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Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease., (© 2018 by the American Diabetes Association.)

Diabetes-associated micro- and macrovascular complications contribute to the increased morbidity and mortality observed in diabetes. Diabetes leads to accelerated generation of advanced glycation end products (AGEs) and activation of their receptor, RAGE, as well as activation of NAD(P)H oxidase (Nox), an enzyme dedicated to the production of reactive oxygen species, which ultimately leads to a pro-inflammatory environment characterised by oxidative stress. This review outlines the current evidence about the contribution of and interaction between the AGE-RAGE axis and Nox derived ROS formation in the development and progression of micro- and macrovascular diabetic complications (especially in atherosclerosis and nephropathy), and the mechanisms by which this occurs. We also outline novel treatments targeting the AGE-RAGE axis and specific Nox isoforms, which hold great promise in attenuating the development of diabetes-associated atherosclerosis and diabetic nephropathy., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)