ReviewArticle The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

Received 26 February 2007; Accepted 24 April 2007Recommended by Subrata ChakrabartiThe polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose.It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemiabecause (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in humantissuesandorgansthataresitesofdiabeticcomplications,and(iii)theproductsofthepathwayandthealteredbalanceofcofactorsgenerate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase,the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but theresults of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators ofpolyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accuratelytissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glialand neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of humanretinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductasegene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindledinterest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare newclinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possibleto learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have goneundiscovered.Copyright © 2007 Mara Lorenzi.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.