Aims: A key enzyme involved in Alzheimer’s disease (AD) progression is the β-secretase enzyme (β-site APP Cleaving Enzyme 1 – BACE1). Individuals with type 2 diabetes have an increased risk of AD, and AD is closely associated with insulin resistance and central glucose impairment. We previously reported that BACE1-/- mice are resistant to diet induced obesity and have improved glucose homeostasis. Therefore the aim of the study was to determine the effect of inhibition of β-secretase (BACE1) on the diabetic phenotype of mice on a high fat diet. Methods: Age matched C57BL/6 mice were fed a high fat diet (HFD, 45% fat) for 20 weeks to engender a diet-induced obesity (DIO) phenotype. Mice were then anesthetised by inhalation of isoflurane and a mid-scapular incision was made to enable subcutaneous implantation of an osmotic minipump. A minipump containing BACE1 inhibitor (BACEi; 10 mg/kg) or vehicle (DMSO/PBS) was implanted and remained for 4 weeks. Body weight and food intake were monitored over the course of the study, while glucose homeostasis was measured at the end of the study. Intraperitoneal glucose (2 mg/kg) and insulin (0.75 U/kg) tolerance tests were performed following an overnight or 4 hour fast respectively. Blood glucose measurements were monitored, from blood taken from the tail vein (~5 l), at regular intervals for 2 hours post administration. All data are expressed as mean ± standard error of mean, and statistical significance determined by two-way ANOVA or Student’s t-test. *p<0.05, **p<0.01, ***p<0.001 versus control. Results: Infusion of BACE1 inhibitor to obese mice caused a significant reduction in body weight (-8.79 % ± 1.45; P < 0.001) relative to their starting weight, while vehicle treatment had no effect (1.35 % ± 0.96). Food intake was not significantly different between vehicle and BACEi treated mice. Glucose disposal was significantly improved in the BACEi treated mice (AUC: 2004 ± 119, 1561 ± 90.0; P < 0.01), whereas insulin sensitivity, as determined by insulin tolerance test, was unaltered. Conclusions: Peripheral administration of an inhibitor of the protease, BACE1 reduced body weight and improved glucose disposal in DIO mice. As BACE1 has been validated as a therapeutic target for Alzheimer’s disease these data suggest that BACE1 inhibitors, currently in clinical trials, may also be useful therapeutic agents for the treatment of obesity associated with type 2 diabetes.