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• W18703456 abstract "The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. Several biochemical features and a large body of data implicate the polyol pathway as a plausible and important contributor to diabetic retinopathy and other complications of diabetes. In both humans and experimental animals, all retinal cell types known to be affected by diabetes contain aldose reductase (AR), the first and rate-limiting enzyme of the pathway. Metabolism through the pathway is accelerated by elevated cytoplasmic glucose concentrations induced by hyperglycemia. The resulting altered concentrations of pathway products and cofactors can cause osmotic and oxidative stress, the latter through multiple mechanisms that include the generation of precursors of advanced glycation endproducts. These stresses eventually lead to apoptosis and proinflammatory events. In diabetic individuals, certain polymorphisms of the AR gene are associated with high AR expression levels and an accelerated or more severe course of retinopathy. Conversely, genetic ablation of AR in mice results in protection from diabetic retinopathy. In rats with experimental diabetes, drugs that inhibit AR are, as of today, the only drugs documented to prevent the whole spectrum of abnormalities induced by diabetes in glial cells, neurons, and vascular cells of the retina. This may have translational importance, because human diabetic retinopathy has recently become known to include glial and neuro-nal abnormalities. The efficacy of AR inhibitors (ARIs) has been, for the most part, disappointing in humans. The major reason for the discrepant results in clinical vs. preclinical studies is likely discrepant doses; for example, in recent studies the ARI sorbinil proved successful in preventing retinopathy in diabetic rats when given at a dose 20-fold larger than the dose used unsuccessfully in a past clinical trial. It has become clear that larger doses of ARIs ensure that metabolic flux through both steps of the pathway is inhibited — as opposed to merely reducing sorbitol accumulation. A current hypothesis posits that normalization of glucose flux through the pathway is required in order to prevent excessive turnover of pathway cofac-tors and oxidative stress; and that the latter is a critical, if not the main, determinant of the tissue consequences of excess polyol pathway activity. Testing this concept in humans will become possible when new drugs, capable of inhibiting aldose reductase with higher in vivo efficacy and safety than the older ARIs, become available. It is reasonable and important to advocate, and work toward, the discovery of such drugs because some features of diabetic retinopathy appear best or uniquely approached via inhibition of excess polyol pathway activity." @default.
• W18703456 created "2016-06-24" @default.
• W18703456 creator A5014233833 @default.
• W18703456 creator A5089099211 @default.
• W18703456 date "2008-01-01" @default.
• W18703456 modified "2023-09-27" @default.
• W18703456 title "The Polyol Pathway and Diabetic Retinopathy" @default.
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