Journal of Hypertension:
Metabolic syndrome, insulin resistance and oxidative stress: adding insights to improve cardiovascular prevention
Acasti Pharma Inc., Montreal, Quebec, Canada
Received 5 April, 2009
Accepted 20 April, 2009
Correspondence to Farhad Amiri, PhD, Acasti Pharma Inc., 2901 Rachel E, Suite 11, Montreal, QC H1W 4A4, Canada Tel: +1 514 394 7974; fax: +1 514 527 5165; e-mail: firstname.lastname@example.org
The metabolic syndrome (MetS) is currently defined as a constellation of cardiovascular risk factors of metabolic origin that promote the development of atherosclerotic cardiovascular disease (CVD) and type 2 diabetes . In the past few years, several clinical and biochemical criteria have been established in order to identify MetS patients, the most widely accepted being: visceral obesity (defined as increased waist circumference), atherogenic dyslipidemia [defined as elevated serum triglycerides and apolipoprotein B (apoB)], an increased number of small low-density lipoprotein (LDL) particles and a reduced level of high-density lipoprotein (HDL) cholesterol, increased blood pressure (BP) and increased plasma glucose [2,3]. Differences among the available guidelines are related to the criteria considered, the number of criteria that need to be fulfilled and the cut-off to define some of the criteria such as waist circumference, lipid and glucose levels and BP.
However, the definition of MetS is still a matter of great debate in clinical practice [4,5]. The main issue for clinicians and scientists is to identify a clinical condition in which metabolic risk factors cluster together rather than to simply associate. In this sense, the following two points need to be better clarified: whether the MetS is predictive of CVD, beyond the additive effects of its individual components, and whether there is a common underlying pathological process that links all the metabolic factors. With respect to the first, some clinical studies and recent meta-analysis have examined the association of the MetS with CVD and found a strong consistent relationship that remains even after adjusting for the individual cardiovascular risk factors [6–9]. Conversely, other studies [10–13] have shown that the increased mortality and/or atherosclerotic CVD associated with the MetS positively correlate with the number of criteria fulfilled and were further increased by the association with additional risk factors, such as cigarette smoking or elevated LDL cholesterol, suggesting that the cardiovascular risk is additive. As for the pathophysiology of the MetS, the most unifying hypothesis is insulin resistance that is defined as the reduction in tissue insulin-mediated glucose uptake. However, both insulin resistance and hyperinsulinemia do not appear as diagnostic criteria in most guidelines used to define MetS, mostly because of the difficulty and expensiveness of measuring them routinely in clinical practice. In this sense, surrogate markers of insulin resistance have been adopted, such as visceral obesity (assessed by waist circumference measurement), but they may not be perfectly related to insulin resistance and may not have the same diagnostic and prognostic value [14,15]. Thus, further studies are needed to improve the predictive power of the MetS in order to provide new diagnostic and prognostic tools to better identify and stratify patients affected by metabolic risk factors.
To better understand the MetS, there is a growing scientific and clinical interest around the so-called underlying risk factors, when taken together with the metabolic risk factors discussed above, which have been shown to contribute to create a proinflammatory and prothrombotic state commonly found in MetS patients. The role of these factors in the diagnosis and prognosis of the MetS is still a matter of debate, and even though their possible clinical application looks interesting, further investigation is needed to better understand whether they have a prognostic value and may represent potential pharmacological targets for MetS patients.
Among the risk factors, oxidative stress, as marker of endothelial dysfunction and inflammation, might be promising. Oxidative stress is well known to play a key role in atherosclerosis, hypertension and cardiovascular complications. A large body of evidence suggests that oxidative stress is increased in MetS, as well as in obesity and diabetes . In insulin resistance patients, increased production of reactive oxygen species (ROS) and elevated oxidation of lipids products, DNA and proteins have been reported in plasma, urine and different tissues, suggesting both systemic and local oxidative stress that seems to be positively correlated to increased plasma insulin.
The NAD(P)H oxidase has been shown to be the major source of ROS production in pathological conditions related to insulin resistance and hyperinsulinemia and has been suggested to be the most important enzyme in the cardiovascular system [17,18]. In its activated form, the enzyme is a complex of membrane-associated (gp91phox and p22phox) and cytosolic (p47phox, p67phox and p40phox) subunits and includes an electron transport chain that transfers electrons from a donor, the cytosolic NAD(P)H, to an acceptor, oxygen, which also generates superoxide (•O2−) as a by-product. NAD(P)H was first discovered in phagocytic cells, in which it plays a crucial role in the oxidative burst, an important component of microbicidal effector cell function. More recently, NAD(P)H oxidase subunits have been shown to be expressed in different cell types, such as adipocytes, inflammatory, skeletal and cardiac muscle cells and fibroblasts [19,20], all of which contribute to enhanced ROS production in conditions related to insulin resistance and hyperinsulinemia. For instance, NAD(P)H oxidase has been shown to play a role in •O2− production in experimental and human atherosclerosis through infiltrated inflammatory cells . In asymptomatic patients, phagocytic NAD(P)H oxidase activity correlates with carotid intima media thickness, a marker of atherosclerosis , and with plasma levels of matrix metalloproteinase-9 (MMP-9), an independent biomarker of cardiovascular risk . Moreover, NAD(P)H oxidase-dependent •O2− production has been suggested to be not only a marker, but also a mediator of atherosclerotic CVD in different experimental models of obesity, diabetes and insulin resistance [24–26]. Thus, it is possible to speculate that increased oxidative stress associated with insulin resistance may be responsible, at least in part, for the development of atherosclerotic complication in obese, diabetic and MetS patients. However, further clinical studies are needed to clarify whether antioxidant therapies may be clinically useful for the prevention of atherosclerotic cardiovascular complications in insulin resistance patients.
Metabolic syndrome, insulin resistance and oxidative stress: adding diagnostic and prognostic insights
In the current issue of the journal, Fortuño et al.  provide new insights into the complex relationships between MetS, insulin resistance and oxidative stress. The authors evaluated 125 MetS patients in whom the diagnosis of MetS was established according to current American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement guidelines , including at least three criteria among the following: visceral obesity, hypertriglyceridemia, low HDL cholesterol, high BP or use of antihypertensive medication and high fasting glucose or use of glucose-lowering treatment. MetS patients were further stratified and divided into two groups, according to the presence or absence of insulin resistance (defined by the homeostatic model assessment index), and classified as either insulin resistance or insulin-sensitive patients. Fortuño et al.  have showed a correlation between plasma insulin levels and peripheral blood mononuclear cell (PBMC) •O2− production and systemic oxidative stress, suggesting a key role for insulin in the regulation of oxidative stress. These data were further supported by the in-vitro findings demonstrating the ability of insulin to upregulate p22phox subunit mRNA in PBMC and macrophages. In addition to showing that insulin resistance is a major determinant of oxidative stress in MetS, the authors suggested that the association with insulin resistance and increased oxidative stress may increase the atherosclerotic cardiovascular risk in MetS patients, as shown by increased levels of MMP-9. Thus, the study of Fortuño et al.  highlights the prognostic value of plasma insulin and oxidative stress in MetS patients, and suggests that their measurement may represent an interesting and informative clinical tool in order to better define the cardiovascular risk in MetS.
Balancing study's strengths and limitations
The study by Fortuño et al.  is a very good example of translational science, in which the authors have attempted to integrate basic science experiments in a clinical setting. In their study, the authors have tried to elucidate the relationship between oxidative stress, insulin resistance and cardiovascular risk in patients affected by MetS. In particular, they have identified a subgroup of MetS patients with insulin resistance that appear to have increased oxidative stress compared with insulin-sensitive MetS patients, suggesting a role of insulin on ROS production. However, insulin resistance MetS patients displayed significantly higher BMI and waist circumference compared with insulin-sensitive patients. Thus, it is possible that increased visceral adiposity may have played the main role in insulin, oxidative stress and MMP-9 increase. Finally, the definition of cardiovascular risk adopted in their study may present some limitations, requiring further clinical investigations. In fact, even though available evidence substantiates that MMP-9 levels represent an independent risk factor for atherosclerotic CVD [28,29], long-term clinical studies considering CVD as end-point are needed to confirm the prognostic value of MMP-9 in MetS patients.
There is still need in clinical care for a better understanding and management of MetS patients. Thus, translational studies that investigate diagnostic and prognostic mechanisms are interesting and clinically relevant in order to optimize the predictive value of the MetS in CVD prevention. Adding insights on the proinflammatory, prooxidant and prothrombotic risk factors such as •O2− production, NAD(P)H oxidase activation and MMP-9 expression, that are commonly found in MetS patients, seems interesting and challenging and may lead to future clinical applications. However, further investigation is needed to better understand whether these underlying risk factors have diagnostic and prognostic value and whether their use is routinely feasible in clinical practice and may represent potential pharmacological targets for MetS patients.
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