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The metabolic syndrome: cluster with a self-fulfilling loop?

Clemenz, Markus; Kintscher, Ulrich; Unger, Thomas

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doi: 10.1097/01.hjh.0000202813.79964.4a
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In a recent issue of the journal, Strahorn et al. [1] presented impressive experimental data regarding the genetical analysis of the metabolic syndrome components in rats. The study elegantly demonstrates for the first time that chromosome Y and a section on chromosome 2 are in significant (inter)coherence with the metabolic syndrome in a high fructose diet, high blood pressure rat model. The authors state that, in earlier studies, the QTL on chromosome 2 has already been demonstrated to play a role in blood pressure regulation and to affect glucose metabolism in two diabetic rat strains. Interestingly, the authors indicate, that chromosome Y is known for blood pressure and serum lipid level regulation. This might implicate a distinct role of sex in the development of the metabolic syndrome.

The metabolic syndrome is defined as a specific cluster of risk factors for cardiovascular and metabolic disease that might be pathophysiologically linked to insulin resistance. For some time, numerous leading specialists in the field have raised sustained doubts as to whether the metabolic syndrome, as a separate clinical entity, diagnosis or obligation to treat, has the right to exist or whether every single risk factor of cardiovascular and metabolic disease should be diagnosed and treated individually. In a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes, Kahn et al. [2] summarize the concerns regarding the metabolic syndrome.

They state that the metabolic syndrome is not clearly defined. Three important organizations (US National Cholesterol Education Program: Adult Treatment Panel III, World Health Organization, and the International Diabetes Federation) give their own different recommendations on how to diagnose the syndrome, and which thresholds to use, leading to a dazzling array of disease patterns with different cardiovascular risks [3–5]. Subsequently, clinical and epidemiological sessions in metabolic syndrome conferences have dealt with the question of whether patients that match the first definition are also being detected with the second or the third.

Furthermore, the attempt to relate the components of the metabolic syndrome to a unifying pathological process is ambiguous. The aetiology of the component clustering is unclear and the decision regarding why certain factors are included, and others are not, is difficult to follow.

Numerous hypothetical common underlying pathophysiological mechanisms, such as endothelial dysfunction, excess adipose tissue, inflammation or most frequently insulin resistance in all components of the metabolic syndrome. However, none of these mechanisms has been proven to comprise the pathophysiological mediator of the syndrome.

With regard to the use of the metabolic syndrome for predicting cardiovascular risk, other predictive algorithms considering a more comprehensive selection of risk factors, by including smoking, age, physical activity, sex or family history, have been shown to exhibit an even better predictive value for heart disease. Here, the Framingham Risk Score is still one of the most commonly applied [6], and the nine risk factors used in the INTERHEART study were at least able to predict most of the myocardial infarctions, in low and middle income countries, that account for 80% of cardiovascular disease [7].

One could ask why scientists preferably linger in loops of arbitrarily clustered definitions that, to some extent, predict arterial disease, instead of investigating the causative molecular mechanisms by which single risks really lead to cardiovascular disease, and thereby discovering and defining potential new targets for therapy.

However, as much as the metabolic syndrome is criticized, one should bear in mind the vast exceptional advantages that have been gained on all levels of society, science and health care ever since the metabolic syndrome was deployed. Following the early 1990s, the prevalence of adiposity [8] and diabetes [9] has been progressively rising, and a sedentary lifestyle with low physical activity and high energy intake is even spreading over our children like an invasion from Mars.

No one would deny that the metabolic syndrome is a suitable concept to deal with obese patients in a clinical setting, to educate patients about the connection between their lifestyle, health risks and medical outcomes, and to accord them first priority in clinical action. With the metabolic syndrome, physicians have an extremely powerful and vitally important tool to communicate these coherences in a reasonable, simplified and persuasive way to patients. One could almost be in favour of the hypothesis that the simplicity of identifying patients who are at high risk for bad outcomes, and who are in greatest need for clinical intervention, makes a great deal both of the doctors commitment to treat and of the patient to comply. Once risk identification and action from patients and physicians is achieved, the risk can be reversed as much as possible through lifestyle changes, particularly weight reduction and increased physical activity, and thereby mortality can be reduced and quality of life can be improved. And that is certainly a crucial point.

It appears that the metabolic syndrome is a clinically valuable and working prototype that is far away from perfectly describing all aspects of cardiovascular and metabolic disease prediction, with a relevant, common underlying, pace-making pathophysiological pathway remaining to be identified.

To conclude, the metabolic syndrome is a waning star that struggles along, not knowing whether to fall to insignificance or to rise again to clinical fame and glory. Although important, it faces severe definition and purpose-of-construct problems, and is far away from an integrative solution. How can genetics now help us to understand this syndrome?


1 Strahorn P, Graham D, Charchar FJ, Sattar N, McBride MW, Dominiczak AF. Metabolic syndrome loci in the stroke prone spontaneously hypertensive rat. J Hypertens 2005; 23:2177–2184.
2 Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28:2289–304. Diabetologia 2005; 48:1684–1699.
3 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. for the American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 25:2735–2752.
4 Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus, Geneva, 59p, WHO/NCD/NCS/99.2.
5 International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Brussels: IDF, 2005.
6 Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 12:1837–1847.
7 Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:937–952.
8 Overweight and Obesity: Obesity Trends: US Obesity Trends 1985–2004. Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, USA.
9 Diabetes Public Health Resource: Data & Trends: National Diabetes Surveillance System: Prevalence of Diabetes. National Center for Chronic Disease Prevention and Health Promotion. Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, USA.
© 2006 Lippincott Williams & Wilkins, Inc.