EFFECT OF TOLRESTAT, AN ALDOSE REDUCTASE INHIBITOR, ON NEUTROPHIL RESPIRATORY BURST ACTIVITY IN DIABETIC-PATIENTS

One hypothesis for the reduction in oxidative killing of neutrophils i n diabetic patients is that increased polyol pathway activity during h yperglycemia reduces intracellular levels of nicotinamide adenine dinu cleotide phosphate (NADPH), resulting in the reduction of neutrophil s uperoxide production during the respiratory burst. To test this hypoth esis, we assessed the effect of tolrestat, an aldose reductase inhibit or, on neutrophil respiratory burst activity (NRBA) in diabetic patien ts. We measured fasting plasma glucose (FPG), hemoglobin A(1) (HbA(1)) , and NRBA levels in 79 diabetic patients and 48 normal controls. NRBA was reassessed in 34 patients after 4 weeks of tolrestat or placebo t reatment, in seven controls after 4 weeks of tolrestat treatment, and in seven patients after 4 weeks of blood glucose control. NRBA was det ermined by flow cytometry, which detected fluorescent 2',7'-dichlorofl uorescein (DCF) in neutrophils formed from 2',7'-dichlorofluorescein d iacetate (DCF-DA) during phorbol myristate acetate (PMA)-induced respi ratory bursts. Diabetic patients showed lower NRBA than the normal con trols (mean cellular fluorescence, 438 +/- 103 v 668 +/- 101, mean +/- SD, P < .001). NRBA in diabetic patients showed a negative correlatio n with HbA(1) (r = .336, P < .005). Tolrestat treatment for 4 weeks in 17 patients restored the reduced NRBA to an almost normal level (rela tive NRBA, 0.55 +/- 0.20 v 0.99 +/- 0.36, P < .05) despite the fact th at FPG level did not change (11.8 +/- 2.8 v 11.4 +/- 2.8 mmol/L). NRBA of these patients after tolrestat treatment was not significantly dif ferent from that of seven control subjects treated with tolrestat for 4 weeks. In 17 placebo-treated patients, there were no significant cha nges in NRBA and FPG level. The vigorous blood glucose control for 4 w eeks in seven patients (16.6 +/- 2.1 v 8.6 +/- 2.3 mmol/L) also restor ed the reduced NRBA to almost normal (relative NRBA, 0.55 +/- 0.21 v 0 .90 +/- 0.30, P <.05). The result that the reduced NRBA in diabetic pa tients was restored to almost normal either by tolrestat treatment or by blood glucose control strongly supports the hypothesis of this stud y. Copyright (C) 1997 by W.B. Saunders Company.