Epidemiology of the metabolic syndrome and the RISC study
INSERM Unit 258, 16 Avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France
* Corresponding author. E-mail address: balkau{at}vjf.inserm.fr
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Introduction |
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 Top Introduction Frequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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The concept of the metabolic syndrome, comprising central obesity, hypertension, raised triglycerides and low HDL-cholesterol, and raised fasting plasma glucose concentrations, is now well established. However, it has only been possible to compare prevalence data between populations since the introduction of generally accepted definitions of the syndrome. Three definitions of the metabolic syndrome are currently in common use: the World Health Organization (WHO) definition; the European Group for the study of Insulin Resistance (EGIR) definition; and the National Cholesterol Education Programme Expert Panel Adult Treatment Panel III (ATP III) definition.1–3 It is problematic to compare the prevalence data in published studies when different definitions are used. Furthermore, studies often differ not only with respect to the study design and population selection but also with respect to the precise definition of the metabolic syndrome used. Importantly, the WHO definition requires a hyperinsulinaemic clamp to measure insulin resistance when surrogate measures such as fasting insulin or the homeostasis model index are usually used.4
Ideally, a single definition for the metabolic syndrome would allow direct comparisons between prevalence data in different populations. The International Diabetes Federation (IDF) consensus definition, which is due to be published in 2005, will therefore be a positive development.
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Frequency of the metabolic syndrome in Europe |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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WHO and EGIR definitions
The EGIR carried out a detailed analysis of eight European studies to investigate the prevalence of the metabolic syndrome in Europe.5 The frequencies of the metabolic syndrome, according to the WHO definition, were compared between these studies. Further, for non-diabetic subjects, the frequencies for the WHO and EGIR definitions were compared. In total, data for 8200 men and 9363 women were analyzed (Table 1).
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The frequency of the metabolic syndrome, using either the WHO or the EGIR definition, increased with age and was almost always higher in men than in women for a given age group. In non-diabetic subjects, the frequency of the WHO defined syndrome in subjects aged 40–55 varied according to study and was between 7 and 36% for men and between 5 and 22% for women. For the same age group, the EGIR syndrome was less frequent: 1–22% in men and 1–14% in women. Overall, the frequency of the WHO syndrome in men was 50% higher than that of the EGIR syndrome, although there were variations between studies. This higher frequency was mainly due to the differing definitions of central obesity, which resulted in a higher frequency of central obesity with the WHO definition.
ATP III definition
The frequency of the metabolic syndrome, using the ATP III definition, was evaluated in the DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) study in a French population.6 The persistence and incidence of the syndrome after 3 years of follow-up were also analysed. Data were from 2109 men and 2184 women, aged between 30 and 64, who were examined at inclusion and 3 years later. As before, the results showed that the frequency of the syndrome increased with age and was higher in men than in women. Except for low-HDL cholesterol in men, the frequency of each syndrome abnormality tended to increase with age in both sexes (Figure 1A and B).
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At baseline, 10% of men and 7% of women had the metabolic syndrome. If the definition included treatment for diabetes, hypertension, and dyslipidaemia, the syndrome frequencies increased to 16% for men and 11% for women. High blood pressure was the most frequent abnormality: 69% in men and 46% in women at inclusion. However, only 11 and 8%, respectively, had the syndrome both at inclusion and at 3 year follow-up. The most stable abnormality was waist circumference with an 80% rate of persistence at 3 years. Hyperglycaemia was the least stable with only a 60% rate of persistence.
In France, the WHO MONICA (Monitoring Cardiovascular disease) study found that the frequency of the metabolic syndrome, using the ATP III definition, was almost double in Toulouse when compared with Lille.7 This study used a common protocol for the study sites and indicates the variability even within one country. Care must therefore be taken when extrapolating prevalence for a particular town or area to that for an entire country.
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Frequency of metabolic syndrome in the USA |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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A recent study in the USA compared the prevalence of the metabolic syndrome using the ATP III and WHO definitions.8 Data were taken from a nationally representative sample of the US population from the Third National Health and Nutrition and Examination Survey (NHANES III). The aim of the study was to examine how prevalence estimates might differ according to the definition used. A total of 8608 subjects aged 20 or older had complete information for the study variables and were included in the analyses. They included 4167 men, 4441 women; 3500 whites, 2372 African-Americans, 2388 Mexican-Americans, and 348 participants of other races or ethnicities (Table 2).
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The prevalence estimates differed for various population subgroups, especially between ethnic groups.8 Further, the agreement for the two definitions was 80% overall, with some subjects being classified as having the syndrome by one definition but being exempt from the other.
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Role of insulin resistance in definitions |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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Insulin resistance refers to a reduced ability to utilize insulin to control glycaemia. In insulin-sensitive individuals, insulin promotes glucose uptake in target tissues and inhibits glucose production by the liver. Insulin resistance was the underlying feature of the metabolic syndrome as originally described by Reaven.9 It is associated with abnormalities in glucose and lipid metabolisms, as well as with higher arterial blood pressure. These abnormalities are associated with an increased risk of cardiovascular disease (CVD) and are often present before the onset of overt type 2 diabetes. By including insulin resistance explicitly, the WHO definition identifies the proposed underlying mechanism for the metabolic syndrome more directly.1 In contrast, the ATP III definition does not include any surrogate measure of insulin resistance, although the waist circumference is often considered to be one such measure.3 However, as the five ATP III criteria are all associated with insulin resistance, it has been suggested that the ATP III criteria may result in the identification of many participants who are likely to have insulin resistance.8 In contrast, an analysis of data from the DESIR study found that the ATP III definition does not cluster closely with hyperinsulinaemia, a surrogate measure of insulin resistance. By definition, 25% of all subjects had hyperinsulinaemia but only one-half of those with metabolic syndrome were hyperinsulinaemic.6
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Insulin resistance and CVD |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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Experimental and clinical studies have suggested ways in which insulin resistance or hyperinsulinaemia may initiate CVD. However, there is currently no evidence for the direct role of insulin resistance as a cardiovascular risk factor. The San Antonio Heart Study has linked hyperinsulinaemia with incident diabetes, hypertension, and dyslipidaemia.10 However, hyperinsulinaemia is the physiological result of insulin resistance, insulin secretion, and insulin clearance. Furthermore, hyperinsulinaemia may have pathophysiological effects distinct from those of insulin resistance itself.11
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Introduction to the RISC study |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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The EGIR recognized the need for the prospective evaluation of insulin resistance as an independent CVD risk factor and designed the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study to examine insulin resistance and CVD risk. This study is designed to include 1500 healthy people aged 30–60 in 20 centres in 13 countries.12 Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis. The strengths of the RISC study are that it is a large sample of the European population; it uses the gold standard methodology for the measurement of insulin sensitivity; and it evaluates atherosclerosis and its progression by measuring the carotid artery intima-medial thickness (cIMT), a good predictor of cardiovascular events.
The primary objective of the RISC study is to establish whether insulin resistance predicts the development of atherosclerosis as measured by cIMT. Other objectives are to determine whether insulin resistance predicts the deterioration of CVD risk markers, onset of diabetes, and obesity. The study has also been designed to determine the genetic and environmental contributions to insulin resistance. Understanding the relative importance of genetic and environmental factors and how they interact is critically important for the development of specific treatments and for the identification of high-risk individuals. Further, the study aims to develop a novel method to identify more easily insulin resistant subjects in clinical practice.
- Euglycaemic hyperinsulinaemic clamp
- Ultrasound examination of extracranial carotid arteries, measure of cIMT
- Lifestyle and medical history questionnaire
- Measure of physical activity using both a questionnaire and an accelerometer
- Physical examination (including body weight, waist and hip circumferences, body fat by bio-impedance, blood pressure, heart rate)
- Ankle brachial pressure (to evaluate peripheral arterial disease)
- Biological tests [including oral glucose tolerance test (OGTT), lipid profile, and urine analysis]
- Genetic analysis
RISC follow-up examinations (after 3 and 10 years)
- Ultrasound examination of cIMT (to examine progression of atherosclerosis)
- Review of hospital records with a diagnosis of CVD
- Lifestyle and medical history questionnaire
- Measure of physical activity using both a questionnaire and an accelerometer
- Physical examination (including body weight, waist and hip circumferences, evaluation of body fat by bio-impedance, blood pressure)
- Ankle brachial pressure (to measure progression of peripheral artery disease)
- Biological tests (including OGTT, lipid profile, and urine analysis to evaluate progression to diabetes, dyslipidaemia)
- Primary endpoint
- Changes in cIMT
- Changes in cIMT
- Secondary endpoints
- Deterioration of CVD risk factors (e.g. blood pressure, lipids, glucose metabolism, body composition)
- Deterioration of CVD risk factors (e.g. blood pressure, lipids, glucose metabolism, body composition)
RISC—objective 1
To establish whether insulin resistance predicts deterioration of CVD risk markers, diabetes, obesity, atherosclerosis, and CVD events.
A large epidemiological study using the gold standard measure of insulin resistance—the hyperinsulinaemic euglycaemic clamp—is the only way to address this first objective. Because the procedure is technically elaborate, time consuming, and costly to perform, there are few large-scale studies and fasting insulin is often used as a surrogate marker. However, in Europe, there is widespread expertise in the use of the clamp method, enabling the possibility of a multicentre study.
Several studies have shown that cIMT is a good indicator of early atherosclerosis and that an increased intima-medial thickness is a risk factor for CVD.
The RISC study design will also examine whether subjects who are more insulin resistant at baseline examination tend to develop diabetes, CVD, and obesity.
Other variables related to insulin resistance, which will be prospectively studied, include hypertension, low HDL-cholesterol, and high triglycerides.
RISC—objective 2
To determine genetic and environmental contributions to insulin resistance and CVD.
Both genetic and environmental factors contribute to the development of CVD, diabetes, obesity, and insulin resistance. Understanding the relative importance of genetic and environmental factors and how they interact are critically important for the development of specific treatments and for the identification of high-risk individuals.
Genetic factors
Despite the clear evidence that genes play a role in the development of insulin resistance, no major genes have been identified. In contrast, evidence points to the interaction of multiple gene effects in determining the overall level of insulin resistance. The RISC study will screen for variants of the IRS-1,TNF-alpha, and PPAR-gamma genes, which have been linked with insulin resistance. In addition, new candidate genes will emerge and will be genotyped as part of the project.
Environmental factors
It has previously not been established how much of the variation in insulin resistance in different populations is attributable to differences in physical activity and body composition. RISC will assess the roles that physical activity and body composition play in insulin sensitivity even in the overweight and obese patients. Motion sensors as well as a questionnaire will be used to measure physical activity.
Inflammatory factors
The role of markers of haemostasis and inflammation
Plasminogen activator inhibitor-I (PAI-1), C-reactive protein, fibrinogen, vascular adhesion molecules, and intracellular adhesion molecules, as well as homocysteine, will be determined. The role of these atherosclerotic risk factors will be studied in relation to obesity and insulin insensitivity.
RISC—objective 3
To develop a novel method based on mathematical modelling to identify insulin resistant subjects in clinical practice.
The RISC study aims to use information obtained from the gold standard clamp technique to develop a method of assessing insulin sensitivity, using insulin and glucose concentrations from the OGTT. This will enable future evaluation of insulin sensitivity on a larger scale without recourse to the labour-intensive euglycaemic hyperinsulinaemic clamp method.
This new technique would be widely applicable in both epidemiological studies and clinical practice, allowing physicians to identify and treat subjects with insulin resistance earlier.
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References |
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TopIntroductionFrequency of the metabolic...Frequency of metabolic syndrome...Role of insulin resistance...Insulin resistance and CVDIntroduction to the RISC...References |
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- World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation 1999.
- Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diabetes Med 1999;16:442–443.[CrossRef][ISI][Medline]
- NCEP Expert Panel on the 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 cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
[Free Full Text] - Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–419.[CrossRef][ISI][Medline]
- Balkau B, Charles MA, Drivsholm T et al. Frequency of the WHO metabolic syndrome in European cohort and an alternative definition of insulin resistance syndrome. Diabetes Metab 2002;28:364–376.[ISI][Medline]
- Balkau B, Vernay M, Mhamdi L et al. The incidence and persistence of the NCEP (National Cholesterol Education Program) metabolic syndrome. The French D.E.S.I.R. study. Diabetes Metab 2003;29:526–532.[ISI][Medline]
- Gomila S, Dallongeville J. Epidémiologie du syndrome métabolique en France. [French] Med Nutr 2003;39:89–94.
- Ford ES, Giles WH, Dietz WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care 2003;26:575–581.
[Abstract/Free Full Text] - Reaven GM. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1597–1607.
- Haffner SM, Valdez RA, Hazuda HP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992;41:715–722.[Abstract]
- Weyer C, Hanson RL, Tataranni PA. A high plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathologic role of relative hyperinsulinaemia. Diabetes 2000;49:2094–2101.[Abstract]
- Hills SA, Balkau B, Coppack SW. 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.[Medline]
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