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The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR-/-) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR+/+) and AR-/- mice. Under short-term diabetic conditions, AR-/- mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR+/+ mice. Sorbitol levels in the sciatic nerves of diabetic AR+/+ mice were increased significantly, whereas sorbitol levels in the diabetic AR-/- mice were significantly lower than those in diabetic AR+/+ mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH[sub 2]-terminal kinase (JNK), depletion of reduced glutathione, increase of super-oxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR+/+ mice were not observed in the diabetic AR-/- mice, indicating that the diabetic AR-/- mice were protected from oxidative stress in the sciatic nerve. The diabetic AR-/- mice also excreted less 8-hydroxy-2'-deoxygnanosine in urine than diabetic AR+/+ mice. The structural abnormalities observed in the sural nerve of diabetic AR+/+ mice were less severe in the diabetic AR-/- mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR+/+ nerves, similar to those in diabetic AR-/- mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage. Diabetes 55:1946-1953, 2006 [ABSTRACT FROM AUTHOR]

Pioglitazone, one of thiazolidinediones, a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, is known to have beneficial effects on macrovascular complications in diabetes, but the effect on diabetic neuropathy is not well addressed. We demonstrated the expression of PPAR-gamma in Schwann cells and vascular walls in peripheral nerve and then evaluated the effect of pioglitazone treatment for 12 weeks (10 mg/kg/day, orally) on neuropathy in streptozotocin-diabetic rats. At end, pioglitazone treatment improved nerve conduction delay in diabetic rats without affecting the expression of PPAR-gamma. Diabetic rats showed suppressed protein kinase C (PKC) activity of endoneurial membrane fraction with decreased expression of PKC-alpha. These alterations were normalized in the treated group. Enhanced expression of phosphorylated extracellular signal-regulated kinase detected in diabetic rats was inhibited by the treatment. Increased numbers of macrophages positive for ED-1 and 8-hydroxydeoxyguanosine-positive Schwann cells in diabetic rats were also corrected by the treatment. Pioglitazone lowered blood lipid levels of diabetic rats, but blood glucose and nerve sorbitol levels were not affected by the treatment. In conclusion, our study showed that pioglitazone was beneficial for experimental diabetic neuropathy via correction of impaired PKC pathway and proinflammatory process, independent of polyol pathway.

Drastic increase in a population of diabetic patients urges to establish effective treatment or management of peripheral neuropathy, the most common complication of diabetes. Recent studies emphasize the occurrence of peripheral neuropathy in patients with impaired glucose tolerance, which condition is now shown to augment polyol pathway as well as non-enzymatic protein glycation in the peripheral nerve, exerted by postprandial hyperglycemia. Such metabolic cascades in turn result in tissue-specific alterations of cellular signaling, represented by decreased protein kinase C (PKC) activity and Na, K-ATPase activity in the peripheral nerve and contrariwise increased PKC activity in microvessels. The decrease in nerve PKC activity was demonstrated to associate with reduced membrane alpha-isoform expression and the increase in vessel PKC activity was due to membrane beta-isoform expression, respectively. Dual mechanisms of nerve and vascular alterations in addition to multiple metabolic factors may operate in the development of diabetic neuropathy in a complicated manner. Consequently, inhibition of hyperglycemia as well as specific intervention of single molecules related to altered cellular signaling is the essential approach for the primary prevention of diabetic neuropathy.