Inhibition of phospholipase D and superoxide generation by glucose in diabetic neutrophils

Diabetics are prone to infection, in part, due to neutrophil dysfunction and impaired superoxide generation. The mechanism of impaired superoxide generation in diabetes remains unknown. We report herein that neutrophils from poorly controlled diabetics have impaired ability to generate superoxide in response to N-formyl-Met-Leu-Phe (FMLP) but not to 4 beta-phorbol 12-myristate 13-acetate (PMA). Phosphatidic acid, a phospholipase D (PLD) -mediated product of membrane phosphatidylcholine is decreased in response to FMLP. The impaired superoxide generation and activation of phospholipase D are readily reversible once the diabetic neutrophils are incubated in normal glucose concentration. These data show that decreased superoxide generation by neutrophils in insulin-dependent diabetics is, in part, due to impaired activation of phospholipase D and is solely due to high glucose concentrations.