Exercise as Treatment for Neuropathy in the Setting of Diabetes and Prediabetic Metabolic Syndrome: A Review of Animal Models and Human Trials

Background: Peripheral neuropathy is among the most common complications of diabetes, but a phenotypically identical distal sensory predominant, painful axonopathy afflicts patients with prediabetic metabolic syndrome, exemplifying a spectrum of risk and continuity of pathogenesis. No pharmacological treatment convincingly improves neuropathy in the setting of metabolic syndrome, but evolving data suggest that exercise may be a promising alternative. Objective: The aim of the study was to review in depth the current literature regarding exercise treatment of metabolic syndrome neuropathy in humans and animal models, highlight the diverse mechanisms by which exercise exerts beneficial effects, and examine adherence limitations, safety aspects, modes and dose of exercise. Results: Rodent models that recapitulate the organismal milieu of prediabetic metabolic syndrome and the phenotype of its neuropathy provide a strong platform to dissect exercise effects on neuropathy pathogenesis. In these models, exercise reverses hyperglycemia and consequent oxidative and nitrosative stress, improves microvascular vasoreactivity, enhances axonal transport, ameliorates the lipotoxicity and inflammatory effects of hyperlipidemia and obesity, supports neuronal survival and regeneration following injury, and enhances mitochondrial bioenergetics at the distal axon. Prospective human studies are limited in scale but suggest exercise to improve cutaneous nerve regenerative capacity, neuropathic pain, and task-specific functional performance measures of gait and balance. Like other heath behavioral interventions, the benefits of exercise are limited by patient adherence. Conclusion: Exercise is an integrative therapy that potently reduces cellular inflammatory state and improves distal axonal oxidative metabolism to ameliorate features of neuropathy in metabolic syndrome. The intensity of exercise need not improve cardinal features of metabolic syndrome, including weight, glucose control, to exert beneficial effects.