الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
 |  | from | 162 |  |  |
| | | from | 162 | | |
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.