longitudinal human phenotyping, incomplete animal models, underdeveloped biomarkers, and neglected dimensions such as epigenetic memory, circadian disruption, and sex-specific biology. This Review integrates emerging mechanistic insights—from endothelial dys-function and mitochondrial permeability transition to short-chain fatty acid sig-naling and ceramide neurotoxicity—with an urgent call for precision medicine approaches. By aligning metabolic, vascular, immune, and microbial interventions within longitudinal, biomarker-driven frameworks, the field stands poised to shift from symptom management to strategies that can slow, halt, or even reverse the neurological toll of diabetes.