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.
Key Words Diabetic retinopathy – polyol pathway – aldose reductase – sorbitol dehydrogenase – aldose reductase polymorphisms – sorbitol – fructose – osmotic stress – oxidative stress – advanced glycation endproducts – pericytes – endothelial cells – Müller glial cells – apoptosis – inflammation – aldose reductase inhibitors.