Contributions of polyol pathway to oxidative stress in diabetic cataract

Abstract

There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue. The substantial decrease in the level of reduced glutathione (GSH) with concomitant rise in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that glucose autoxidation and nonenzymatic glycation do not contribute significantly to oxidative stress in diabetic lenses. AR reduction of glucose to sorbitol probably contributes to oxidative stress by depleting its cofactor NADPH, which is also required for the regeneration of GSH. Sorbitol dehydrogenase, the second enzyme in the polyol pathway that converts sorbitol to fructose, also contributes to oxidative stress, most likely because depletion of its cofactor NAD+ leads to more glucose being channeled through the polyol pathway. Despite a more than 100% increase of MDA, oxidative stress plays only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol pathway is likely to be an important contributing factor in the slow-developing diabetic cataract as well as in the development of other diabetic complications.--Lee, A. Y. W., Chung, S. S. M. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23-30 (1999)

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…First, it causes cell damage, and second, it potently activates stress-sensitive signaling pathways including P3 MAPK and JNK. The activation of this pathway has been shown to cause diabetic complications in transgenic mice with over expression of aldolase reductase and the inhibition of this enzyme retards or prevents development of neuropathy, nephropathy, retinopathy and cataract formation (42,(75)(76)(77)(78). The excess of utilization of reduced NADP by aldose reductase may lead to deficiency or depletion of GSH which may have serious metabolic and physiologic consequences.…”

Acute irreversible diabetic cataract in adolescence: a case report

“…3 Reduction of glucose to sorbitol by aldose reductase (AR) leads to accumulation of sorbitol, which produces osmotic stress. It also produces oxidative stress by depleting cofactor NADPH that is an important cofactor for regeneration of reduced glutathione (GSH).…”

“…It also produces oxidative stress by depleting cofactor NADPH that is an important cofactor for regeneration of reduced glutathione (GSH). 3 Some authors also mention the probable importance of genetic factors in their case studies but the mechanism is still poorly understood. 4 Our patient was started on insulin and just after a week, noticed blurring of vision.…”

Assessment of Oxidative Stress Markers and Carotid Artery Intima-Media Thickness in Elderly Patients Without and with Coronary Artery Disease

“…In earlier studies a marked decrease in GSH were reported in diabetic patients [49,50]. In hyperglycemia, glucose is preferentially used in polyol pathway that consumes NADPH necessary for GSH regeneration by the glutathione reductase, therefore, hyperglycemia may indirectly cause GSH depletion causing increase in oxidative stress [51]. The limitation of the present study is its sample size.…”