Inflammatory Axis and Sirtuins' in Overweight Pre-diabetics Patients

Overview

In obese patients the superficial adipose tissue works as an endocrine active tissue to express different cytokines, and multiple molecular pathways implied in the cross talking with different part of the human body, such as the cardiovascular system. To date, adipocytes and adipose tissue-derived macrophages and adipose tissue synthesize, and secrete several cytokines, and sirtuins. In this setting, the excess of body fat is linked to heart contractile dysfunction. All these pathways are differently expressed in obese diabetic patients as compared to obese non diabetic patients. Intriguingly, in diabetic obese patients the hyper-expression of inflammatory cytokines is associated to a hypo-expression of sirtuins. Furthermore, microRNAs (miRs) as miR 195 and miR 27 could be implied in the regulation of this complex cellular and molecular axis.Therefore, this molecular pattern in diabetic obese patients may correlate to altered myocardial performance, and to the development of heart failure disease. In this study authors will evaluate at baseline by peripheral blood samples and by the abdominal fat tissue, and than at 12 months of follow-up by perupheral blood analysis, the expression of cytokines sirtuins and miR 195/27 comparing pre-diabetics obese patients vs. non pre-diabetics obese patients.

In obese patients the visceral fat, and the superficial adipose tissue work as an endocrine active tissue to express different cytokines, and multiple molecular pathways implied in the cross talking with different part of the human body, such as the cardiovascular system. To date, adipocytes, and adipose tissue-derived macrophages and adipose tissue, synthesize and secrete several cytokines, like tumor necrosis factor (TNF)-5 and interleukin (IL)-6, and anti-apoptotic proteins, such as sirtuins. Sirtuins are NAD+-dependent deacetylase involved in the control of energy metabolism, adipocyte hypertrophy, and of different cardiac reparative, and rimodellative functions. Furthermore Sirtuins could cross talk with inflammatory/oxidative stress axis, and could be modulated by miR 195/27 expression. In this setting, the excess of body fat is linked to heart contractile dysfunction. It is intuitive to speculate that, all these pathways are differently expressed in obese diabetic patients as compared to obese non diabetic patients. Intriguingly, in diabetic obese patients the hyper-expression of inflammatory cytokines is associated to a hypo-expression of sirtuins, and over expression of miR 195 and miR 27. Therefore, this molecular pattern in diabetic obese patients may correlate to altered myocardial performance, and to the development of heart failure disease. Authors' study hypothesis is that, this complex altered bidirectional pattern between the inflammatory and apoptotic pathways axis may be due to a progressive increase in adipose tissue, produced by long-term alterations in energy balance. However, all these alterations may be measured in adipocytes as well as in adipose tissue derived macrophages, and by peripheral blood assay. Intriguingly, no data evaluated these pathways in pre-diabetics obese patients, and their possible correlation to cardiac function worsening, and to the development of heart failure disease. Actually, the pre-diabetic obese subjects represent a population of patients associated to higher risk to develop cardiovascular disease, myocardial dysfunction, and heart failure. In these patients a not clear indication exists about the right dietetic and/or drug treatment to control the hyperglycemia. However, there is discussion about the necessity or not to introduce hypoglycemic drug therapy added to a hypocaloric diet therapy to control the hyperglycemic overload. Therefore, the aim of the present study will be to evaluate at baseline the abdominal fat tissue expression of cytokines, sirtuins, miR 195 and miR 27 (by direct tissue biopsy) and by peripheral blood samples in pre-diabetics obese patients vs. non pre-diabetics obese patients. As second, during six and twelve months of follow up by peripheral blood samples analysis authors will evaluate the abdominal fat tissue expression of cytokines, miR 195 and miR 27 in pre-diabetics obese patients treated by hypocaloric diet-therapy as compared to pre-diabetics obese patients treated by hypocaloric diet-therapy plus metformine. At the end, authors will report their correlation to myocardial performance index (MPI) as an index of myocardial performance in pre-diabetics obese patients treated by hypocaloric diet-therapy as compared to pre-diabetics obese patients treated by hypocaloric diet-therapy plus metformine. Authors may speculate to observe a different cytokines, sirtuins, miR 195 and miR 27 expression at visceral fat and peripheral blood in pre-diabetics obese patients vs. non pre-diabetics obese patients. As second, authors may find that, hypoglycemic drug therapy may induce a down regulation of peripheral blood cytokines, a hyper expression of sirtuins, and a down regulation of miR 195 and miR 27 involved in the control of energy metabolism, and of adipocyte hypertrophy, and secondary implied in a better cardiac function at follow up.