SIRT1, p66Shc, and Set7/9 in Vascular Hyperglycemic Memory

Abstract

Diabetes represents a ramping public health issue in the Western world owing to overnutrition and reduced physical activity coupled with genetic susceptibility (1,2). Nowadays, obesity is a major determinant of insulin resistance, which results in compensatory hyperinsulinemia with subsequent impairment of insulin secretion and rise of blood glucose levels. Over the last 30 years, the detrimental effects of hyperglycemia on the vessel wall have promoted major research efforts leading to the understanding that high glucose decreases availability of endothelium-derived nitric oxide (NO) and triggers vascular inflammation via an array of mechanisms involving the overproduction of reactive oxygen species (ROS) (3,4). Although the identification of different signaling pathways has opened several windows of opportunity to prevent diabetic vascular disease, we are still far from having found a thorough and, most of all, effective approach against cardiovascular burden of diabetes. Indeed, recent clinical trials have shown that normalization of blood glucose failed to reduce cardiovascular outcomes in the diabetic population (5–7). It is noteworthy that intensive glucose-lowering therapy in these trials was started after a median duration of diabetes ranging from 8 to 11 years (8). By contrast, glucose-lowering treatment of patients with new-onset diabetes was shown to be beneficial (9–12). These findings hint that early preservation of physiological metabolic environment is crucial for interfering with the natural history of diabetic vasculopathy. In this Perspective, the landmark Diabetes Control and Complications Trial (DCCT) and the follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC), demonstrated not only that intensive glycemic control in subjects with type 1 diabetes reduced the risk of microvascular complications but also that episodes of poor glycemic control can lead many years later to the long-term complications of diabetes (9,12). More recently, the 10-year posttrial monitoring follow-up of the …