Red blood cell (RBC) concentrations of sorbitol and reduced glutathione (GSH) were evaluated in 29 type 11 diabetic subjects and eight normal controls. In erythrocytes from diabetic subjects, sorbitol levels were higher (18.7 +/- 1.33 v 11.2 +/- 0.7 nmol/g hemoglobin [Hb], P < .001) and GSH levels were lower (5.48 +/- 0.19 v8.33 +/- 0.24 micromol/g Hb, P < .01) than in nondiabetics. RBC sorbitol levels were positively correlated with fasting blood glucose (r =.57, P < .001) but not with HbAlc (r =.16, P < .05). RBC GSH levels showed a negative correlation with fasting blood glucose (r = -.35, P <.05) and with HbA1c (r = -.34, P < .05) and a significant negative correlation with RBC sorbitol levels (r = -.62, P < .001). Stepwise regression analysis highlighted the fact that the hyperglycemia-dependent increase in RBC sorbitol was significantly influenced by GSH concentrations (partial F = 14.6, P < .001). These data suggest the hypothesis that the hyperglycemia-induced enhanced activity of the polyol pathway leads to GSH depletion and, in turn, GSH depletion, reducing the glycolytic flux to pyruvate, enhances the rate of glucose metabolism through the polyol pathway. The overall effect is a progressive worsening of metabolic pseudohypoxia and depletion of GSH, resulting in lower defense against oxidative stress.