Background  Not only the obese, but also the non-obese adults have the high prevalence of metabolic syndrome in the upper normal weight. The aim of this study was to assess the prevalence rates of metabolic syndrome and its individual components in non-obese adult Taiwanese (body mass index (BMI) ≤ 26.9 kg/m²).
Methods  A cross-sectional study was conducted from January 2006 to December 2007. One thousand six hundred and fifty-nine subjects (aged 47.5±12.4 years), 60.8% of which were men, were enrolled. The prevalence and odds ratios of metabolic syndrome, defined by the American Heart Association/National Heart, Lung and Blood Institute (2005), were analyzed in the BMI category according to 2.0 unit increments, in individuals seeking a health examination.
Results  The higher the BMI categories, the more prevalent the metabolic syndrome was in women and in men (P <0.001). Compared with those women with a BMI ≤20.9 kg/m², the odds ratios for metabolic syndrome in women were 1.3 (95% CI: 0.5–3.2) with BMI 21.0–22.9 kg/m², 3.0 (1.3–7.1) with BMI 23.0-24.9 kg/m², and 8.6 (3.6–20.8) for women with BMI 25.0–26.9 kg/m², after controlling for age, smoking status, alcohol consumption, betel nut chewing, blood routine, biochemical data, hepatitis B virus surface antigen and anti-hepatitis C virus. The corresponding odds ratios in men were 1.6 (0.6–4.2), 3.7 (1.6–8.8), and 9.9 (4.2–23.2).
onclusions  Individuals in the upper normal weight and slightly overweight BMI range have relatively high prevalence and increased risk of having metabolic syndrome. Therefore, physicians should screen metabolic syndrome in not only obese but also non-obese individuals for the prevention of cardiovascular disease.

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The prevalence of type 2 diabetes is rapidly increasing worldwide,^1,2 primarily due to the global increase in obesity and sedentary lifestyles.³ However, there are many individuals who are not obese on the basis of body mass index (BMI), but are hyperinsulinemic, insulin-resistant, and predisposed to type 2 diabetes and premature coronary heart disease in general practice.⁴

Moreover, people with metabolic syndrome are at increased risk for developing type 2 diabetes mellitus⁵ and cardiovascular disease⁶ as well as suffering increased mortality from cardiovascular disease and all causes.⁷

The metabolic syndrome affects one in three to four adults older than 20 years,⁸ and its prevalence is likely to increase.⁹ Genetic abnormalities, fetal malnutrition, and visceral adiposity may play roles in the pathophysiology of insulin resistance and metabolic syndrome.¹⁰ Metabolic syndrome is a constellation of central obesity, hyperglycemia, hypertension, hypertriglyceridemia and high-density lipoprotein cholesterol (HDL-C), according to the definition of the American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI, 2005).^11,12

Ruderman et al¹³ first proposed the term “metabolically obese, normal-weight” (MONW) as applied to individuals in 1981; however, the concept of the MONW individual was originally noted in a large epidemiological study by Abraham et al¹⁴ in 1971. A formal definition was not developed until 1981 by Ruderman et al.¹³ It was suggested that MONW individuals were those whose BMI (weight in kilograms divided by the square of the height in meters) was considered normal, but who had any one of the following metabolic disorders that could be improved via caloric restriction: type 2 diabetes, hypertension, and hypertriglyceridemia. Ruderman et al⁴ revisited the definition of MONW in 1998, and included components of metabolic syndrome, polycystic ovarian syndrome (PCOS), premature coronary heart disease (CHD), uric acid, low birth weight, inactivity, ethnic group, and family history of the metabolic disorders.

In the past, most notions about the metabolic syndrome emphasized the importance of obesity. In fact, non-obese individuals often have some metabolic associated disorders but they are often ignored relatively to obesity. In 2004, St-Onge et al¹⁵ proposed a new definition of metabolically obese, normal-weight individuals as those who have the metabolic syndrome. They revealed that individuals in the upper normal-weight and slightly overweight BMI range have a relatively high prevalence and are at increased risk of having the metabolic syndrome in whites, blacks and Hispanics. In 2008, Wildman et al¹⁶ also found there was a high prevalence of clustering of cardiometabolic abnormalities among normal-weight individuals. In Taiwan, data from the 40-year group with the criteria of the National Cholesterol Education Program′s Adult Treatment Panel III report (NCEP ATP III)¹⁷ showed the prevalence of metabolic syndrome in men and women. They revealed BMI associated with increased odds of metabolic syndrome,¹⁸ but did not reveal its prevalence rate among individuals within the various BMI categories. The main objective of this study was to determine the prevalence rates and likelihood of having metabolic syndrome defined by AHA/NHLBI and waist circumference by Asia-Pacific guideline and its individual components in non-obese individuals (BMI ≤ 26.9 kg/m²) in Taiwan of China.

Study populations
The authors conducted a cross-sectional study in Taichung, Taiwan from January 2006 to December 2007. The subjects were recruited from the health examination center of a regional hospital at Taichung, a third largest city in Taiwan, China. The purpose of the health checkup program is to promote public health through the early detection of chronic diseases.

Of the total sample, we excluded those who were <18 years of age, obese (BMI >27.0 kg/m²), pregnant, missing height or weight measurements and other confounding factors, did not fast for a minimum of 8 hours before their blood samples obtained, and were missing one or more of the metabolic syndrome components. A total of 1659 subjects were retained for analysis in this study. The Ethics Committee of Cheng Ching Hospital approved the current study.

Definitions of metabolic syndrome
We used the AHA/NHLBI 2005 and waist circumference by Asia-Pacific guideline of the metabolic syndrome^11,12 as the main outcome measures. As detailed in the AHA/NHLBI report, participants having three or more of the following criteria were defined as having the metabolic syndrome: waist circumference greater than 90 cm in men and 80 cm in women; serum triglycerides level of at least 150 mg/dl; HDL-C less than 40 mg/dl in men and 50 mg/dl in women; blood pressure of at least 130/85 mmHg (including using antihypertensive medication); or a serum glucose level of at least 100 mg/dl (including the use of antidiabetic medication, insulin or oral agents).

Physical examination and laboratory test
Smoking and drinking were categorized as yes and never. Never drinkers were those who self-reported that they did not regularly drink beer, wine or hard liquor.

Body weight and height were measured to the nearest 0.1 kg and 0.1 cm, respectively. Waist circumference was measured to the nearest 0.1 cm, and was calculated as the average of one measurement taken after inspiration and one taken after expiration at the level of mid-distance between the bottom of the rib cage and the top of the iliac crest. Three blood pressure measurements were obtained with the subject in a seated position using a manual mercury sphygmomanometer.

Fasting blood specimens were collected from all participants after an 8-hour overnight fast. The blood samples were sent to the clinical laboratory of Cheng Ching Hospital within one hour for analysis. Anticoagulated whole blood was used to determine erythrocyte count, leukocyte count, hemoglobin, and platelet count with a Cell Dyn^® 3500 hematology AutoAnalyzer (Abbott Laboratories, US). Biochemical tests were performed using a Hitachi^® 747 analyzer (Roche Diagnostics, Mannheim, Germany). Hepatitis B virus surface antigen and anti-hepatitis C virus were detected using a microparticle enzyme immunoassay (Architect^® i2000; Abbott Laboratories, US). Hepatitis B virus antigen was considered negative if the titer was <2.0 and hepatitis C virus (HCV) antibody was considered negative if the titer was <1.0.

Statistical analysis
The SPSS15.0 was used for all statistical analyses and a P value less than 0.05 was considered statistically significant. Continuous numerical variables are presented as means ± standard deviation (SD) and categorical variables as number and percent. The analysis included an independent samples two-tailed t test for equality of means between sexes for variables distributed normally. The authors compared the prevalence of metabolic syndrome and its individual components according to BMI category using chi-square test, and the linear trend was tested. Using 2.0 unit increments in BMI, all individuals were subdivided into four BMI groups (≤20.9, 21.0–22.9, 23.0–24.9 and 25.0–26.9 kg/m²). Logistic regression analysis was also used to examine the associations between BMI classification and metabolic syndrome. Dummy variables were created to compute odds ratios and 95% CIs for these factors. The BMI category ≤20.9 kg/m² was used as the referent group (odds ratio=1.0). For age, blood routine and biochemical data, if a significant association existed, the variable was used as a continuous variable for further control of confounding factors. The odds ratios were adjusted for age, smoking status, alcohol consumption, betel nut chewing, blood routine (white blood cell, hemoglobin, and platelet), biochemical data (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, creatinine, uric acid, hepatitis B virus surface antigen and anti-hepatitis C virus).

The total of 1659 subjects enrolled 1008 men (60.8%) and 651 women (39.2%). The mean age was (47.5±12.4) years, and the range of age was 18 to 83 years. The mean BMI was (23.0±2.4) kg/m². The prevalence of tobacco use, alcohol consumption and betel nut chewing were 26.8%, 18.9% and 4.3%, respectively. The prevalence of hepatitis B virus surface antigen and were 14.2% and 3.5% respectively.

Subject characteristics are presented in Table 1. Except HDL-C and platelet, men had higher mean values of BMI, waist circumference, triglyceride, blood pressure, and other variables. They were significantly different between the sexes. Moreover, women had higher anti-hepatitis C virus rate. There was no significant sex difference in age.

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Table 1. Subject characteristics by sex (n=1659)

The prevalence for each component of metabolic syndrome and its components was shown in Table 2. Compared with men, a greater proportion of women had a large waist circumference (P <0.001), and up to 73.3% of the women with a BMI of 25.0–26.9 kg/m² had a large waist circumference.

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Table 2. Prevalence of each metabolic risk factor within sex and BMI category

The prevalence of high glucose levels increased with increasing BMI in both sexes (P <0.001). Similarly, the prevalence of all the components of the metabolic syndrome increased with increasing BMI (P <0.001).

Depending on sex, the prevalence (standard error (SE)) of metabolic syndrome increased in a graded fashion from 4.3% (1.4), 10.7% (2.2), 22.8% (3.5) to 49.5% (5.0) at BMI from ≤20.9 kg/m² to 25.0–26.9 kg/m² in women (P <0.001), and 4.9% (1.8), 7.5% (1.9), 17.6% (2.0) to 36.6% (2.8) in men (P <0.001) (Figure 1).

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Figure 1. Prevalence (SE) of metabolic syndrome within sex and BMI category.

Compared to women with BMI ≤20.9 kg/m², the odds ratios for metabolic syndrome were 1.3 (95% CI 0.5–3.2) with BMI 21.0–22.9 kg/m², 3.0 (1.3–7.1) with BMI 23.0–24.9 kg/m², and 8.6 (3.6-20.8) for women with BMI 25.0–26.9 kg/m², after controlling for age, smoking status, alcohol consumption, betel nut chewing, blood routine, biochemical data, hepatitis B virus surface antigen and anti-hepatitis C virus. The corresponding odds ratios in men were 1.6 (0.6–4.2), 3.7 (1.6–8.8) and 9.9 (4.2–23.2), respectively (Figure 2).

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Figure 2. Odds ratios of the metabolic syndrome in women, men and total subjects according to BMI category. Odds ratios were adjusted for age, smoking status, alcohol consumption, betel nut chewing, white blood cell, hemoglobin, platelet, alanine aminotransferase, Aspartate aminotransferase, alkaline phosphatase, total bilirubin, creatinine, uric acid, hepatitis B virus surface antigen and anti-hepatitis C virus. The ≤20.9 kg/m2 category was used as the referent group (odds ratio=1.0).

Not only obese, but non-obese individuals may also have metabolism associated disorders. Similarly, the results showed metabolism syndrome was highly prevalent and BMI-dependent, especially in women, in individuals with upper normal and slightly elevated BMI, so the concept of the MONW individual must be emphasized.

Insulin resistance syndrome has recently been thought to be an underlying feature of metabolic syndrome.¹⁹ In 1998, the World Health Organization (WHO)²⁰ first proposed a unifying definition for the syndrome, and chose to call it the metabolic syndrome rather than insulin resistance syndrome. In 2001, the Third Report of the National Cholesterol Education Program′s Adult Treatment Panel III Report (NCEP ATP III) provided a working definition of this syndrome, a simplified approach to the clinical identification.¹⁷ Due to the lack of standardization and the unavailability of assays for insulin sensitivity in Asia, use of the NCEP ATP III criteria is preferred because they can be easily applied to the primary care setting in many parts of Asia.

Using ATP III definition, Ford et al²¹ estimated that approximately 22% of US adults (24% after age adjustment) have the metabolic syndrome. The worldwide prevalence of the metabolic syndrome has been described at about 10%–55% in various populations.²² The prevalence of the metabolic syndrome is likely to increase in the world, due to the global epidemic of obesity and diabetes.⁹ In Taiwan, data from the 40-year group, with ATP III criteria, reported that the prevalence of the metabolic syndrome were 29.2% in women and 37.7% in men.¹⁸ Li and coworkers′ study²³ showed the prevalence of metabolic syndrome was 8.3% by ATP III in subjects without hypertension and of metabolic syndrome was 32.9% in men; 53.1% in women in hypertensive individuals in China. Other Asian countries have shown 14%–30% rates of metabolic syndrome.^24-28 Our study showed 23.5%, 27.8% overall and 15.2%, 18.7% in non-obese subjects according to ATP III and AHA/NHLBI definition of metabolic syndrome respectively.

Overall prevalence of the metabolic syndrome within different ethnicities in St-Onge′s¹⁵ study was 9.6% to 18.5% at BMI 25.0–26.9 kg/m² in men, and 15.0% to 22.5% in women. Our Asian study showed 36.6% in men and 49.5% in women at this BMI category, which was a higher prevalence than St-Onge′s study. The prevalence of the metabolic syndrome was highly associated with BMI categories in men and women (P <0.001). After adjusting all the confounding variables, odds ratios of the metabolic syndrome increased within BMI categories in men and women.

Our study showed one subject fulfilled the metabolic syndrome at BMI <18.5 kg/m². Also, in this BMI category, there were 9, 2, 6, 9, 3 subjects be abnormal in fasting plasma sugar, triglyceride, HDL-C, blood pressure, waist circumference, respectively. We must be alert to the metabolic associated disorders, even in individuals who are underweight (BMI <18.5 kg/m²). So, we proposed the term of metabolically obese, non-obese (MONO) individuals to emphasize the importance of non-obese individuals in the present of metabolic associated disorders.

The high prevalence of abnormal metabolic risk factors among individuals with upper normal to slightly elevated BMI in this cohort suggests that current recommendations for weight loss may need to be modified. Weight loss in individuals with BMI <25.0 kg/m² should be considered if they also have the metabolic syndrome.¹⁵ Current weight-loss recommendations do not advise patients with BMI <25.0 kg/m² to lose weight, and it is not recommended for patients with BMI <27.0 kg/m² to use pharmaceutical agents as adjuncts to weight-loss regimens.²⁹ Weight loss in individuals with BMI <25.0 kg/m² should be considered if they also have the metabolic syndrome.¹⁵

There are some limitations to the present study. Although the authors cannot infer this result to all Taiwanese, those who with metabolic syndrome are at increased risk for developing diabetes mellitus and cardiovascular disease, so the high prevalence of this condition may also have serious implications for Taiwan health care costs.

The cross-sectional nature of the study does not permit causal inferences to be made about the relationship between BMI and the metabolic syndrome, but an increase in BMI is probably the cause of metabolic syndrome. We controlled age, cigarette smoking, alcohol consumption, betel nut chewing, blood routine, biochemical data, hepatitis B virus surface antigen and anti-hepatitis C virus. The metabolic syndrome or insulin resistance syndrome is also associated with non-alcoholic fatty liver disease (NAFLD);^30,31 abnormal ALT is the leading cause of NAFLD, and is a predictor of type 2 diabetes.³² The association of uric acid with cardiovascular disease is controversial, but it is a risk factor in Ruderman′ s definition of the MONW individual.⁴ We did not control for the other risk factors of a MONW individual: a family history of the associated metabolic disorders, and the predisposing factors of low birth weight and inactivity and PCOS,⁴ but the results showed the same trend, compared with St-Onge′s¹⁵ and Wildman′s¹⁶ study.

In conclusion, individuals in the upper normal-weight and slightly overweight BMI range have a relatively high prevalence and are at increased risk of having metabolic syndrome and its components. The results showed the same trends as in St-Onge′s and Wildman′s study. Moreover, the metabolic syndrome exists even in individuals with lower normal weight, and underweight men. Therefore, physicians should screen metabolic syndrome in not only obese but also non-obese individuals in the prevention of type 2 diabetes and cardiovascular diseases.

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