MinireviewOxidative stress and metabolic syndrome
Introduction
Although one of the earliest references to metabolic syndrome can be traced to Camus as early as 1966 (Camus 1966), it was not until 1988 that the characterization of this syndrome began to receive greater interest. At that time, Reaven termed it “syndrome X” and, in 1989, Kaplan called it “the deadly quartet” (Kaplan, 1989, Reaven, 1988), referring to the aggregation of coronary artery disease (CAD) risk factors, including insulin resistance (hyperinsulinemia), hypertension, hypertriglyceridemia and visceral obesity (Bjorntorp 1991). DeFronzo and Ferrannini (1991) subsequently suggested that insulin resistance was the underlying factor behind these symptoms and, once acquired, those with a genetic predisposition would develop all the other aspects of the disorder. However, they pointed out that diet, exercise and weight loss could reduce insulin resistance, suggesting that the final phenotypic expression involves both genetic and acquired influences. Additionally, Haffner et al. (1992) coined the term “insulin resistance syndrome” for the disorder to highlight the fact that insulin resistance preceded other aspects of the syndrome. Since this array of factors is associated with abnormal carbohydrate and lipid metabolism, it is usually referred to as “metabolic syndrome” (Ferrannini et al. 1991). Subsequent to the initial list of risk factors, several additional characteristics have been suggested to be components of the syndrome, including visercal obesity (Ross et al. 2002), hepatic steatosis (Hamaguchi et al. 2005) and inflamed adipose tissue (Aquilante et al., 2008, Hung et al., 2008, Saltevo et al., 2007), dyslipidemia (including small, dense low-density lipoprotein (LDL) particles and depressed high-density lipoprotein cholesterol (HDL-C)), enhanced clotting factor activity (i.e. elevated levels of fibrinogen and tissue plasminogen activator inhibitor-1) (Landin et al. 1990), endothelial dysfunction (Suzuki et al. 2008), inflammation (Lemieux et al., 2001, Yudkin et al., 1999) and oxidative stress (Van Guilder et al. 2006). The clustering of these risk factors in the same individual results in a highly atherogenic risk profile. Various population studies have revealed familial clustering of the aspects encompassing metabolic syndrome (Bouchard and Tremblay, 1990, Haffner et al., 1988, Knowler et al., 1981).
Like the World Health Organization (Alberti and Zimmet 1998) and other organizations (Alberti et al. 2005), the National Cholesterol Education Program's (NCEP's) Adult Treatment Panel (ATP) III guidelines (Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) 2001) have established criteria for the diagnosis of metabolic syndrome. Relative to primitive societies, the prevalence of metabolic syndrome is extremely high in westernized societies (Roberts and Barnard 2005). A multi-ethnic representative US sample of 12,363 men and women 20 years and older from the third National Health and Nutrition Examination Survey (NHANES) was evaluated for metabolic syndrome as defined by the ATP III diagnostic criteria (abdominal obesity, hypertriglyceridemia, low HDL, hypertension and fasting hyperglycemia) and the disorder was found to be present in 22.8% and 22.6% of the men and women, respectively. Metabolic syndrome was present in 4.6%, 22.4% and 59.6% of normal-weight, overweight and obese men, respectively, and physical inactivity was associated with an increased risk of developing the syndrome (Park et al. 2003). Additionally, of those over 60 years of age (Ford et al. 2002), it has been estimated that approximately 43% overall and 80% of those with type 2 diabetes (T2D) have metabolic syndrome (Isomaa et al. 2001). Given the estimated prevalence was based on the results of NHANES III (1988–1994), it is likely that the current prevalence is higher.
It should be acknowledged (despite not being the subject of this article) that the use of the term metabolic syndrome has been questioned for a variety of reasons (Kahn et al., 2005, Reaven, 2004, Reaven, 2006). These include, but are not limited to: 1) it occurs only in insulin-resistant persons, which the ATP III criteria does not directly evaluate; 2) many individuals may not satisfy the somewhat arbitrary cutoffs for diagnosis, i.e. might be sufficiently insulin resistant and have additional CAD risk factors to be at significant increased cardiovascular disease (CVD) risk; and 3) it has low clinical utility since treating the individual factors may be a less effective approach than addressing the underlying problem, which is generally lifestyle-induced insulin resistance in genetically susceptible individuals. In fact, published data support this contention (Liao et al. 2004).
Section snippets
Reactive oxygen species and oxidative stress
Reactive oxygen species (ROS) are ubiquitous, highly reactive, short-lived derivatives of oxygen metabolism produced in all biological systems that react with surrounding molecules at the site of formation. These species, which include the superoxide radical (O2−), the hydroxyl radical (OH), and hydrogen peroxide (H2O2), along with reactive nitrogen species, such as nitric oxide (NO) and the peroxynitrite radical (ONOO), are oxygen derivatives that play important roles in vascular biology.
Antioxidant systems
The natural antioxidant system consists of a series of antioxidant enzymes and numerous endogenous and dietary antioxidant compounds that react with and inactivate ROS. The primary antioxidant enzymes include, but are not limited to, superoxide dismutases (SOD), catalase (CAT) and glutathione peroxidase (GPX). Meanwhile, the nonenzymatic antioxidants include, among others, vitamin C, vitamin E, β-carotene, reduced glutathione and numerous phytochemicals. Cells must maintain their levels of
Oxidative stress and metabolic syndrome
The potential role of oxidative stress in metabolic syndrome is rapidly evolving. Reported results support the concept that increased oxidative stress may play an important role in metabolic syndrome-related manifestations, including atherosclerosis, hypertension and T2D (Ceriello and Motz 2004). Oxidative stress is also associated with adiposity and insulin resistance in men (Urakawa et al. 2003) and in those with metabolic syndrome (Ford et al. 2003), suggesting that oxidative stress could be
Oxidative stress and coronary artery disease
Those with metabolic syndrome have a significantly higher risk of CAD and higher rates of all-cause mortality, even in the absence of baseline CVD or T2D (Hu et al., 2004, Isomaa et al., 2001, Lakka et al., 2002). For example, Lakka et al. (2002) reported that middle-aged men with metabolic syndrome exhibited a four-fold greater risk of death over an 11-year follow-up as compared to healthy men. Additionally, Sattar et al. (2003) noted that men with four or five features of the syndrome have
Oxidative stress and hypertension
Antioxidant/oxidant balance is well established as an important physiological regulator of arterial pressure and recently, its role in the pathogenesis of hypertension has been substantiated. Endothelial dysfunction is a cause of hypertension, mediated in part by oxidative stress, and antioxidants provide defense against vascular oxidative stress by neutralizing free radicals and protecting NO from inactivation, thereby exerting beneficial effects on vascular function and structure. Taddei et
Oxidative stress and type 2 diabetes
Many aspects of the relationship between oxidative stress, insulin resistance and T2D have been investigated (as reviewed by (Wei et al. 2008)) and we will limit our focus to the concept that oxidative stress can induce insulin resistance, contributing to T2D. Data from the Framingham Offspring Study demonstrated that among the 528 obese individuals, the prevalence of insulin resistance was 41%–61% across 8-iso-PGF2α tertiles, suggesting that systemic oxidative stress is indeed associated with
Effects of lifestyle modification on oxidative stress and metabolic syndrome
Several studies have demonstrated that the pathogenesis of the metabolic syndrome is largely attributable to dietary factors and activity levels. For example, men with a VO2max ≤ 29.1 mL/kg/min were approximately seven times more likely to exhibit metabolic syndrome than those with a VO2max ≥ 35.5 mL/kg/min, (Lakka et al. 2003). In 19223 men 20–83 years old, Katzmarzyk et al. (2004) investigated the effects of cardiorespiratory fitness and mortality in healthy men and in those with the metabolic
Conclusion and future directions
Metabolic syndrome, although only more recently defined and investigated, exhibits a prevalence of nearly 25% of the US adult population and epitomizes the integrative nature of modern chronic disease, given its endocrine, metabolic and cardiovascular underpinnings. Oxidative stress is associated with many of the components of the syndrome, leading to the concept that the amelioration of risk factors comprising metabolic syndrome, including insulin resistance, elevated blood pressure, elevated
Acknowledgement
Christian K. Roberts was funded by the Amercian Heart Association, Western States Affiliate (#0765139Y) during the writing of this review.
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