Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients

Recent studies have suggested that elevated cellular lipid peroxidation may play a role in the development of cellular dysfunction and other complicat ions of diabetes. People with type 1 diabetes frequently encounter elevated levels of the ketone bodies acetoacetate (AA), beta-hydroxybutyrate (BHB), and acetone (ACE). This study was undertaken to test the hypothesis that k etosis might increase lipid peroxidation and lower glutathione (GSH) levels of red blood cells (RBCs) in diabetic patients. This study demonstrates th at incubation of AA with normal RBCs in phosphate-buffered saline (37 degre es C for 24 h) resulted in marked GSH depletion, oxidized glutathione accum ulation, hydroxyl radical generation, and in-creased membrane lipid peroxid ation. Increases in oxygen radicals and lipid peroxidation and depletion of GSH in RBCs were not observed with BHB or ACE treatments. Similarly, there was a significant generation of superoxide ion radicals even in a cell-fre e buffer solution of AA, but not in that of BHB. The presence of BHB togeth er with AA. did not influence the capacity of AA to generate oxygen radical s in a cell-free solution or the increase in lipid peroxidation of RBCs inc ubated with AA. The antioxidants vitamin E and N-acetylcysteine (NAC) block ed increase in lipid peroxidation in AA-treated RBCs. To examine the effect s of ketone bodies in vivo, studies were performed that showed a significan t decrease in GSH and an increase in lipid peroxidation levels in RBCs of h yperketonemic diabetic patients, but not in normoketonemic type 1 diabetic patients, when compared with age-matched normal subjects. This study demons trates that elevated levels of the ketone body AA. can increase lipid perox idation and lower GSH levels of RBCs in people with type 1 diabetes.