الفهرس | Only 14 pages are availabe for public view |
Abstract Cellular energy metabolism consists of a number of pathways. Mitochondrial respiration and ATP synthesis are two pathways lying at the heart of metabolism. Mitochondrial respiration consists of the oxidation of mitochondrial substrate (NADH) supplied by nutrients which couple the electron transport chain (ETC) to the pumping of proton out across the mitochondrial membrane. The ATP synthase couples the transport of proton across the membrane to the synthesis of ATP inside the mitochondrial matrix. Thus mitochondria convert energy stored in nutrient into ATP/ADP that drives work within the body. However, nothing comes without cost. Molecular oxygen, the final electron acceptor for cytochrome c oxidase, is ultimately reduced to water. However, a small quantity of O2 may be incompletely reduced as a leakage of single electrons, causes the reduction of O2 to superoxide (O2¯˙). Intracellular signaling effectors, including H2O2 reflect the balance between the electron leak from the electron transport system, superoxide formation and scavenging of H2O2 by endogenous antioxidants in the matrix. In physiological conditions a homeostatic balance exists between endogenous oxidants, ROS formation and their elimination by endogenous antioxidants. However, under conditions of overnutrition and physical inactivity, typical to those facing metabolic syndrome, the oversupply of substrates generating surplus reducing equivalents could in turn be expected to elevate the redox state and increasing oxidative stress. We focus in the present work on oxidative stress events leading to individual disease factor appearance in metabolic syndrome patients. Metabolic syndrome patients show altered mitochondrial metabolism as evidenced by more than 100% increase in 8-OHdG (a critical biomarker of oxidative stress) compared to control. Metabolic abnormalities detected in our results defined the presence of abdominal obesity (increased waist circumference), IR along with its associated hyperinsulinemia, elevated TG and fasting glucose, low HDL and high blood pressure. We obtain also a linear combination of variables, including: waist circumference, hypertension, hyperglycemia, IR, dyslipidemia and oxidative stress markers (8-OHdG, MDA and SOD). Abdominal obesity (increase WC) is consistent with increased oxidative stress markers, representing the trigger for systemic oxidative alterations. Positive correlation between fasting glucose and 8-OHdG suggests a role of hyperglycemia in increase of intracellular glucose metabolism and consequent increase in ROS production. High plasma oxidative stress markers (8-OHdG& MDA) correlate also positively with elevated TG, LDL and with low HDL. Also, Malondialdehyde (lipid peroxidation index) correlates with low HDL. It is likely that stressors in various forms hit the organism at many different levels (molecular integration between lipid and glucose) and that this adds up to a pathogenic process moving toward insulin resistance obtained in our results. Thus, oxidative stress plays a number of potential mechanisms in the pathophysiology of metabolic syndrome. Positive correlation between oxidative stress markers and insulin resistance in our metabolic syndrome patients may suggest that several factors that cause insulin resistance have a common pathway in the excessive formation of ROS. Thus, the present work links intracellular metabolic balance to the control of insulin sensitivity. We also place the etiology of obesity-induced insulin resistance, which is a component of metabolic syndrome in the context of mitochondrial bioenergetics. Several studies have suggested that increased oxidants by chronic overnutrition coupled with decreased endogenous antioxidant capacity results in oxidative stress. In the present work a significant decrease in total SOD enzyme suggests decreased endogenous mitochondrial capacity in our metabolic syndrome patients. Accordingly, for many years, interest has focused on strategies that enhance removal of ROS using either antioxidants or drugs that enhance endogenous antioxidant defense. Another object in the present study was to evaluate the prognostic value of oxidative stress markers in a group of metabolic syndrome subjects receiving atorvastatin treatment (a synthetic lipid-lowering agent), and a second group receiving atorvastatin plus vitamin E (as an antioxidant), both groups were followed up for 3 months. Our results reveal improvements in the quantitative estimation of oxidative stress markers (8-OHdG, MDA and SOD) in both groups. However, this level of supplementation with combined treatment (atorvastatin+ vitamin E) did not alter significantly 8-OHdG, while it decreased significantly MDA and LDL levels when compared with treatment with atorvastatin alone, reflecting the importance of antioxidant vitamins in reducing lipid peroxidation and oxidative stress level. Therefore, combination therapy that simultaneously addresses multiple mechanisms for the pathogenesis of metabolic disorders is an attractive emerging concept for slowing progression of oxidative stress complications. Combined therapy with statins and antioxidant vitamins demonstrates additive beneficial effects on dyslipidemia and lipid peroxidation when compared with monotherapies in patients with metabolic syndrome and cardiovascular risk factors due to both distinct and interrelated mechanisms. These additive beneficial effects of combined therapies are consistent with laboratory and recent clinical studies. Thus, combination therapy may be an important paradigm for treating and slowing progression of atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and hyperlipidemia. We suggest that oxidative stress markers correlate with outcomes in metabolic syndrome patients treated with atorvastatin revealing antioxidant properties of atorvastatin by reducing lipid peroxidation (MDA) and ROS production (8-OHdG). Significant reduction in cholesterol, LDL, TG and obvious increase in HDL in both groups was also obtained. We can suggest also that the beneficial effect of atorvastatin appear to be greater than that might be expected from changes in lipid levels alone, and as a result of a direct decrease in oxidative stress. We can suggest that mitochondrial dysfunction leading to increased oxidative stress markers (8-OHdG& MDA) may occur during overnutrition coupled with limited physical activity, and thereby contribute to the genesis and maintenance of the metabolic syndrome. We suggest a great benefit of dietary intervention for the metabolic syndrome population, i.e. simply reestablishing cellular metabolic balance by limiting caloric intake and/or increasing metabolic demand through increased physical activity. Insulin resistance,elevated triglycerides and defect of mitochondrial oxidative capacity are all related abnormalities switched-on in response to metabolic stress. We can say also that oxidative stress may be a major determinant factor in the loss of both insulin sensitivity and mitochondrial function associated with overnutrition. Thus oxidative stress plays a number of potential mechanisms in the pathophysiology of metabolic syndrome. Thus present study suggests that mitochondrial dysfunction leading to oxidative stress as evidenced by increased (8-OHdG& MDA) is a consequence of altered cellular metabolism that develops with nutritional overload. We recommend further testing and exploration of this proposal for the role of mitochondria in the metabolic syndrome which may contribute to our understanding of its origin, maintenance and the development of further therapy. |