Insulin Treatment Directly Restores Neutrophil Phagocytosis and Bactericidal Activity in Diabetic Mice and Thereby Improves Surgical Site Staphylococcus aureus Infection

Abstract

ABSTRACTBacterial infections, including surgical site infections (SSI), are a common and serious complication of diabetes.Staphylococcus aureus, which is eliminated mainly by neutrophils, is a major cause of SSI in diabetic patients. However, the precise mechanisms by which diabetes predisposes to staphylococcal infection are not fully elucidated. The effect of insulin on this infection is also not well understood. We therefore investigated the effect of insulin treatment on SSI and neutrophil function in diabetic mice.S. aureuswas inoculated into the abdominal muscle in diabeticdb/dband high-fat-diet (HFD)-fed mice with or without insulin treatment. Although the diabeticdb/dbmice developed SSI, insulin treatment ameliorated the infection.db/dbmice had neutrophil dysfunction, such as decreased phagocytosis, superoxide production, and killing activity ofS. aureus; however, insulin treatment restored these functions.Ex vivotreatment (coincubation) of neutrophils with insulin and euglycemic control by phlorizin suggest that insulin may directly activate neutrophil phagocytic and bactericidal activity independently of its euglycemic effect. However, insulin may indirectly restore superoxide production by neutrophils through its euglycemic effect. HFD-fed mice with mild hyperglycemia also developed more severe SSI byS. aureusthan control mice and had impaired neutrophil phagocytic and bactericidal activity, which was improved by insulin treatment. Unlikedb/dbmice, in HFD mice, superoxide production was increased in neutrophils and subsequently suppressed by insulin treatment. Glycemic control by insulin also normalized the neutrophil superoxide-producing capability in HFD mice. Thus, insulin may restore neutrophil phagocytosis and bactericidal activity, thereby ameliorating SSI.