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.
Hoque et al. (2025) studied this question.