The role of obesity for the metabolic syndrome definition is controversial (1,2) even though obesity is strongly related to insulin resistance (fasting insulin levels) (3), chronic inflammation (high-sensitivity C-reactive protein [hsCRP] levels) (4), and coronary heart disease (CHD) (5). Obesity is considered an essential criterion by the International Diabetes Federation definition (1). However, the National Cholesterol Education Program-Adult Treatment Panel III definition accepts any three of five criteria (2). If obesity were essential, significant insulin and hsCRP levels and CHD risk would not be present in lean subjects. We examined this hypothesis in populations from Mexico City and Spain because of their distinct risk factor profile (more cases of type 2 diabetes, low HDL cholesterol, and hypertriglyceridemia in Mexico City vs. more cases of hypertension and hypercholesterolemia in Spain) (6).

The Mexico City Diabetes Study (7,8) from Mexico City and the Spanish Insulin Resistance Study (6) and Segovia Study (9) from Spain were designed as population-based studies. The two studies from Spain were fused in a single dataset because protocols and one of the principal investigators (M.S.-R.) were the same for both studies.

Nondiabetic subjects were considered eligible for analysis (in Spain, n = 1,311; in Mexico City, n = 1,918) because of the absence of a reliable surrogate of insulin resistance for diabetic subjects. Framingham risk equations were used to estimate CHD risk (10) for two reasons: 1) absence of prospective data in Spain and 2) small number of both cardiovascular events and lean subjects with multiple metabolic disorders in Mexico City. Specific insulin was measured by radioimmunoassay in Mexico City (interassay coefficient of variation [CV] 3–7%) (Linco Research, St. Louis, MO) (7) and by immunoassay in Spain (9.1–11.4%) (Linco Research); hsCRP was measured by immunoassay in Mexico City (8.9%) (Calbiochem, Darmstadt, Germany) (8) and in Spain (3.3%) (Beckman Coulter, Fullerton, CA).

Components of the metabolic syndrome were defined according to the International Diabetes Federation criteria (1): hypertriglyceridemia (≥1.7 mmol/l), low HDL cholesterol level (<1.0 mmol/l in men and <1.3 mmol/l in women), high blood pressure (systolic blood pressure ≥130 mmHg, diastolic blood pressure ≥85 mmHg, or pharmacological treatment), fasting hyperglycemia (≥5.6 mmol/l), and elevated waist circumference (≥94 cm in men and ≥80 cm in women).

We used one-way ANCOVA to analyze insulin and hsCRP levels and Framingham risk estimates to account for the effect of age and sex. We performed analyses on the log-transformed values of insulin and hsCRP levels and on the logit transformation of Framingham risk estimates to correct for skewness and kurtosis. These variables were then back-transformed to their natural units for presentation.

In Spain and Mexico City, 26.3 and 55.2% of subjects had three or more metabolic disorders, respectively. Normal waist circumference was present in 5.2% of Spanish subjects with three or more metabolic disorders and in 4.8% of Mexican counterparts.

Among subjects with one or more metabolic disorders, elevated waist circumference was directly related to the number of disorders (Table 1). Insulin and hsCRP levels and CHD risk estimates were not increased in subjects with elevated waist circumference after adjusting for number of metabolic components, except for insulin levels in Mexico City.

Among subjects with three or more metabolic disorders, age- and sex-adjusted estimates of CHD risk were not increased in subjects with elevated waist circumference (yes vs. no) (Spain: 14.5 [13.8–15.3] vs. 14.9% [11.6–19.1], P = 0.836; Mexico City: 7.4 [7.1–7.6] vs. 9.7% [8.4–11.2], P < 0.001), and neither were hsCRP levels (Spain: 1.86 ± 0.11 vs. 1.72 ± 0.47 mg/l, P = 0.734; Mexico City: 1.73 ± 0.05 vs. 1.60 ± 0.22 mg/l, P = 0.546). Insulin levels were not increased in subjects with elevated waist circumference (yes vs. no) in Spain (13.5 ± 0.4 vs. 11.1 ± 1.5 μIU/ml, P = 0.171) but were increased in Mexico City (15.3 ± 0.3 vs. 12.5 ± 0.9 μIU/ml, P = 0.004).

In the U.S. population, 4.6% of men and 6.2% of women with normal weight have three or more metabolic disorders (11). Normal-weight individuals may have insulin resistance. Insulin-resistant, normal-weight individuals have more cardiovascular disease risk factors (12,13), greater CHD and diabetes risks (14–16), and more total and intra-abdominal fat than insulin-sensitive, normal-weight individuals (14). Similarly, absence of central obesity, as assessed by waist circumference, cannot rule out the presence of multiple metabolic disorders (17). Our results indicate that significant insulin and hsCRP levels and CHD risk estimates may be present in subjects with metabolic disorders other than obesity.

There is much support in the literature for the concept that waist circumference is not an independent predictor of CVD and that risk increases with number of components (18,19). The component most strongly associated with insulin resistance is obesity, but clustering of metabolic disorders greatly exceeds chance association in both obese and lean individuals (3). The cross-sectional design of this study limits our ability to reach conclusions. Nevertheless, our results suggest that the metabolic syndrome is not found exclusively in obese individuals.

Table 1—

Number of metabolic disorders, insulin and hsCRP levels, and CHD risk estimates stratified by waist circumference category in nondiabetic subjects with one or more metabolic disorders

Elevated waist circumferenceNormal waist circumferenceP
Spain    
    n 956 187 — 
    No. of metabolic disorders* 2.21 ± 0.03 1.42 ± 0.07 <0.001 
    Fasting insulin level (μIU/ml)* 11.2 ± 0.2 9.5 ± 0.5 0.001 
    Fasting insulin level (μIU/ml)† 11.0 ± 0.2 10.5 ± 0.5 0.335 
    hsCRP level (mg/l)* 1.60 ± 0.05 1.46 ± 0.12 0.324 
    hsCRP level (mg/l)† 1.57 ± 0.05 1.58 ± 0.13 0.923 
    CHD risk estimate over 10 years (%)* 10.5 (10.2–10.9) 10.2 (9.3–11.1) 0.425 
    CHD risk estimate over 10 years (%)† 10.2 (9.8–10.5) 12.5 (11.5–13.2) <0.001 
Mexico City    
    n 1,455 429 — 
    No. of metabolic disorders* 2.83 ± 0.02 1.56 ± 0.06 <0.001 
    Fasting insulin level (μIU/ml)* 14.3 ± 0.1 9.4 ± 0.3 <0.001 
    Fasting insulin level (μIU/ml)† 13.5 ± 0.1 11.4 ± 0.3 <0.001 
    hsCRP level (mg/l)* 1.62 ± 0.05 1.35 ± 0.07 0.006 
    hsCRP level (mg/l)† 1.57 ± 0.05 1.46 ± 0.09 0.349 
    CHD risk estimate over 10 years (%)* 6.1 (5.8–6.3) 5.6 (5.3–5.9) 0.027 
    CHD risk estimate over 10 years (%)† 5.5 (5.4–5.6) 7.8 (7.4–8.2) <0.001 
Elevated waist circumferenceNormal waist circumferenceP
Spain    
    n 956 187 — 
    No. of metabolic disorders* 2.21 ± 0.03 1.42 ± 0.07 <0.001 
    Fasting insulin level (μIU/ml)* 11.2 ± 0.2 9.5 ± 0.5 0.001 
    Fasting insulin level (μIU/ml)† 11.0 ± 0.2 10.5 ± 0.5 0.335 
    hsCRP level (mg/l)* 1.60 ± 0.05 1.46 ± 0.12 0.324 
    hsCRP level (mg/l)† 1.57 ± 0.05 1.58 ± 0.13 0.923 
    CHD risk estimate over 10 years (%)* 10.5 (10.2–10.9) 10.2 (9.3–11.1) 0.425 
    CHD risk estimate over 10 years (%)† 10.2 (9.8–10.5) 12.5 (11.5–13.2) <0.001 
Mexico City    
    n 1,455 429 — 
    No. of metabolic disorders* 2.83 ± 0.02 1.56 ± 0.06 <0.001 
    Fasting insulin level (μIU/ml)* 14.3 ± 0.1 9.4 ± 0.3 <0.001 
    Fasting insulin level (μIU/ml)† 13.5 ± 0.1 11.4 ± 0.3 <0.001 
    hsCRP level (mg/l)* 1.62 ± 0.05 1.35 ± 0.07 0.006 
    hsCRP level (mg/l)† 1.57 ± 0.05 1.46 ± 0.09 0.349 
    CHD risk estimate over 10 years (%)* 6.1 (5.8–6.3) 5.6 (5.3–5.9) 0.027 
    CHD risk estimate over 10 years (%)† 5.5 (5.4–5.6) 7.8 (7.4–8.2) <0.001 

Data are means ± SD or median(range) unless otherwise indicated.

*

Results adjusted for age and sex.

†

Results adjusted for age, sex, and number of components of the metabolic syndrome.

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Published ahead of print at http://care.diabetesjournals.org on 22 May 2007. DOI: 10.2337/dc06-2627.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

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2007