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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Introduction to the metabolic syndrome

George Alberti*

Department of Endocrinology and Metabolic Medicine, Mint Wing, St Marys Hospital, Praed Street, London W2 1NY, UK

* Corresponding author. E-mail address: george.alberti{at}ncl.ac.uk


   Introduction
Top
 Introduction
Aetiology
 Definition
 Prevalence
 New IDF definition
 References
 
The metabolic syndrome has its origins in 1923 when Kylin1 described a syndrome involving hypertension, hyperglycaemia and hyperuricaemia. In the 1940s Vague2 wrote about abdominal obesity and fat distribution and its relation to diabetes and other disorders. Following this, in 1965 an abstract was presented at the European Association for the Study of Diabetes annual meeting by Avogaro and Crepaldi3 which again described a syndrome which comprised hypertension, hyperglycaemia, and obesity.

The field moved forward significantly following the 1988 Banting Lecture given by Gerry Reaven.4 He described ‘a cluster of risk factors for diabetes and cardiovascular disease’ and named it ‘Syndrome X’. His main contribution was the introduction of the concept of insulin resistance.

In 1989, Kaplan5 renamed the syndrome ‘The Deadly Quartet’ and in 1992 it was again renamed ‘The Insulin Resistance Syndrome’.6 It is now agreed that the well-established term ‘metabolic syndrome’ remains the most usual description of this cluster of metabolic abnormalities.


   Aetiology
Top
 Introduction
 Aetiology
Definition
 Prevalence
 New IDF definition
 References
 
It has long been thought that insulin resistance may be the underlying pathophysiology in metabolic syndrome as many of the components of the metabolic syndrome are associated with insulin resistance. However, although insulin resistance is a core early abnormality in the pathogenesis of type 2 diabetes and is strongly associated with atherogenic dyslipidaemia and a proinflammatory state, it is less tightly associated with hypertension. While there are data to support the concept that insulin resistance or its associated hyperinsulinaemia are independent risk factors for cardiovascular disease (CVD), this association is yet to be confirmed in large scale, prospective clinical studies.7–11

Obesity is also considered to be an important factor in the aetiology of the metabolic syndrome as it contributes to hyperglycaemia, hypertension, high serum cholesterol, low HDL cholesterol, insulin resistance, and is associated with higher CVD risk.

With the development of imaging techniques to measure central fat precisely and to distinguish particularly intra-abdominal (visceral) from subcutaneous fat, several studies have shown that central fat accumulation is predictive of the features of the metabolic syndrome.12

In clinical and epidemiological studies, obesity is strongly associated with all cardiovascular risk factors. However, the mechanisms underlying the association between central obesity (particularly visceral obesity) and the metabolic syndrome are not fully understood and are likely to be complex.

While there is much debate about the relative importance of both insulin resistance and obesity in the pathophysiology of the metabolic syndrome, other interrelated factors such as endothelial dysfunction are suggested by some to be the underlying cause while others place importance on lifestyle plus a genetic contribution as the main aetiological factors.13 Clearly more research is needed into the aetiology of the syndrome.


   Definition
Top
 Introduction
 Aetiology
 Definition
Prevalence
 New IDF definition
 References
 
A number of expert groups have attempted to develop a unifying definition for the metabolic syndrome. Important definitions have been produced by The World Health Organization (WHO), The European Group for study of Insulin Resistance (EGIR), and The National Cholesterol Education Program—Third Adult Treatment Panel (NCEP ATP III).14–16

The 1999 WHO definition
The 1999 WHO definition of the metabolic syndrome was written by diabetologists and published as a working definition that could be modified when more data became available. It is based on the assumption that insulin resistance is one of the major underlying contributors to the metabolic syndrome, and features impaired glucose regulation (impaired glucose tolerance, diabetes or insulin resistance) at its core. In addition, the definition requires the presence of two additional risk factors from: hypertension, obesity, raised triglycerides (TG), or low HDL (Table 1).


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  		Table 1 The 1999 WHO definition of metabolic syndrome
 
The 1999 EGIR definition
Following the publication of the WHO definition in 1999, the EGIR proposed a modified version to be used in non-diabetic subjects only. The group were interested in insulin resistance and this became the cornerstone of their definition. EGIR proposed the use of fasting insulin levels to estimate insulin resistance and impaired fasting glucose (IFG) as a substitute for impaired glucose tolerance (IGT) (Table 2).


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  		Table 2 The 1999 EGIR definition of metabolic syndrome
 
The 2001 ATP III definition
In 2001, cardiologists and lipidologists in the United States produced a new definition of the metabolic syndrome—the ATP III definition. This definition was designed to facilitate diagnosis in clinical practice and therefore does not include a measurement of insulin resistance. The ATP III guidelines state that metabolic syndrome may be diagnosed when a patient has three or more of five clinically identifiable risk factors. These include abdominal obesity, high TG level, low HDL cholesterol level, hypertension, and an elevated fasting glucose level. Importantly, the ATP III definition includes a waist circumference of >102 cm as a measure of obesity. Also, as glucose tolerance tests are not performed in the United States, a fasting glucose level ≥6.1 mmol/L (110 mg/dL) was included (Table 3).


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  		Table 3 The 2001 ATP III definition of metabolic syndrome
 

   Prevalence
Top
 Introduction
 Aetiology
 Definition
 Prevalence
New IDF definition
 References
 
The existence of multiple definitions for metabolic syndrome has inevitably led to confusion and to the publication of many studies and research papers comparing the merits of each definition. It is also difficult to make direct comparisons among data from studies when different definitions have been used.

The difference in prevalence rates for the metabolic syndrome using WHO, EGIR, and ATP III can be demonstrated by data from a large Australian study of lifestyle and glucose intolerance—the AusDiab study.17 Although each of the three definitions identified ~16–21% of the Australian population as having metabolic syndrome (20.9% with WHO, 18.4% with ATP III, 15.9% with EGIR), there was a large variability and only ~9% of individuals met the criteria for all three definitions (Figure 1).



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  		Figure 1 Data showing the per cent prevalences within the total population. (Reproduced with the permission of the AusDiab study group.)

 
Prevalence data for the metabolic syndrome in different countries and in different ethnic groups clearly show that the syndrome is a large problem everywhere in the world and that the number of people affected continues to grow. Patients with metabolic syndrome are at a high risk of developing cardiovascular disease and/or type 2 diabetes. It is therefore important that these individuals be identified and treated as early as possible.


   New IDF definition
Top
 Introduction
 Aetiology
 Definition
 Prevalence
 New IDF definition
References
 
In June 2004, the International Diabetes Federation (IDF) held a workshop with the aim of establishing global consensus on a unified working diagnostic tool, that could be used everywhere so that data can be compared properly across the world. The workshop also highlighted areas where more knowledge is needed. Participants at the workshop were in agreement that the general features of the metabolic syndrome include:

  • Abnormal body fat distribution. Central obesity is the form of obesity most strongly associated with the metabolic syndrome, and is independently associated with all of the syndrome's criteria.12 It presents clinically as increased waist circumference.
  • Insulin resistance. Insulin resistance is present in the majority of people with the metabolic syndrome. It strongly associates with other metabolic risk factors and correlates univariantly with CVD risk. However, an association between insulin resistance and hypertension has not been firmly established. Moreover, the mechanisms underlying the link between insulin resistance and CVD still need further investigation.10
  • Atherogenic dyslipidaemia. The dyslipidaemia found in patients with the metabolic syndrome presents in routine lipoprotein analysis as raised triglycerides and low concentrations of HDL cholesterol. A more detailed analysis usually reveals other lipoprotein abnormalities including elevated apolipoprotein B, small dense LDL particles, and small HDL particles. All of these abnormalities are independently atherogenic.
  • Elevated blood pressure. Elevated blood pressure strongly associates with obesity and glucose intolerance, and commonly occurs in insulin-resistant persons.
  • Proinflammatory state. A proinflammatory state is recognized clinically by elevated C-reactive protein levels. It is commonly present in patients with the metabolic syndrome. This may be because excess adipose tissue releases inflammatory cytokines that may elicit higher CRP levels.
  • Prothrombotic state. A prothrombotic state characterized by increased plasminogen activator inhibitor 1 and fibrinogen also associates with the metabolic syndrome.

The new IDF metabolic syndrome definition will be published in 2005.


   References
Top
 Introduction
 Aetiology
 Definition
 Prevalence
 New IDF definition
 References
 

  1. Kylin E. Studien uber das Hypertonie-Hyperglyka ‘mie-Hyperurika’ miesyndrom. Zentralbl Inn Med 1923;44:105–127.
  2. Vague J. La differenciation sexuelle, facteur determinant des formes de l'obesité. Presse Medl 1947;53:339–340.
  3. Avogaro P, Crepaldi G. Essential hyperlipidemia, obesity and diabetes. Diabetologia 1965;1:137.
  4. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–1607.[Abstract]
  5. Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989; 149:1514–1520.[Abstract/Free Full Text]
  6. Haffner SM, Valdez RA, Hazuda HP et al. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992;41:715–722[Abstract]
  7. Isomaa B, Almgren P, Tuomi T et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–689.[Abstract/Free Full Text]
  8. Bonora E, Formentini G, Calcaterra F. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects. Diabetes Care 2002;25:1135–1141.[Abstract/Free Full Text]
  9. Resnick HE, Jones K, Ruotolo G et al. Insulin resistance, the metabolic syndrome, and risk of incidence cardiovascular disease in non-diabetic American Indians: The Strong Heart Study. Diabetes Care 2003;26:861–867.[Abstract/Free Full Text]
  10. The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:688–696.[Abstract/Free Full Text]
  11. Hills SA, Balkau B, Coppack SW et al. The EGIR–RISC study (The European Group for the Study of Insulin Resistance: relationship between insulin sensitivity and cardiovascular disease risk): 1: methodology and objectives. Diabetologia 2004;47:566–570.[CrossRef][Web of Science][Medline]
  12. Carr A, Workman C, Carey D et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 2004;363:429–438.[CrossRef][Web of Science][Medline]
  13. Grundy SM, Brewer HB, Cleeman JI et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433–438.[Free Full Text]
  14. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation 1999.
  15. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diab Med 1999;16:442–443.[CrossRef][Web of Science][Medline]
  16. NCEP. Expert panel on detection, evaluation and treatment of high blood pressure in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection and evaluation and treatment of high blood cholesterol in adults. (Adult Treatment Panel III). JAMA 2001;285:2486–2497.[Free Full Text]
  17. Dunstan DW, Zimmet PZ, Welborn TA et al. The rising prevalence of diabetes and impaired glucose tolerance. The Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 2002;25:829–834.[Abstract/Free Full Text]

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