Resistance to the effects of insulin and insulin like growth factor-1 (IGF-1) in endothelial cells (EC) may promote the progression of type 2 diabetes and EC dysfunction. To dissect the effect of the combination of insulin and IGF-1 resistance specifically in EC on glucose homeostasis, nitric oxide (NO) availability and atherosclerosis, gene-modified mice were generated carrying non-functional mutated human IGF-1R K1003R, specifically in EC (mIGFREO) under the control of Tie2 promoter-enhancer.In insulin tolerance testing mIGFREO had enhanced insulin-mediated glucose lowering and consistent with enhanced insulin sensitivity lower fasting free fatty acids and triglycerides compared to wild type littermates (WT). Hyperinsulinaemic-euglycaemic clamp studies confirmed increased insulin sensitivity in mIGFREO (sample size 12) and consistent with this muscle Akt phosphorylation relative to Akt was significantly increased in mIGFREO, whilst liver ratio remained unchanged. As expected, both insulin and IGF-1 greatly stimulated eNOS activity and phosphorylation were significantly blunted in EC from mIGFREO. mIGFREO had significant increase in EC Nox4 NADPH oxidase (Nox4) expression and consistent with increased Nox4, mIGFREO EC generated increased hydrogen peroxide. Endothelial function assessed by vasorelaxation of aorta to acetylcholine, remained unchanged between mIGFREO and WT littermates. The basal level of eNOS phosphorylation was enhanced in the mIGFREO endothelial cells compared to WT littermates. Interestingly, when crossed onto an ApoE deficient background, mIGFREO mice did not develop accelerated atherosclerosis. Furthermore, mIGFREO backcrossed on an IR haploinsufficient background (IRKO), the mIGFREO mice demonstrated accelerated endothelial regeneration after femoral artery wire compared to IRKO.These data reveal an intriguing relationship between insulin and IGF-1 resistance at the level of EC and whole body insulin sensitivity. Despite reduced insulin-mediated NO generation, the combination of insulin and IGF-1 resistance leads to enhanced whole body insulin sensitivity and does not promote atherosclerosis.