Glucotoxic Mechanisms and Related Therapeutic Approaches

Neuropathy is the earliest and commonest complication of diabetes. With increasing duration of diabetes, frequency and severity of neuropathy are worsened. Long-term hyperglycemia is therefore implicated in the development of this disorder. Nerve tissues require glucose energy to function and survive. Upon excessive glucose entry into the peripheral nerve, the glycolytic pathway and collateral glucose-utilizing pathways are overactivated and initiate adverse effects on nerve tissues. During hyperglycemia, flux through the polyol pathway, formation of advanced glycation end-products, production of free radicals, flux into the glucosamine pathway, and protein kinase C activity are all enhanced to negatively influence nerve function and structure. Suppression of these aberrant metabolic pathways has succeeded in prevention and inhibition of the development of neuropathy in animal models with diabetes. Satisfactory results were not attained, however, in patients with diabetes and further clinical trials are required. In this review, the author summarizes the hitherto proposed theories on the pathogenesis of diabetic neuropathy related to glucose metabolism and future prospects for the effective treatment of neuropathy.