Abstract. Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction.Diabetes causes increased oxidative stress in various tissues as evidenced by increased levels of oxidized DNA, proteins, and lipids. Besides damaging the functions of these molecules, oxidative stress also triggers a series of cellular responses, including the activation of protein kinase C (PKC) (1,2), transcription factor NF-B (3), and JNK stress-associated kinases (4), and so forth. Inappropriate activation of these important regulatory molecules would have deleterious effects on cellular functions, and it is thought to contribute to the pathogenesis of various diabetic complications (5). However, it is not clear how hyperglycemia leads to increased oxidative stress. It is most likely the combined effects of increased levels of reactive oxygen species (ROS) and decreased capacity of the cellular antioxidant defense system. Glucose auto-oxidation (6), nonenzymatic glycation (7), and the interaction between glycated products and their receptors (8), overproduction of ROS by mitochondria (9), and the polyol pathway (10,11) all are potential sources of hyperglycemia-induced oxidative stress. This report focuses on the contribution of the polyol pathway to oxidative stress.The polyol pathway consists of two enzymes. The first enzyme, aldose reductase (AR), reduces glucose to sorbitol with the aid of its co-factor NADPH, and the second enzyme, sorbitol dehydrogenase (SDH),...
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 (
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