After metabolic syndrome was first introduced to identify persons at greater cardiovascular disease (CVD) risk, it has been associated with an increased risk of CVD and type 2 diabetes (T2D). Obesity has been considered as the fundamental factor in metabolic syndrome and it is thought to be mediated, at least in part by the role of the adipocyte in controlling circulating free fatty acids and the development of insulin resistance. However, the obese population is not perfectly overlapped with the population with metabolic syndrome. Is metabolic syndrome a better predictor than obesity to prevent CVD and T2D? Has metabolic syndrome been considered as a cluster of risk factors or an additional independent risk factor to assess CVD and T2D risk? The debate on the necessity of metabolic syndrome diagnosis seems not to be ended. Various definitions of metabolic syndrome were advocated by different organizations with emphasis on different components, and these definitions have different abilities to predict CVD and T2D among different populations because of fundamental philosophical differences. In the definitions of metabolic syndrome, only the cutoffs of each component were presented but rather continuous values or the degree of the severity of the syndrome with multiple cutoffs. Moreover, metabolic syndrome did not incorporate all the risk factors as known for CVD and T2D, such as physical activity. Future prospective studies with the measurement of sophisticated metabolic markers and of abdominal visceral and subcutaneous adiposity are needed to examine if the metabolic syndrome is a good CVD and T2D risk predictor over obesity and other risk factors. In practice, prevention action should be taken at the stage of obesity and providers need to pay attention to any components in the definition of metabolic syndrome even if the number of positive components has not achieved three or more.
Cardiovascular disease (CVD) is the number one cause of death in the worldwide. According to the World Health Organization (WHO)’s report, an estimated 17.3 million people died from CVD in 2008, representing 30% of all global deaths.1 Globally, 346 million people have diabetes mellitus, with type 2 diabetes (T2D) making up about 90% of the cases.2 More than 80% of CVD and diabetes mellitus deaths take place in low- and middle-income countries. A few risk factors have been linked to risk of CVD and T2D, and current prevention guidelines are targeting on preventing these risk factors: healthy diet, regular physical activity, maintaining a normal body weight and so on.3 However, no perfect algorithms of CVD and T2D risk assessment existed so far. Incorporating a cluster of metabolic abnormalities, metabolic syndrome was advocated by several organizations as a major predictor of CVD and T2D.4, 5, 6 Metabolic syndrome has been associated with an increased risk of T2D and CVD. Metabolic syndrome was introduced to identify persons at greater CVD risk; however, whether the diagnosis of the metabolic syndrome has an impact on CVD and T2D risk was still uncertain. Metabolic syndrome may be considered as a cluster of risk factors or an additional independent risk factor to assess CVD and T2D risk. Prospective studies, which consider the measurement of sophisticated metabolic markers and of abdominal visceral and subcutaneous adiposity, are needed to evaluate the effect of metabolic syndrome on CVD risk assessment, however, such studies were still limited. Therefore, the debate on the necessity of metabolic syndrome diagnosis seems not to be ended in both epidemiological and clinical practices.
What is metabolic syndrome?
In 1988, Reaven proposed a set of metabolic abnormalities which not only increased the risk of T2D but also contributed to the development of CVD. Reaven used a scary-sounding term ‘syndrome X’ to describe the clustering abnormalities.7 As the term ‘syndrome X’ was also documented in cardiology, the term insulin resistance syndrome became more frequently used to describe the abnormalities meant by Reaven. Reaven proposed insulin resistance as the underlying factor and did not include abdominal obesity as a condition of the syndrome.7
As the risk factors have been examined by more and more studies, definitions with more accurate and clearer conditions have been released. In general, all the definitions include a measure of obesity, insulin resistance, elevated blood pressure and atherogenic dyslipidemia, however, the threshold criteria, the core component, and the number and the combination of the components vary among different definitions. The WHO was the first organization to outline the clinical criteria of metabolic syndrome.4 The WHO emphasizes the definition more on potential for T2D. Diabetic disorders manifested as having impaired glucose tolerance, impaired fasting glucose or insulin resistance were the essential component of the WHO definition of metabolic syndrome.4
The National Cholesterol Education Program Adult Treatment Panel III (ATP III) released its definition of the metabolic syndrome in 2001.5 The goal of the ATP III was more or less different from that of the WHO with less focus on T2D but more focus on CVD risks. The ATP III treated five components equally and considers any three of the abnormalities as the metabolic syndrome. From the point of view of risk prevention, the ATP III aims to focus on primary prevention in persons with multiple risk factors.5
The most recent version of the metabolic syndrome was the result of a consensus conference organized by the International Diabetes Federation (IDF) that involved 21 researchers in the worldwide.6 The IDF’s definition is used only for obese population because central obesity defined by waist circumference (WC) is the only essential component of its metabolic syndrome definition.6
Even though three different definitions share similar components, recent studies have indicated that these definitions have different abilities to predict CVD and T2D among different populations because of fundamental philosophical differences.8, 9, 10, 11 The ATP III version of the metabolic syndrome is the most democratic with no hierarchical relation between the five components. Although in the case of the WHO and IDF, the metabolic syndrome could only be defined among insulin-resistant persons and obese persons, respectively.
Insulin resistance and metabolic syndrome
The mechanisms underlying the metabolic syndrome are not fully understood; however, several studies have shown that insulin resistance is a key factor associated with clustering metabolic abnormalities, which include a typical atherogenic dyslipidemic state (high triglyceride and apolipoprotein B concentrations, an increased proportion of small dense low-density lipoprotein particles and a reduced concentration of high-density lipoprotein-cholesterol, high-density lipoprotein particles also being smaller in size), a prothrombotic profile, and a state of inflammation.12 Therefore, insulin resistance is viewed as the underlying cause for clusters of subsequently occurring disorders.13, 14, 15, 16, 17
Insulin resistance is defined as resistance to insulin-stimulated glucose uptake. Insulin resistance is thought to be the result of obesity or an inherited genetic defect. However, the degree to which this association is a result of obesity and the temporal relationship between obesity and insulin resistance is still uncertain. As people gain weight, the sensitivity of muscle tissue to the action of insulin declines.18 To counterbalance this insulin-resistant state and maintain normal glucose levels, augmented levels of insulin are secreted resulting in hyperinsulinemia.13 In addition, insulin resistance is associated with increased levels of free fatty acids and their metabolities, increased concentrations of cytokines and deficient adiponectin secretion. Studies have shown that free fatty acid metabolites act to prevent the insulin signal being transmitted through the insulin action cascade.15 The insulin resistance/hyperinsulinemia may in turn increase triglyceride levels, systolic and diastolic blood pressure, and reduced high-density lipoprotein cholesterol levels, which results in the metabolic syndrome.
Among three definitions of metabolic syndrome, only the WHO definition emphasizes insulin resistance as an essential component for diagnosis and requires the presence of T2D, impaired fasting glucose, impaired glucose tolerance or insulin resistance for diagnosis.4
Obesity and metabolic syndrome
In contrary, many researchers believed obesity has more fundamental role in metabolic syndrome than insulin resistance. In metabolic syndrome, the components of dyslipidemia, hyperglycemia and hypertension are directly related to the risk of CVD, whereas the association between obesity component and the risk is different. The effect of obesity is thought to be mediated, at least in part by the role of the adipocyte in controlling circulating free fatty acids and the development of insulin resistance.19, 20
Based on the National Health and Nutrition Examination Survey, the prevalence of obesity (defined by body mass index, BMI) was 22.9% in 1988–1994, 32.2% in 2003–2004 and 34.3 in 2005–2006 among USA adults aged 20 and over.21 Using the same database and the definition from National Cholesterol Education Program ATP III, the unadjusted prevalence of metabolic syndrome was 21.8% in 1988–199422 and 34.4% in 2003–2006.23 The prevalence is similar for obesity and metabolic syndrome based on the same USA national representative database. However, the obese population is not perfectly overlapped with the population with metabolic syndrome. Still using 1988–1994 National Health and Nutrition Examination Survey, Park et al.24 reported that metabolic syndrome was present in ∼60% of obese adults, which means that ∼40% of obese adults could not be identified with metabolic syndrome using ATP III definition. The metabolic syndrome occurs more commonly in obese persons; however, the relation is not because of obesity, per se, but rather to the fact that obesity increases the risk of other factors, that is, insulin resistant.25, 26
Evidence has shown that measurements of BMI and WC are highly correlated,27 and that not all overweight or obese persons are insulin resistant.14 A possible explanation to this discrepancy might be the different effect of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) on metabolic abnormities.28 The obesity defined by BMI and abdominal obesity defined by WC is an overall concept including both fat mass and fat-free mass, which have opposing effects on health.29 As the technologies develop, fat mass and lean mass could be differentiated by equipments such as dual-energy X-ray absorptiometry.30, 31 However, the VAT and SAT could not separated by such instruments.32 Imaging studies have generally reached the conclusion that it is the excess of VAT but not the amount of SAT, which is the key correlate of the metabolic abnormalities observed in overweight/obese persons. For example, individuals perfectly matched for SAT, but with various VAT, have been shown to be markedly different in their levels of insulin resistance and glucose tolerance. However, after being matched for VAT, individuals with low or high levels of SAT were not found to be different in insulin sensitivity.33, 34 Thus, VAT seems to be more appropriate to be used as a feature of metabolic syndrome than BMI or WC.
Limitations of metabolic syndrome
As discussed above, three definitions of metabolic syndrome vary considerably. First of all, both the WHO (insulin resistant) and the IDF (central obesity) insist one essential criterion to be met in the definition of metabolic syndrome.4, 6 For individuals without insulin resistant or central obesity, they will never been identified as metabolic syndrome regardless of the severity of hypertension and dyslipidemia. In addition, the five components were considered equally in ATP III definition.5 Different combination of metabolic syndrome components may have different risks of CVD and T2D. Studies also showed that persons meeting any two criteria were at no less risk than were those meeting three criteria.35 Moreover, the criteria of obesity in WHO’s definition is based on BMI or waist-to-hip ratio, which are different with that used in ATP III and IDF definition (WC). Even though WC was used in both ATP III and IDF definitions, the cutoff values are different. Furthermore, the hyperinsulinemic and euglycemic clamp testing in WHO definition is not feasible in large-scale, population-based research studies, thus this will be a major limitation of application of this criteria in such designs. Therefore, there is still substantial confusion between the conceptual definitions of the metabolic syndrome and the clinical screening parameters and cutoff values proposed by various organizations (WHO, ATP III and IDF).
The fat distribution (deposition of visceral and subcutaneous fat) and its association with metabolic complications vary across different populations. Previous evidence showed that blacks were more likely to accumulate subcutaneous fat for a given BMI than were whites,36, 37 whereas Asians had more visceral fat.38 Nevertheless, current criteria of metabolic syndrome from WHO and ATP III are not designed based on different race/ethnicity populations.
Metabolic syndrome was born to assess and predict CVD and T2D risk. Sophisticated risk-assessment algorithms are needed to quantify T2D and CVD risk resulting from the presence of classical risk factors and the presence of abdominal obesity or insulin resistance-related metabolic markers. Metabolic syndrome seems to be an appropriate indicator, but it definitely does not incorporate all the risk factors. For instance, physical activity was not incorporated in the definition of metabolic syndrome. Overweight and obese individuals were reported with lower levels of cardiovascular fitness than normal weight individuals.39 In addition, individuals with metabolic syndrome have been shown lower levels of cardiovascular fitness than healthy individuals.40 Physical activity has also been associated with risk of CVD and T2D in many studies.41, 42 Thus, physical activity may influence the association between metabolic syndrome and risk of diseases. Katzmarzyk examined the impact of cardiorespiratory fitness on the association between obesity/metabolic syndrome and CVD mortality. They found that the risks of CVD mortality associated with obesity and metabolic syndrome were no longer significant after adding cardiovascular fitness in the models, which means that the risks could be explained largely by the cardiovascular fitness.43 Therefore, lacking of physical activity components in a diagnosis designing to identify CVD and T2D risks may be not appropriate. In addition, metabolic syndrome did not include several traditional risk factors such as smoking, age and family medical history, which were raised by some global CVD risk calculators such as the Framingham risk score, the PROCAM algorithm or the European SCORE.12, 44, 45 If we used metabolic syndrome to assess or predict CVD and T2D risk, metabolic syndrome is not sufficient to adequately capture the additional risk related to CVD and T2D.
In the definition of metabolic syndrome, only the cutoffs of each component are presented but rather continuous values or the degree of the severity of the syndrome with multiple cutoffs. Continuous variables and classification on the severity of metabolic syndrome will provide more information for clinical practice. Taking obesity for example, the overall relative risk of T2D per unit of BMI increased by 1.18 per unit of BMI and a linear relation between BMI and the relative risk of T2D.46 The association between BMI and mortality was usually reported as positive,47, 48 J-shaped49 or U-shaped,50 which mean the mortality was much higher among extremely obese individuals than among obese, overweight or normal individuals. If the metabolic syndrome could be classified as several degrees, this definition will be more significant and helpful to predict CVD and T2D risks.
Recommendations and future directions
Metabolic syndrome has been linked to risks of CVD and T2D by solid evidence.51, 52 However, this does not mean it is a useful criterion in both clinical and prevention practice. In clinical practice, diagnosis of metabolic syndrome helps healthcare providers to identify individuals at risk. However, providers should be careful to label the patients with the term ‘metabolic syndrome’.45 Despite a significant relationship with risk of CVD and T2D, metabolic syndrome is not a disease and this relationship may be influenced by other factors, which are not included in the components of the syndrome. Providers need to pay attention to any components in the definition of metabolic syndrome even if the number of positive components has not achieved three or more.14
Although the temporal relationship between obesity and other features of metabolic syndrome could not ascertained so far, obesity has been considered as the fundamental factor in metabolic syndrome.20 Prevention action should be taken at the stage of obesity (visceral obesity), which will prevent from insulin resistance and other metabolic abnormities. We should not wait for the accumulation of these metabolic abnormities achieving three or more as defined in metabolic syndrome.
Prospective studies about the effect of metabolic syndrome on prevention of CVD and T2D were not found in the literature to date. Prospective studies with the measurement of sophisticated metabolic markers and of abdominal visceral and subcutaneous adiposity are needed to examine if the metabolic syndrome is a good CVD and T2D risk predictor over other risk factors. Metabolic syndrome may be an independent risk factor of CVD and T2D rather than an appropriate tool to assess global risk of CVD and T2D.