Diabetes mellitus (DM) is a major risk factor for cardiovascular disease causing both microvascular and macrovascular impairment [1, 2]. Despite the abundant data on the beneficial effect of strict glycemic control on microvascular disease  the management of macrovascular disease is less well established. The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) , mostly based on insulin treatment, did not confirm that aggressive glycemic control reduces the incidence of macrovascular events. Beyond a possible U-shape association of glycemic control with atherosclerosis progression, insulin resistance and the type of treatment may be implicated in this unexpected finding. Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors) have also been tested for their hypoglycemic control and have recently been found ineffective in reducing cardiovascular events .
In light of these observations, Akoumianakis I. et al. recently examined the role of insulin-induced vascular redox dysregulation . From this study we have learnt that in patients with coronary artery disease endogenous insulin status was associated with reduced nitric oxide bioavailability and that in the vasculature exposed to insulin there is activation of NADPH oxidases and uncoupling of endothelial NO synthase leading to reduced bioavailability of endogenous NO. Indeed, insulin drives oxidative atherosclerotic damage in the vessel wall which may explain not only the accelerated atherosclerotic lesions in patients with DM but also the minimum effects of insulin treatment. Downstream, insulin damage may be reversed by insulin sensitization, using DPP-4 inhibitors, and these finding may explain how the combined treatment with DDP-4 inhibitors and insulin can reduce incidence of strokes .
Beyond confirming the pathophysiologic mechanism implicated in the redox vascular damage in the presence of insulin resistance, this study also raises several questions that merit further investigation. Firstly, it remains to be answered how redox status in the vasculature is implicated in the different effects of hypoglycemic treatment in the microvascular and macrovascular complications and whether NOX isoenzymes, Rac1 and phosphatidylinositol 3kinase/Akt are regulated by insulin. The role of Glucagon-like peptide-1 receptor antagonists (GLP-1ra), which have a direct impact on insulin sensitivity and have documented atherosclerosis protection, in the restoration of oxidative vascular damage may provide further insights in the complex interplay between insulin treatment and macrovascular disease status .
Despite the vast majority of data concerning DM and atherosclerosis, the underlying pathophysiologic mechanisms driving macrovascular and microvascular complications and the interplay between treatment agents and vascular injury continue to focus research interest and merit clinical attention.