Role of polyol pathway in nonenzymatic glycation

In order to confirm the link between nonenzymatic glycation and the polyol pathway, we observed the effect of treatment with epalrestat (Ep), an aldose reductase inhibitor, on the concentration of advanced glycation end-products (AGEs) in erythrocytes from diabetic patients. We also examined the effect of the drug on erythrocyte fructose 3-phosphate (F3P), a novel metabolite that has been reported to relate to the polyol pathway, and ascertained the glycation capability of F3P and its possible breakdown product, 3-deoxyglucosone (3DG), by incubating the metabolites with bovine serum albumin (BSA). Incubation of BSA with F3P or 3DG resulted in a greater production of AGEs in comparison with the incubation with glucose or fructose. F3P was significantly increased in erythrocytes from diabetic patients compared with those from nondiabetic individuals and was lower in patients who had been treated with Ep than in those who were free from the compound. A treatment of patients with Ep for 1 month resulted in a significant decrease in F3P. Erythrocyte AGEs were significantly elevated in diabetic patients compared with nondiabetic individuals and tended to be lower in patients taking Ep than in those without Ep. Administration of Ep for 2 months decreased AGEs. These results show that the polyol pathway is likely to play a substantial role in the nonenzymatic glycation of proteins and the suppression of E3P as well as AGEs by an aldose reductase inhibitor may explain in part the preventive effect of the drug on diabetic complications.