Although Staphylococcus aureus is a major pathogen implicated in diabetic foot infections, little is known about the pathogenesis of this disease. A model of S. aureus infection in the hindpaw of nonobese diabetic (NOD) mice was developed. The experimental infection was exacerbated in diabetic mice (blood glucose levels >19 mmol/l) compared with nondiabetic mice, and the diabetic animals were unable to clear the infection over a 10-day period. Insulin-mediated control of glycemia in diabetic mice resulted in enhanced clearance of S. aureus from the infected tissue. Diabetic mice showed reduced tissue inflammation in response to bacterial inoculation compared with nondiabetic NOD animals, and this was consistent with the novel finding of significantly decreased tissue levels of the chemokines KC and MIP-2 in diabetic mice. Blood from nondiabetic and diabetic NOD mice killed S. aureus in vitro, whereas the bacteria multiplied in blood from diabetic mice with severe hyperglycemia. The impaired killing of S. aureus by diabetic mice was correlated with a diminished leukocytic respiratory burst in response to S. aureus in blood from diabetic animals. This animal model of hindpaw infection may be useful for the analysis of host defects in innate immunity that contribute to recalcitrant diabetic foot infections. Diabetes 54:2904 -2910, 2005 D iabetes afflicts ϳ16 million individuals in the U.S., and it is estimated that 2 million of these individuals will eventually develop chronic foot ulcers and infections (1). The most common cause of hospitalization for diabetic patients is foot infections (1), and the susceptibility of the diabetic host to these infections is multifactorial. Diabetes results in numerous physiologic perturbations in the host such as neuropathy and vasculopathy, and these can play a prominent role in the development of the diabetic foot (2).Staphylococcus aureus is the predominant pathogen in nonlimb-threatening foot infections, particularly in diabetic patients who have not yet received antimicrobial therapy (3-5). Although limb-threatening infections in the diabetic individual are frequently polymicrobial, S. aureus is a major pathogen in these infections (6). Type 1 diabetic patients show more frequent colonization of the nose and skin by S. aureus than nondiabetic and non-insulindependent diabetic individuals (7-9). The emergence of S. aureus strains resistant to multiple antibiotics has made the treatment of staphylococcal infections especially problematic. Methicillin-resistant S. aureus strains have become increasingly prevalent among both nosocomial and community-acquired infections (10,11). Recently, S. aureus isolates resistant to vancomycin, one of the antibiotics of last resort, were recovered from patients with chronic foot ulcers (12,13). Although the increased susceptibility of diabetic patients to bacterial infections is well established, the chronicity associated with these infections remains poorly understood.Many investigations have focused on the nonobese diabetic (NOD) mouse as a...