Contributions of polyol pathway to oxidative stress in diabetic cataract

There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unc lear. Using transgenic mice that overexpress aldose reductase (AK) in their lenses, we found that the flux of glucose through the polyol pathway is th e major cause of hyperglycemic oxidative stress in this tissue. The substan tial decrease in the level of reduced glutathione (GSH) with concomitant ri se in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that g lucose autoxidation and nonenzymatic glycation do not contribute significan tly to oxidative stress in diabetic lenses. AK reduction of glucose to sorb itol probably contributes to oxidative stress by depleting its cofactor NAD PH, which is also required for the regeneration of GSH. Sorbitol dehydrogen ase, the second enzyme in the polyol pathway that converts sorbitol to fruc tose, also contributes to oxidative stress, most likely because depletion o f its cofactor NAD(+) leads to more glucose being channeled through the pol yol pathway. Despite a more than 100% increase of MDA, oxidative stress pla ys only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol p athway is likely to be an important contributing factor in the slow-develop ing diabetic cataract as well as in the development of other diabetic compl ications.