Abstract:

Diabetic peripheral neuropathy (DPN) is one of the most common and intractable complications of diabetes mellitus. Its irritating symptoms, such as paresthesia, hyperalgesia and allodynia, can be causes of insomnia and depression; whereas its progression to more advanced stages can result in serious consequences, such as lower limb amputations and lethal arrhythmias. The pathogenesis of DPN remains largely unknown, but long-term exposure to hyperglycemia is likely to play a major role in metabolic and vascular abnormalities in the peripheral nervous system (PNS). In the PNS,blood glucose is transported into the cells in an insulin-independent manner. Under normoglycemic conditions, most of the cellular glucose is converted into pyruvate through the glycolytic pathway, and further metabolized in the cytosol or mitochondria.Under hyperglycemic conditions, however, saturation of the glycolytic pathway and augmentation of glucose flux into the several collateral pathways (e.g., polyol pathway, hexosamine pathway, protein kinase C (PKC) pathway, and advanced glycation endproduct (AGE) pathway) appears to be detrimental to the PNS constituents,in particular, neurons, Schwann cells and blood vessels. Aldose reductase (AR), the first  and rate-limiting enzyme in the polyol pathway, is predominantly localized to Schwann cells in the PNS. AR catalyzes the conversion of glucose to sorbitol using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor, and sorbitol dehydrogenase (SDH) catalyzes the conversion of sorbitol to fructose using nicotinamide adenine dinucleotide (NAD+). The enhanced AR activity in Schwann cells under high glucose environments is thought to affect nerve functions through various mechanisms, e.g.,osmotic stress and impaired uptake of myo-inositol and taurine due to sorbitol accumulation, acceleration of AGE synthesis from fructose and its metabolites, and reduced activity of nitric oxide synthase (NOS) and glutathione reductase (GR) due to NADPH consumption by AR. Depletion of nitric oxide resulting from NOS inhibition can be a cause of diminished nerve blood flow, whereas a decrease in reduced glutathione (GSH) levels resulting from GR inhibition can trigger oxidative stress.AR-deficient (AR–/–) mice exhibited no obvious phenotypes in the PNS, and they were protected from diabetes-induced reduction of nerve conduction velocity (NCV) and GSH levels in sciatic nerves. In contrast, transgenic mice overexpressing human AR in Schwann cells displayed more advanced neurological manifestations than non-transgenic littermates under diabetic conditions. These findings support the idea that AR hyperactivity is a major contributing factor in the development and progression of DPN.