The metabolic syndrome

Metabolic syndrome represents a cluster of clinical, biochemical and humoral abnormalities associated with impaired insulin action in glucose metabolism. In the literature also the term syndrome of insulin resistance, dysmetabolic syndrome X, Reaven syndrome or Kaplans dead quartet can be found. Hyperinsulinaemia, central obesity, essential hypertension, dyslipidaemia, impaired glucose homeostasis or type 2 diabetes, hyperuricaemia, hypercoagulable state, endothelial dysfunction and increased markers of inflammation such as C-reactive protein, selectines, adhesion molecules, pro-inflammatory cytokines are the typical components of metabolic syndrome increasing the risk of cardiovascular complications. List of currently recognized clinical and biochemical manifestations continues to expand and include also non-alcoholic steatohepatitis, polycystic ovaric syndrome (PCOS), hyperhomocysteinaemia and others. No standard definition of metabolic syndrome has been routinely used. The WHO initially proposed a definition of metabolic syndrome in 1998, and more recently NCEP-ATP III provided a new working definition in 2001, which is more suitable for clinical practice. Prevalence of metabolic syndrome is very high, about 25-30% in Caucasians, depending on diagnostic criteria used. The clinical significance of metabolic syndrome is augmented by its association with increased and accelerated atherosclerosis. Whether IR predicts cardiovascular disease (CVD) independently of diabetes and other CVD risk factors is still a matter of controversy. Recently there is a growing evidence that metabolic syndrome increases also the risk of all-cause mortality and risk of certain tumors.     

The metabolic syndrome

The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.     

The metabolic syndrome

The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.     

The metabolic syndrome in polycystic ovary syndrome

Much overlap is present between the polycystic ovary syndrome (PCOS) and the metabolic syndrome. This article reviews the existing data regarding the prevalence, characteristics, and treatment of the metabolic syndrome in women with PCOS. The prevalence of the metabolic syndrome in PCOS is approximately 43-47%, a rate 2-fold higher than that for women in the general population. High body mass index and low serum HDL cholesterol are the most frequently occurring components of the metabolic syndrome in PCOS. The pathogenic link between the metabolic syndrome and PCOS is most likely insulin resistance. Therefore, the presence of the metabolic syndrome in PCOS suggests a greater degree of insulin resistance compared to PCOS without the metabolic syndrome. Obesity, atherogenic dyslipidemia, hypertension, impaired fasting glucose/impaired glucose tolerance, and vascular abnormalities are all common metabolic abnormalities present in PCOS. Lifestyle modification has proven benefit and pharmacological therapy with insulin-sensitizing agents has potential benefit in the treatment of the metabolic syndrome in women with PCOS.     

The metabolic syndrome in Japan

Since its conception, the metabolic syndrome has received worldwide recognition as a useful clinical aid for predicting cardiovascular risk. The earliest definition, which included risk factors such as insulin resistance, hyperglycemia, hypertension, and cholesterol, has undergone many transformations. Two revisions have focused on visceral adiposity as an essential component of the syndrome, particularly in Asian populations. The Japanese national guidelines have also suggested that abnormalities in adipose tissue metabolism are an underlying molecular cause of the syndrome. In addition, emerging evidence suggests that lowering the threshold of waist circumference in Asian populations increases the prevalence of the metabolic syndrome. Inevitably, this widening of the threshold will capture more patients at risk of cardiovascular events. The aim of this Article is to consider the country-specific impact of the metabolic syndrome, using the evolution of the definition in Japan as a model.     

The metabolic syndrome and inflammation

The metabolic syndrome (MS) is a clustering of cardiovascular risk factors, with insulin resistance as a major feature. This syndrome has been variously defined, but generally consists of 3 or more of the following components: hyperglycemia, hypertension, hypertriglyceridemia, low HDL, and increased abdominal circumference and/or BMI at >30 kg/m(2). The WHO criteria require the presence of insulin resistance to make the diagnosis. The current review focuses particularly on the association of the MS and the proinflammatory state as well as treatment options to prevent the development of coronary heart disease (CHD). Chronic inflammation is frequently associated with the MS. Inflammatory markers that have been associated with MS include hs-CRP, TNF-alpha, fibrinogen, and IL-6, among others. The link between inflammation and the MS is not fully understood. One postulated mechanism is that these cytokines are released into the circulation by adipose tissue, stimulating hepatic CRP production. The prothrombotic molecule PAI-1 is also increased in the MS. Adiponectin, produced exclusively by adipocytes, is decreased in obesity. The association of these proinflammatory and prothrombotic markers with the MS is discussed in detail. The general goals of treatment of the MS are prevention of CHD events and diabetes if not already present. The approach to treatment of those with the MS should include lifestyle changes, including weight loss and exercise as well as appropriate pharmacological therapies. Certain medications, which may be used in persons with MS, have been shown to have beneficial effects on clinical outcome and/or anti-inflammatory effects.     

The metabolic syndrome in HIV

The metabolic syndrome (MS) is a term used to describe the clustering of risk factors for cardiovascular disease (CVD), including elevated triglyceride (TG), low high density lipoprotein cholesterol (HDL), hypertension, hyperglycemia/ insulin resistance and intra-abdominal obesity. This paper discusses why the prevalence of MS in the setting of HIV has been reported to range from 7-45% and how antiretroviral drugs might contribute to the development of MS. The MS has been reported to be a 'CVD risk enhancer', and much debate is ongoing on the independent risk of CVD associated with the MS. Based on a limited number of studies on MS in HIV with clinical end-points, there is no data to support that the MS is independently associated with an increased risk of CVD.     

The metabolic syndrome in women

The metabolic syndrome, an increasingly prevalent disorder, is known to significantly enhance the risk of developing cardiovascular disease and diabetes. The syndrome is defined by a constellation of cardiac risk factors that include obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. There are several unique features of the metabolic syndrome in women. An insulin-resistant state associated with both polycystic ovarian syndrome and increased abdominal fat may contribute to the development of the metabolic syndrome and increase cardiovascular risk when present. Menopause heralds a decline in circulating estrogen levels, which may increase cardiovascular risk through effects on adiposity, lipid metabolism, and prothrombotic state. The key elements involved in managing the metabolic syndrome are dietary and lifestyle modification. Appropriate treatment may also include managing individual cardiac risk factors with the use of antihypertensive and lipid-modifying agents among others.     

The metabolic syndrome in women

The metabolic syndrome is estimated to be present in 47 million US residents with a similar age-adjusted prevalence in men (24%) and women (23%). The consideration of various metabolic risk factors as a single entity in the metabolic syndrome provides clinicians with a tool by which they can identify a population at increased risk for type 2 diabetes mellitus and increased cardiovascular morbidity and mortality. Cardiovascular disease is the leading cause of mortality in women in the US. To reduce the risk of cardiovascular disease, efforts have focused on modifying the metabolic risk factors that constitute the metabolic syndrome: abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. In addition, because of several circumstances specific to women, including pregnancy, polycystic ovary syndrome, oral contraceptive therapy use, and menopause, there are special considerations regarding risk factor identification, modification, and clinical management. This article provides a review of diagnostic and therapeutic issues that clinicians should consider when caring for women at risk for developing or diagnosed with the metabolic syndrome.     

The metabolic syndrome: Insulin resistance

Insulin resistance is the most accepted unifying theory explaining the pathophysiology of the metabolic syndrome. However, epidemiologic studies indicate that a substantial proportion of patients with the metabolic syndrome do not have evidence of insulin resistance, and the correlation between insulin resistance and individual components of the syndrome is weak to moderate. Insulin resistance may play an important role in the development of hyperglycemia and dyslipidemia, which can further aggravate insulin resistance. The implication of insulin resistance in hypertension appears to be less strong than its role in causing hyperglycemia and dyslipidemia. Obesity may be another pathogenic factor in the metabolic syndrome that may help initiate or worsen insulin resistance. However, like insulin resistance, obesity is not universal in the metabolic syndrome, and many obese subjects do not have metabolic abnormalities. This review provides an update on the relationship between insulin resistance and main components of the metabolic syndrome: hyperglycemia, dyslipidemia, hypertension, and obesity.     

The adrenal and the metabolic syndrome

This review discusses the possible interrelationships between adrenal steroid hormones and the metabolic syndrome. Abnormal regulation of the hypothalamic-pituitary-adrenal axis has been proposed. Studies in the United Kingdom associated the metabolic syndrome with low birth weight and hyperactivity of the entire axis. In Italy, increased pituitary responsiveness to stimulation with vasopressin and corticotrophin-releasing hormone was demonstrated in women with central obesity. Swedish researchers have reported that increased stress responses of the axis correlated with a less variable but decreased cortisol level. An allele of the glucocorticoid receptor was also associated with various components of the metabolic syndrome. Evidence also suggests that central obesity is associated with an increased peripheral conversion of cortisol to cortisone and subsequent feedback stimulation of the axis. On the other hand, central fat may have an increased local metabolism in the direction of cortisol. Roles for dehydroepiandrosterone and aldosterone in the syndrome have also been proposed.     

The metabolic syndrome and cardiovascular risk

There are four definitions of the metabolic syndrome that have been recommended by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Expert Panel (NCEP), and the American Association of Clinical Endocrinologists (AACE) separately since 1998. The prevalence of the metabolic syndrome reported from different studies has varied widely, mainly because of differences in the definitions of the syndrome and in the characteristics of the populations studied. Prospective studies on the relationship between the metabolic syndrome and cardiovascular risk are still scanty. Results from several studies including a large population-based Italian study, the Framingham Offspring Study, the Botnia Study, the Kuopio Ischemic Heart Disease Study, the National Health and Nutrition Examination Survey II Mortality Study, the San Antonio Heart Study, and the DECODE study have shown that the presence of metabolic syndrome using different definitions is associated with a significantly increased risk of total mortality and cardiovascular morbidity and mortality.     

The metabolic syndrome and the liver

Together with the worldwide epidemic proportions of obesity the incidence of 'the metabolic syndrome' is rising across countries. The metabolic syndrome is described as a complex condition that is linked to (intra-abdominal) obesity and is characterized by insulin resistance, dyslipidaemia and hypertension. Several definitions for the metabolic syndrome have been suggested, all trying to identify individuals at high risk for both type 2 diabetes and cardiovascular disease. The primary hepatic complication of obesity and insulin resistance is nonalcoholic fatty liver disease (NAFLD). NAFLD is not included as a component of the metabolic syndrome as it is currently defined; however, data suggest an association. Although the data are mainly epidemiological, the pathogenesis of NAFLD and the metabolic syndrome show common components, with the focus on insulin resistance as a key factor. Even so the treatment of patients with the metabolic syndrome and NAFLD shows a certain degree of similarity, and should focus on the management of associated conditions including obesity, glucose and lipid abnormalities. Lifestyle modifications comprising healthy eating habits and regular exercise are the primary interventions recommended to patients with the metabolic syndrome and those with NAFLD. A pharmacological approach like insulin-sensitizing agents, lipid lowering drugs, antihypertensive drugs and antiobesity agents can be successful in the treatment of certain risk factors that are currently clustering with both the metabolic syndrome and NAFLD. In some cases bariatric surgery may be necessary.     

The metabolic syndrome in East Asians

The metabolic syndrome is an emerging epidemic in developing nations, including East Asian countries such as China, Japan, and Korea. Studies examining the metabolic syndrome have used different definitions, with prevalence often highly dependent on the cut points for abdominal obesity utilized, which have been recommended by the International Diabetes Federation to be lower than standards used in Caucasians and other ethnic groups. Prevalence rates have generally varied from 8% to 13% in men and 2% to 18% in women, depending on ethnic group and definition used, and are consistently lower than most Western Caucasian populations. While recent dramatic changes in lifestyle from Westernization of dietary habits and reduced physical activity present challenges, an emphasis on healthful lifestyle changes remains the cornerstone for metabolic syndrome management. In addition, clinical management focusing on control of obesity, elevated blood pressure, dyslipidemia, and hyperglycemia, with consideration of pharmacologic therapy issues unique to certain Asian populations, remains important for reducing associated cardiometabolic risks.     

The endothelium in the metabolic syndrome

The endothelium is responsible for the maintenance of vascular homeostasis. In physiological conditions it acts keeping vascular tonus, laminar blood flow, plasmatic membrane fluidity, the balance between coagulation and fibrinolysis and the inhibition of cellular proliferation, migration and the inflammatory response. Endothelial dysfunction is defined as an alteration of vascular relaxation induced by reduction of endothelium-derived relaxing factors (ERRFs), mainly nitric oxide. These abnormal vasomotor responses occur in the presence of various risk factors for atherosclerosis. The metabolic syndrome is considered a state of chronic inflammation accompanied of endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. This revision will encompass the physiological process of vascular function regulation, methods for in vivo assessment of endothelial dysfunction and therapies capable to improve vascular function and consequently minimize the cardiovascular risk due to metabolic syndrome.