Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised with hyperglycaemia due to a loss of insulin production and/or action on its receptor and is often associated with obesity and cardiovascular disease. Protein-tyrosine phosphatase 1B (PTP1B) has been identified as a negative regulator of the insulin receptor and its expression is increased in T2DM patients. Moreover, PTP1B also plays a role in the modulation of inflammatory response via the JAK/STAT pathway. MSI-1436 and CPT157633 are PTP1B inhibitors which, separately, demonstrated promising effect on the insulin signalling pathway and in-vivo glucose homeostasis (Krishnan et al., 2015; Thompson et al., 2017). Inhibition of PTP1B with MSI-1436 also demonstrated protective and reversal effect against the development of atherosclerotic plaques via its anti-inflammatory action (Thompson et al., 2017). The aim of this project is to compare the effects of both inhibitors at different concentrations on high-fat/high cholesterol diet (HFD) fed C57/B6 mice, then use the optimal dose in APOE-/-, a mouse model of atherosclerosis. All animal procedures were performed under a project license approved by the U.K. Home Office under the Animals (Scientific Procedures) Act 1986. After 8 weeks on HFD, mice were injected weekly intraperitoneally for 5 weeks with saline (n=4) or different concentrations of PTP1B inhibitors (0.5, 1 and 5 mg/kg of animal; MSI 1mg/kg: n=4; others: n=5). Daily weight measurements and metabolic status assessments were performed during the treatment period. Preliminary data suggested that increasing dose of MSI-1436 promotes significant body weight loss after 5 weeks of treatments (MSI 5mg/kg compared to saline: two-way ANOVA, Bonferroni post-hoc test, p<0.0001), when CPT157633 did not affect body weight. This has been confirmed using the Echo-MRI, where a significant fat mass loss in MSI-1436 5mg/kg treated mice was observed (two-tailed t-test, α=0.05, p<0.05) without any change in lean mass. Glucose test tolerance showed an improved glucose homeostasis in mice treated with higher dose of MSI-1436 (two-tailed t-test, α=0.05, p<0.05). These preliminary data suggest that both drugs have a beneficial effect on glucose homeostasis and insulin signalling. The absence of weight loss using CPT157633 indicates that the drug does not cross the blood-brain barrier and does not have an effect on central leptin receptors but has a peripheral effect only while MSI-1436 is known to have an effect on both peripheral and central tissues. Further investigations are required to investigate PTP1B activity in brain tissues to assess the central effect of both drugs. Furthermore, improvement in glucose homeostasis, insulin signalling, and atherosclerotic plaques formation will be assessed at the end of the study after 5 weeks of treatment with PTP1B inhibitors.