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.