Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.

Abstract

To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils. We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor. The sorbitol and myo-inositol contents, and myo-inositol uptake were measured by high performance liquid chromatography and radio isotope technique with 2-[3H]-myo-inositol. After 2 h incubation, the sorbitol content increased with rising extracellular glucose concentrations, while the myo-inositol content decreased. Both AR inhibitors reduced the sorbitol content in neutrophils exposed to 40 mmol/l glucose medium. A 70% fall in the myo-inositol content in neutrophils exposed to 40mmol/glucose medium was attenuated approximately 40% by the addition of AR inhibitors. myo-Inositol uptake into neutrophils was inhibited by high glucose. AR inhibitors significantly ameliorated the decrease in myo-inositol uptake, but did not completely normalize it. Our present in vitro studies showed that the glucose-induced metabolic alterations in human neutrophils were similar to those in tissues prone to diabetic complications, and that AR inhibitors effectively corrected glucose-induced imbalances of the polyol pathway and myo-inositol uptake in neutrophils. In addition, our study suggests that glucose-induced metabolic alterations may result in the neutrophil dysfunction and that an AR inhibitor may be capable ameliorating it.