The objective of this project is to determine how polymorphonuclear leukocyte (PMN) function is impaired in diabetes and whether the impairments in cell function are reversible. Although altered PMN function has been previously reported to occur in diabetes, the causes of cell dysfunction are not well understood. In addition, therapeutic interventions to improve PMN function are not established. Because infection is a major cause of morbidity in diabetic patients, the causes of impaired PMN function and means to improve cell function may of clinical importance. Glucose metabolism through the polyol pathway during periods of hyperglycemia may be associated with depletion of cellular myo- inositol. Myo-inositol is in an equilibrium with phosphatidyinositol, a phospholipid of critical importance in PMN stimulus-response coupling. It is therefore proposed that altered phosphatidylinositol metabolism is a cause of impaired PMN function in diabetes. Impaired PMN function caused by glucose metabolism through the polyol pathway may be of clinical importance because therapeutic interventions to prevent or reverse depletion of myo-inositol are available. Aldose-reductase inhibitors reduce glucose metabolism through the polyol pathway and myo-inositol supplementation restores cellular inositol concentrations. The proposed studies will characterize an in vitro model of impaired PMN function induced by elevated glucose concentrations. Using this model, the effects of insulin, aldose- reductase inhibitors and myo-inositol on PMN function will be evaluated. PMN from diabetic subjects will be then by studied to determine whether cell function may be improved following normalization of extracellular glucose, treatment with insulin, incubation with aldose-reductase inhibitors or exposure to myo- inositol. The results of these studies may be of value in both the care of diabetic subjects and development of new therapeutic interventions. Methods for rapidly evaluating stimulus-response coupling and PMN function in diabetic patients will be developed. The specific defects in PMN function which are induced by hyperglycemia will be characterized. Potential therapeutic interventions to improve PMN function will be evaluated. The proposed experiments are unique, the model of PMN function is novel but straightforward and the results are likely to be relevant to the care of diabetic patients.
