Type 2 diabetes mellitus (T2DM) is a group of metabolic diseases increasing worldwide (1) and characterized by hyperglycemia. This condition results from defects in insulin secretion, insulin action, or both. Insulin is a hormone produced and secreted from pancreatic beta-cells located in the “islets of Langerhans”. It acts as a critical regulator of glucose metabolism: in the presence of insulin, blood glucose can enter the cells and can be used for energy. When insulin is not sufficiently produced by beta-cells or tissue fail to respond to insulin (condition called insulin-resistance), blood glucose levels increase promoting the onset of diabetes.
Chronic hyperglycemia characterizing diabetes is associated with long-term damage, dysfunction and failure of various organs, especially eyes, kidneys, nerves, heart and blood vessels. Among them, cardiovascular diseases represent the first cause of death of diabetic patients (2).
Diabetes is associated with ageing: the percentage of diabetic patients is 1.4% among 25-44 years old individuals, 3.6% among 45-54 years old individuals, 7.8% among 55-64 years old individuals and over 10% in subjects older than 65 years (3). Moreover, old diabetic patients show higher morbidity and mortality than old subjects without diabetes, because of the increased risk of developing dementia, depression, urinary incontinence and micro- and macrovascular complications (4).
Increased prevalence of T2DM is linked to the extension of lifetime, but also to the increased prevalence of overweight and obesity conditions. Indeed, it has been demonstrated that chronic and high levels of blood circulating fatty acids, as found in obese patients, can induce insulin resistance, loss of beta-cell mass and function, and cardiovascular alterations, conditions characterizing the phenomenon of "lipotoxicity" (5-8) that represents an important pathogenic step implicated in the development of T2DM.
One of the major mechanisms by which fatty acids cause lipotoxicity is the production of reactive oxygen species (ROS) (9,10), inducing oxidative stress capable of determining premature aging. On the other hand, oxidative stress arises from excessive consumption of nutrients that, in turn, are negatively correlated with duration of lifespan. On the contrary, caloric restriction lengthens lifespan (11, 12).
Therefore, oxidative stress and the consequent increase in ROS characterize both aging and lipotoxic damage, and both phenomena may predispose to T2DM.
Intracellular ROS production is a process regulated by many proteins, among which the p66Shc protein plays a crucial role in various tissues (13), because of its capacity to be a redox sensor and to produce pro-oxidants signals activating the apoptotic pathway when phosphorylated at Ser36 (14). Cellular overexpression of p66Shc increases ROS levels and oxidative damage, inducing cellular senescence; on the contrary knockout mice for p66Shc show an extened longevity compared to wild type mice (14, 15).
For the first time, our research team has demonstrated that, in pancreatic beta-cells, saturated fatty acids (SFAs) are able to increase the expression and the activation by phosphorylation at Ser36 of p66Shc, inducing beta-cell apoptosis, partially through ROS production (15). In addition, we have found increased p66Shc gene expression in pancreatic islets of obese patients versus lean subjects (15).
Our additional studies have demonstrated that p66Shc is involved in the modulation of glucose metabolism in skeletal muscle cells, through the negative control of glucose uptake under basal conditions (16). In addition, p66Shc gene expression is increased in circulating monocytes of diabetic patients compared to healthy subjects, in association with markers of oxidative stress (17).
On the other hand, the p66Shc protein could be involved in the pathogenesis of vascular complications of diabetes: we have shown that p66Shc is activated by the pro-inflammatory cytokine TNF-alpha in HUVEC human endothelial cells, resulting in increased oxidative stress that causes endothelial and vascular dysfunction; to note, these processes are the basis of atherogenesis (18) that is commonly associated with ageing.
Finally, preliminary results obtained in our laboratory show that chronic exposure of human cardiac progenitor cells to SFAs induces cellular senescence and increases phosphorylation of Ser36 p66Shc protein by activation of the stress kinase JNK, resulting in induction of cellular apoptosis.
Therefore, both studies form other grous and our own suggest a role of p66Shc protein in both production of intracellular ROS involved in ageing processes and in lipotoxic damage induced by excess of SFAs in different cells (pancreatic beta-cells and human cardiac progenitor cells). Since both processes may contribute to the pathogenesis and development of diabetes, the project idea is to study the role of p66Shc, in order to identify a possible drug target to prevent the onset and progression T2DM and complications associated with it.
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