The International Diabetes Federation estimates that 316million people are currently affected by impaired glucose tolerance(IGT).Most importantly,recent forecasts anticipate a dramatic IGT increase with more that 470million people affected by the year 2035.Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes.However,the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered.Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue,emerging evidence indicates that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity.Indeed,suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide(NO)availability.Here we describe emerging theories concerning endothelial insulin resistance,with particular emphasis on the role oxidative stress.Complex molecular circuits including endothelial nitric oxide synthase,prostacyclin synthase,mitochondrial adaptor p66~(Shc),nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed.Moreover,the review provides insights on the effectiveness of available compounds(i.e.,ruboxistaurin,sildenafil,endothelin receptor antagonists,NO donors)in restoring endothelial insulin signalling.Taken together,these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes. The International Diabetes Federation estimates that 316million people are currently affected by impaired glucose tolerance (IGT) .Most importantly, recent forecasts anticipate a dramatic IGT increase with more that 470million people affected by the year 2035.Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes.However, the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered. Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue, emerging evidence that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity.Indeed, suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide (NO) availability. Heigh et al. lin resistance, with particular emphasis on the role oxidative stress. Complex molecular circuits including endothelial nitric oxide synthase, prostacyclin synthase, mitochondrial adapters p66 ~ (Shc), nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed. Moreover, the review provides insights on the effectiveness of available compounds (ie, ruboxistaurin, sildenafil, endothelin receptor antagonists, NO donors) in restoring endothelial insulin signaling. .aken together, these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes.