Aging is an important risk factor for diabetes and cardiovascular disease (1). Although the vascular implications of endothelial insulin resistance are well understood (2) the effect of enhanced endothelial insulin signaling on glucose regulation and vascular function remain poorly characterized. To investigate this we generated mice with endothelial-specific downregulation of the lipid phosphatase SHIP2 (3). We deleted exons 18-19 of the ship2 gene using Cre-Lox technology under control of the Tie2 promoter generating an inactivate protein. Male heterozygotes (EC-SHIP2+/-) were compared to sex-matched littermate controls. At 8 weeks of age EC-SHIP2+/- mice displayed increased glucose tolerance after glucose challenge (P=0.03) and improved insulin sensitivity (P=0.02) after insulin challenge (glucose/insulin administration via intra-peritoneal injection, blood sampling from tail vein). By 40 weeks of age this phenotype was reversed; EC-SHIP2+/- mice revealed significant insulin resistance 60 min after insulin challenge (P=<0.05). This phenotype was confirmed by euglycemic hyperinsulinemic clamping. In young mice ex vivo aortic vasomotor studies in both controls and EC-SHIP+/- revealed similar contractile responses to phenylephrine and displayed decreased contraction after insulin incubation (Emax 0.88 ± 0.05g vs 0.62 ± 0.05g P=0.002 and 0.83 ± 0.05g vs 0.69 ± 0.05g P=0.025 respectively). Both groups displayed increased contraction after NO synthase inhibitor LNMMA incubation (Emax 0.88 ± 0.05g vs 1.31 ± 0.11g P=0.01 and 0.83 ± 0.05g vs 1.28 ± 0.02g P=<0.0001 respectively). However, at 40 weeks old in EC-SHIP2+/- mice the vasodilatory aortic ring response to insulin was abolished (Emax controls 0.59 ± 0.04g vs 0.47 ± 0.03g P=0.04, EC-SHIP2+/- 0.64 ± 0.04g vs 0.63 ± 0.06g P=0.9) and EC-SHIP2+/- displayed no increase in contraction to LNMMA incubation (Emax controls 0.59 ± 0.04g vs 0.82 ± 0.08g P=0.02, EC-SHIP2+/- 0.64 ± 0.04g vs 0.69 ± 0.07g P=0.5) indicating insulin resistance and lower basal nitric oxide production (NO), suggesting changes in glucose homeostasis may be mediated by NO bioavailability. In conclusion; endothelial functional downregulation of SHIP2 augments whole body glucose disposal in young mice but attenuates whole body glucose disposal in older mice. Our data suggest a previously unrecognised age dependent role for the vascular endothelium in whole body glucose regulation and a novel spatial and temporal specific affect of the lipid phosphatase SHIP2.