Introduction: Insulin resistant type 2 diabetes mellitus (DM) causes accelerated vascular disease. Shc homology 2-containing inositol 5’ phosphatase-2 (SHIP2) is a lipid phosphatase that negatively regulates insulin signalling. This study assessed the effects of SHIP2 inactivation on metabolic and vascular homeostasis.Methods: Mice with global tamoxifen-inducible deletion of the catalytic domain of one SHIP2 allele (SHIP2i) were compared with littermate controls (WT). Metabolic profiling included body weight, glucose and insulin tolerance, and fasting insulin concentration. Recovery from wire-induced femoral arterial endothelial denudation was defined with Evans blue dye. In vitro studies used human umbilical vein endothelial cells (HUVEC) transduced with SHIP2 or control shRNA. Protein abundance was quantified with immunoblotting. Cell migration was assessed in a scratch wound assay, cell proliferation by EdU incorporation, and lamellipodium formation by phalloidin immunofluorescence. Analysis used t-testing, with significance defined as p<0.05.Results: Body mass was similar in WT and SHIP2i mice. SHIP2i mice demonstrated enhanced glucose tolerance (AUC 852 vs 1104; p=0.04) and insulin sensitivity (AUC 768 vs 950; p=0.02). Fasting glucose was similar (6.1 vs 6.4mmol/L; p=0.56), but SHIP2i mice had lower fasting insulin (0.36 vs 0.49ng/ml; p=0.003). Recovery from arterial injury was comparable in WT and SHIP2i mice (56% vs 56%; p=0.97). SHIP2 knockdown (SHIP2) of approximately 75% in HUVEC increased basal phosphorylation of Akt, ERK and eNOS. Nox2 protein was increased (1.39-fold; p=0.41), as was superoxide abundance (1.42-fold; p=0.02). SHIP2 HUVEC had impaired wound closure (33% vs 54%; p=0.002) but similar proliferation (14% vs 16%; p=0.27), and exhibited a disordered non-polarised distribution of lamellipodia, which can impair directional migration.Conclusions: Short-term inactivation of SHIP2 enhances whole-body insulin sensitivity and glucose disposal, and activates multiple signalling cascades in endothelial cells. However, the response to endothelial injury is not enhanced, which may reflect abnormal endothelial cell migration due to failure of appropriate cell polarisation.