Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future

Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.

Automated summary

The proposal of a single unifying mechanism for diabetic complications by Brownlee and colleagues marked a turning point in research, highlighting the role of ROS in diabetes-associated vascular disease pathways. Over a twenty-year journey, studies have focused on ROS generation in diabetes, cell dysfunction, and the pathogenesis of complications, while also exploring alternative mechanisms and the role of oxidative stress as an initial event in hyperglycemia-induced biochemical abnormalities.