Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia

Inexplicable controversies with regard to possible functional defects of ne utrophilic polymorphonuclear leukocytes (PMNs) in diabetes persist. The pur pose of the present study was to elucidate the relative effectiveness of se veral PMN agonists in stimulating lysosomal-enzyme secretion and leukotrien e (LT) B-4 production by PMNs isolated from diabetic subjects. Formyl-methi onyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) induc ed significantly less lysosomal-enzyme secretion and LTB4 production in dia betic-subject PMNs than in normal-subject PMNs. It is surprising that PMNs from these same diabetic subjects responded normally after stimulation with A23187, serum-opsonized zymosan, or phorbol myristate acetate. The in vitr o responsiveness of PMNs stimulated with fMLP or PAF was inversely correlat ed with indices of in vivo glycemic control (fasting plasma glucose and gly cated-hemoglobin levels). In combination, these results indicate that hyper glycemia is associated with sustained decreases in PMN function but only in response to agonists that initiate stimulus-response coupling via G-protei n-coupled receptors. This agonist-selective reduction in PMN responsiveness may contribute to the compromised host defense associated with sustained h yperglycemia in diabetes.