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Critical Roles of Insulin-Induced Senescence in Diabetic Vasculopathy

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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.

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Keywords: Diabetes; akt; insulin; p53; senescence

Document Type: Research Article

Publication date: August 1, 2007

More about this publication?
  • Vascular Disease Prevention publishes reviews as well as original papers to update all those concerned with this topic at the clinical or scientific level. In addition to clinically relevant topics, we consider reviews and original papers dealing with the more scientific aspects of vascular disease prevention. This includes the evaluation of emerging vascular risk factors, research dealing with the pathogenesis of atherosclerosis and the investigation of new treatment options both at the clinical and scientific level (e.g. epidemiology, patient-based studies, experimental models, in vitro experiments or molecular research). Therefore, another function of Vascular Disease Prevention is to bridge the gap between clinical practice and ongoing laboratory-based research.

    In particular, we welcome critical reviews and comments on recent trials. This is a topic that requires regular updates because of the large number of trials published every year.

    Debates are encouraged in the correspondence section of this journal.
    The editorial structure of Vascular Disease Prevention is set up with the aim of dealing with the submitted material as rapidly as possible. Specialist editors will provide a more expert and rapid assessment unlike a more centralized editorial structure.
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