Type 2 diabetes is preceded by insulin resistance, followed by increased endothelial cell production of superoxide and reduction in bioavailability of the vasoprotective signalling molecule, nitric oxide (NO). We demonstrated in preclinical models that type 2 diabetes also causes resistance to insulin-like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release. This study aimed to examine the effect of the endothelial cell-specific combination of insulin and IGF-1 resistance on glucose homeostasis and NO availability. We generated mice expressing mutant IGF-1 receptors (mIGF-1R) which form non-functional hybrid receptors with endogenous insulin receptors (IR) and IGF-1R under the control of Tie2 promoter-enhancer, to induce insulin and IGF-1 resistance specifically in endothelial cells. Despite endothelial insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated glucose lowering, lower fasting free fatty acids and triglycerides. In hyperinsulinaemiceuglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and adipose tissues in response to insulin. mIGFREO had reduced endothelial cell NADPH oxidase 2 (Nox2) expression and increased endothelial cell NADPH oxidase 4 (Nox4) expression. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2) with no increase in superoxide. Furthermore, in vivo treatment with catalase, a H2O2 dismutase restored insulin tolerance to wild type levels in mIGFREO. mIGFREO mice demonstrated a decrease in the expression of the small non-coding RNA, miR-25 in endothelial cells, which is also negative regulator of Nox4. Combined insulin and IGF-1 resistance at the endothelial level leads to a potentially favourable adaptation including a switch in the balance in oxidant species generation from Nox2-derived superoxide, seen in pure insulin resistance to a miR-25 regulated Nox4-derived H2O2 generation which enhances whole body insulin sensitivity.