The metabolic syndrome: what's in a name?

Metabolic syndrome refers to a clustering of established (i.e. ‘traditional’) and emerging (i.e. ‘nontraditional’) cardiovascular disease (CVD) risk factors within a single individual [Matfin, 2009; Grundy, 2007; Fonseca, 2000]. Both the established risk factors, such as obesity, diabetes, dyslipidemia, and hypertension, and other ‘non-traditional’ risk factors are closely related to central obesity (especially intra-abdominal adiposity, which is also known as visceral obesity) [Matfin, 2009; Grundy, 2007; Lawlor et al. 2006; Fonseca, 2000]. The emerging risk factors include dysfunction of inflammation, coagulation, platelets, fibrinolysis, lipoproteins, endothe-lium, and miscellaneous biological processes [Fonseca, 2000]. Individuals may develop these factors in different orders, at different severities, and at different ages [Lawlor et al. 2006]. The underlying pathophysiology of the metabolic syndrome is considered to be related to central obesity and insulin resistance [Matfin, 2009; Grundy, 2007; Reaven, 2006]. Although the exact cause of the metabolic syndrome is not known, the association with obesity is very compelling. Adipocytes are the source of a number of important factors involved in a wide range of processes related to the features of the metabolic syndrome, including glucose and lipid metabolism, inflammation, and thrombosis (e.g. nonesterified fatty acids [NEFAs], adiponectin, leptin, visfatin, and plasminogen activator inhibitor type 1 [PAI-1]) [Iozzo, 2009; Kershaw and Flier, 2004]. With obesity, the outputs of all of these products are higher except for adiponectin, which is abnormally low. Excess release of NEFAs predisposes to ectopic fat accumulation in liver, muscle, and visceral adipose tissue stores and can result in abnormal function (termed ‘lipotoxicity’), including insulin resistance. Adipocyte hypertrophy (large adipocytes are more insulin resistant than smaller ones and secrete more pro-inflammatory adipocytokines) [O'Connell et al. 2010], visceral adiposity, and ectopic fat accumulation (this combination has been termed ‘adiposopathy’ or ‘sick fat’ by Bays in the US [Bays, 2009]) may result in the adverse metabolic and immune consequences that contribute to major CVD risk factors (e.g. glucose intolerance, high blood pressure [BP], and dyslipidemia). Insulin resistance is also considered an important factor in the etiology of this syndrome [Grundy, 2007; Lawlor et al. 2006; Reaven, 2006, 1988]. Insulin resistance can be defined in several ways, but is essentially an impaired biological response to insulin actions in the insulin-responsive tissues (i.e. liver, fat, and skeletal muscle) [Reaven, 2006]. However, despite the potential utility of having all of the CVD risk factors under an umbrella diagnosis of the metabolic syndrome, debate continues about its very existence [Cameron et al. 2009; Preiss and Sattar, 2009; Ferrannini, 2007; Pratley, 2007; Alberti and Zimmet, 2006; Kahn et al. 2005]. This debate is (in part) related to lack of a universally accepted definition of this state, but also to doubts regarding the need for these disparate CVD risk determinants to be ‘lumped’ together under one ‘artificial’ diagnostic heading. Is the utility of the metabolic syndrome simply related to its value as an aide-memoire for physicians to consider other CVD risk factors when confronted with a patient with one or more of these factors? Despite the controversies regarding the metabolic syndrome, this subject remains one of the most discussed and written about by both the lay public and healthcare professionals alike. For example, the term ‘metabolic syndrome’ results in almost 3 million hits on Google (this does not include all of the different permutations such as ‘therapy’, ‘criteria’, etc.) and about 30,000 results on PubMed (accessed 24 April 2010). In addition, the component risk factors include some of the most common and serious public health challenges facing both the developed and developing world today [Hossain et al. 2007]. With improvement in the economic situation in developing countries, increasing prevalence of obesity and the metabolic syndrome is seen in adults and particularly in children. The main causes are increasing urbanization, nutrition transition, and reduced physical activity [Misra and Khurana, 2008]. According to recent worldwide estimates, 1.7 billion people are classified as either overweight or obese, more than 1 billion have hypertension, and more than 500 million have either diabetes or the prediabetes category, impaired glucose tolerance (IGT) [Hossain et al. 2007]. As a consequence of these alarming figures, the prevalence of the metabolic syndrome is also (not surprisingly) very common, with almost 50 million individuals affected in the USA alone [Ford, 2005]. In view of the incredible numbers of people affected by these chronic risk states and associated complications, pharmaceutical companies are exploring the role of existing therapies and are developing many new drugs targeting the metabolic syndrome. Indeed, one review on new therapies for the metabolic syndrome listed the number of potential ‘drug targets’ at nearly 10,000 (i.e. targets in the genome, proteome, transcriptome, etc.) [Flordellis et al. 2005]. However, no drugs are currently approved for the indication of metabolic syndrome [Food and Drug Administration, 2007; Heal et al. 2009].