Critical Roles of Insulin-Induced Senescence in Diabetic Vasculopathy

Excessive calorie intake induces metabolic dysfunction and obesity, leading to the development of type 2 diabetes. Diabetic macroangiopathy is one of the most important complications of type 2 diabetes and it increases the risk of vascular events. Recent clinical studies suggest that impaired insulin signaling rather than hyperglycemia itself is involved in the pathogenesis of diabetes, but the mechanisms underlying the development of diabetic vasculopathy are still largely unknown. Restriction of calorie intake can extend the longevity of organisms ranging from yeast to mice and to prevent age-related conditions such as cancer, deterioration of immune function and increased inflammation. Calorie restriction decreases the plasma levels of glucose, insulin and insulin-like growth factor-1 (IGF-1). Recent genetic studies demonstrated that reduction-of-function mutations affecting insulin/IGF-1/phosphatidylinositol-3 kinase/Akt also extend the lifespan of many organisms, suggesting that these pathways may underlie the mechanism of longevity related to calorie restriction. We recently demonstrated that insulin increases the expression of negative regulators of the cell cycle, such as p53 and p21, and that it promotes endothelial cell senescence in an Akt-dependent manner. We found that the introduction of a dominant-negative Akt mutant decreased the insulin-induced activation of p53 and thus prolonged the lifespan of endothelial cells. Conversely, constitutive activation of Akt promoted senescence-like arrest of cell growth via a p53/p21- dependent pathway. Moreover, it has been shown that senescence of vascular cells is associated with the upregulation of insulin/Akt signaling in patients with type 2 diabetes. Accordingly, we propose that type 2 diabetes can be regarded as a type of premature aging syndrome in which the dysregulation of insulin/Akt signaling promotes cellular senescence, leading to various complications that include macroangiopathy. This concept suggests that anti-senescence therapy might be effective for the treatment of diabetic complications.