Relative risks of the metabolic syndrome according ... - Clinical Science

Clinical Science (2005) 108, 553–559 (Printed in Great Britain)

Relative risks of the metabolic syndrome according to the degree of insulin resistance in apparently healthy Korean adults Seung-Ha PARK∗1 , Won-Young LEE∗1 , Eun-Jung RHEE∗ , Woo-Kyu JEON∗ , Byung-Ik KIM∗ , Seung-Ho RYU† and Sun-Woo KIM∗ ∗

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-Dong, Jongro-Ku, Seoul, South Korea, and †Department of Occupational Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-Dong, Jongro-Ku, Seoul, South Korea

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A new simple criterion for diagnosing metabolic syndrome was proposed in the third report of the NCEP (National Cholesterol Education Program). In the present study, we analysed the association between metabolic syndrome and insulin resistance to investigate the effects of the latter on the prevalence of metabolic syndrome based on the new criteria recommended in the ATP (Adult Treatment Panel) III report. A total of 7057 participants (4472 men and 2585 women), who underwent medical screening at the Sungkyunkwan University Kangbuk Samsung Hospital, were investigated. Fasting insulin levels were measured and components of the metabolic syndrome as defined by the ATP III report were determined. We also applied the criteria for abdominal obesity as defined by APC-WC (Asia–Pacific criteria for waist circumference). The prevalence of metabolic syndrome as defined by ATP III was 5.3 % (5.0 % in men and 5.8 % in women) and 8.9 % (8.1 % in men and 10.3 % in women) by APC-WC. The odds ratio for the metabolic syndrome was significantly higher in subjects with higher insulin resistance than in those with lower insulin resistance. The mean levels of HOMA (homoeostatic model assessment) and fasting insulin were significantly higher in those with more of the components of the metabolic syndrome. A high HOMA ( 2.56) and fasting insulin concentration ( 9.98 µIU/ml; where IU is international unit) were found to be independent risk factors of the metabolic syndrome by multiple regression analysis after adjusting for age, sex and body mass index (P < 0.001). These results show that the metabolic syndrome is significantly correlated with the insulin resistance index, and that appropriate values of HOMA and fasting insulin concentration may serve as a helpful guide for the management of metabolic syndrome.

INTRODUCTION The metabolic syndrome, also called insulin-resistance syndrome or syndrome X, is a cluster of cardiovascular disease risk factors [1,2], and is characterized by insulin

resistance and a close relationship with the development of cardiovascular disease and mortality [3–5]. Insulin resistance induces atherogenic dyslipidaemia by a combination of overproduction of apolipoprotein B and increased catabolism of apolipoprotein A-I particles [6].

Key words: cholesterol, diet, homoeostatic model assessment (HOMA), insulin resistance, lipoprotein, metabolic syndrome, risk factor. Abbreviations: APC-WC, Asia–Pacific criteria for waist circumference; ATP, Adult Treatment Panel; BMI, body mass index; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; HOMA, homoeostatic model assessment; IU, international unit; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; NEFA, non-esterified fatty acid; TNFα, tumour necrosis factor α; VLDL, very-LDL. Correspondence: Dr Won-Young Lee (email [email protected]). 1

These authors contributed equally to the work.

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2005 The Biochemical Society

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S.-H. Park and others

The third report by the NCEP (National Cholesterol Education Program) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP (Adult Treatment Panel) III] suggested that the primary purpose should be the lowering of LDL-C (low-density lipoprotein cholesterol) levels, and proposed a stricter standard LDL-C level [7]. The noticeable point of view was that the report described the treatment of the metabolic syndrome as a target secondary to lowering LDL-C levels, and proposed the risk factors and guidelines for treating the metabolic syndrome. The report also stated that the purpose of treating the metabolic syndrome is to reduce the causal risk factors of this syndrome, such as obesity, a lack of exercise and the threat of non-lipid risk factors. Different studies have reported somewhat variable prevalences of metabolic syndrome according to ATP III criteria. It has been reported that the prevalence was 22–24 % in American adults (24 % in men and 23.4 % in women) and 42–44 % in Americans older than 60 years of age [8], suggesting that the prevalence increases with age. In such patients, the metabolic syndrome is likely to cause a 4-fold increase in cardiovascular disease and a 2-fold increase in Type II diabetes compared with normal adults [8,9]. In a study on Korean metropolitan subjects [10], the prevalence of metabolic syndrome according to ATP III criteria was determined to be 6.8 % (5.2 % in men and 9 % in women). When the prevalence was examined based on APC-WC (Asia–Pacific waist circumference) criteria, it was 10.9 % (9.8 % in men and 12.4 % in women), showing a lower incidence than in American adults. However, the incidence of metabolic syndrome is likely to increase steadily in view of the westernization of the diet, excess food intake and the increased elderly population. In the present study, we analysed the degree of relationship between the insulin-resistance index, HOMA (homoeostatic model assessment), and fasting insulin levels in the development of the metabolic syndrome, and then determined the relative risk of the metabolic syndrome according to HOMA and the fasting insulin level.

METHODS Subjects Study participants were selected from our database of 10 710 subjects. A total of 3653 subjects were excluded from the analysis, because waist circumferences were not available or due to the exclusion criteria of the study. The cross-sectional study was performed using data obtained from 7057 subjects > 20 years of age (4472 men and 2585 women; mean age, 41.1 + − 8.8 years) who underwent health screenings at Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine from January–May 2002. The characteristics of the study C


Table 1 Clinical characteristics of the study population

Values are means + − S.D. MS-ATP, metabolic syndrome defined by ATP III criteria with waist circumference determined by ATP III (> 102 cm for men and > 88 cm for women); MS-APC, metabolic syndrome defined by ATP III criteria with waist circumference determined by APC-WC ( 90 cm for men and 80 cm for women). †P < 0.05 and ‡P < 0.001 compared with men, as determined by Student’s t test.

n Age (years) BMI (kg/m2 ) Waist circumference (cm) Fasting glucose (mmol/l) Triacylglycerols (mmol/l) Total cholesterol (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting insulin (µIU/ml) HOMA Prevalence of MS-ATP Prevalence of MS-APC

Total

Men

Women

7057 41.1 + − 8.8 23.5 + − 2.9 79.7 + − 8.9 4.99 + − 1.11 1.59 + − 1.15 5.28 + − 0.91 1.47 + − 0.38 3.09 + − 0.76 118.2 + − 16.2

4472 41.3 + − 8.2 23.7 + − 2.9 83.5 + − 7.1 5.08 + − 1.17 1.81 + − 1.26 5.40 + − 0.91 1.38 + − 0.34 3.18 + − 0.77 118.3 + − 16.4

2585 40.9 + − 9.7† 23.2 + − 2.8 73.1 + − 7.7‡ 4.84 + − 0.95‡ 1.21 + − 0.79 5.12 + − 0.89 1.62 + − 0.39‡ 2.93 + − 0.73 117.8 + − 15.9

75.9 + − 11.1

76.1 + − 11.2

75.4 + − 10.7†

8.06 + − 3.20 1.85 + − 0.96 5.3 % 8.9 %

8.18 + − 3.32 1.91 + − 1.01 5.0 % 8.1 %

7.87 + − 2.97‡ 1.75 + − 0.85‡ 5.8 % 10.3 %†

population are described in Table 1. They were selected among the subjects undergoing health screening after applying exclusion criteria, including a previous history of diabetes mellitus, liver disease (viral or alcoholic hepatitis), abnormal renal function (> 1.5 mg/dl serum creatinine), a history of acute or chronic medical illnesses, cardiovascular diseases and those taking drugs for hypertension, diabetes and hyperlipidaemia. This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital, and informed consent was obtained from all participants.

Anthropometric measurements and blood chemistry We measured height, weight, waist circumference and diastolic and systolic blood pressures in all subjects. BMI (body mass index; kg/m2 ) was calculated using the measured height and weight. Waist circumference was taken midway between the inferior margin of the last rib and the crest of the ilium in the horizontal plane whilst in an upright position. After a 12-h fast, serum glucose, total cholesterol, triacylglycerol (triglyceride) and HDLC (high-density lipoprotein cholesterol) concentrations were determined using an autoanalyser (747 Automatic analyser; Hitachi, Tokyo, Japan). Serum insulin levels were measured using an immunoradiometric assay (Biosource, Nivelles, Belgium). The intra- and inter-assay variability coefficients were 2.1–4.5 % and 4.7–12.2 %

Relative risk of the metabolic syndrome according to insulin resistance

respectively. No cross-reaction was observed with human proinsulin when measuring insulin levels. LDL-C levels were measured using the homogeneous enzymatic calorimetric test.

Table 2 Correlations between components of the metabolic syndrome and insulin resistance

Values are Pearson’s coefficients. All coefficients were significant, with P values < 0.001.

Definition of the metabolic syndrome

Variable

HOMA

Fasting insulin

Diagnosis of the metabolic syndrome was made when the subject satisfied more than three of the following five criteria, which are based on ATP III criteria: abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women), hypertriglyceridaemia ( 1.69 mmol/l), low HDL-C (< 1.04 mmol/l in men and < 1.29 mmol/l in women), hypertension ( 130/ 85 mmHg), and fasting hyperglycaemia ( 6.1 mmol/l). The following was applied to define abdominal obesity based on the APC-WC [11]: abdominal obesity = waist circumference 90 cm in men and 80 cm in women

Triacylglycerols HDL-C Fasting glucose Systolic blood pressure Diastolic blood pressure Waist circumference

0.36 0.31 0.56 0.14 0.15 0.27

0.31 − 0.28 0.23 0.09 0.11 0.15

Evaluation of insulin resistance The insulin-resistance index, HOMA [12], was used to evaluate insulin resistance using the following formula: HOMA = [fasting insulin (µIU/ml) × fasting blood glucose (mmol/l)]/22.5 where IU represents international units.

Statistical analysis SPSS program (Version 10.0) for Windows was used for statistical analysis. Because of the skewness and kurtosis of the triacylglycerols, insulin and HOMA, their values were logarithmically transformed for analysis. Values in each group were compared using Student’s t test and ANOVA. Odds ratios were obtained using the χ 2 test. Relative risk was calculated using logistic multiple regression analysis. Post-hoc analysis was done using Scheffe’s multiple comparison test. P values of less than 0.05 were considered significant.

RESULTS General characteristics of the study subjects The characteristics in the 7057 study subjects, including the level of fasting insulin and level of HOMA, are shown in Table 1. The prevalence of metabolic syndrome based on ATP III criteria and the incidence based on APC-WC are also shown in Table 1. Table 2 shows that both HOMA and fasting insulin levels were significantly correlated with components of the metabolic syndrome.

Odds ratios of risk factors of the metabolic syndrome according to insulin resistance When subjects were compared after dividing them into four groups from highest to lowest level according to HOMA and fasting insulin levels (Table 3), the group with the higher indices of insulin resistance (higher HOMA and fasting insulin) had higher odds ratios of the risk factors of the metabolic syndrome.

Table 3 Odds ratios of individual components of the metabolic syndrome according to insulin resistance

Values are odds ratio (95 % CI). Odds ratios were obtained using the χ 2 test. ∗ Reference group. WC-ATP, waist circumference determined by ATP III (> 102 cm for men and > 88 cm for women); WC-APC, waist circumference determined by APC-WC ( 90 cm for men and 80 cm for women); TG, triacylglycerols; BP, blood pressure; FG, fasting glucose. Group I, HOMA < 1.22; Group II, 1.22 HOMA < 1.69; Group III, 1.69 HOMA < 2.20; Group IV, HOMA 2.20. Group A, insulin < 5.71 µIU/ml; Group B, 5.71 µIU/ml insulin < 7.65 µIU/ml; Group C, 7.65 µIU/ml insulin < 9.99 µIU/ml; Group D, insulin 9.99 µIU/ml. Groups HOMA quartiles Group I∗ Group II Group III Group IV Insulin quartiles Group A∗ Group B Group C Group D

High WC-ATP

High WC-APC

High TG

Low HDL-C

High BP

High FG

1 1.5 (0.6–3.6) 2.8 (1.2–6.4) 11.0 (5.3–22.9)

1 1.6 (1.2–2.0) 2.9 (2.3–3.7) 8.5 (6.8–10.6)

1 1.6 (1.4–1.9) 2.5 (2.2–3.0) 5.7 (4.9–6.6)

1 1.3 (1.0–1.6) 2.3 (1.8–2.8) 3.4 (2.8–4.1)

1 1.4 (1.2–1.6) 1.6 (1.3–1.8) 3.0 (2.5–3.5)

1 3.6 (1.6–8.0) 6.3 (3.0–13.5) 52.6 (26.0–106.4)

1 1.2 (0.5–2.9) 2.6 (1.2–5.7) 9.8 (4.9–19.5)

1 1.7 (1.3–2.2) 2.9 (2.3–3.7) 8.0 (6.4–10.0)

1 1.4 (1.2–1.7) 2.3 (2.0–2.7) 4.3 (3.7–5.0)

1 1.2 (0.9–1.5) 2.3 (1.9–2.8) 3.1 (2.6–3.8)

1 1.3 (1.1–1.5) 1.6 (1.4–1.9) 2.1 (1.8–2.5)

C

1 0.9 (0.7–1.3) 1.5 (1.1–2.1) 3.0 (2.2–4.0)


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Table 4 Odds ratios of the metabolic syndrome according to insulin resistance

Values are odds ratio (95 % CI). ∗ Reference group. MS-ATP and MS-APC are as defined in the caption to Table 1. HOMA and insulin quartile groups are as defined in the caption to Table 3. Groups HOMA quartiles Group I∗ Group II Group III Group IV Insulin quartiles Group A∗ Group B Group C Group D

MS-ATP

MS-APC

1 2.5 (1.5–4.2) 3.8 (2.3–6.1) 12.8 (8.2–19.9)

1 1.8 (1.3–2.5) 2.8 (2.0–3.9) 9.1 (6.8–12.3)

1 1.2 (0.8–1.8) 2.4 (1.7–3.4) 4.0 (2.9–5.6)

1 1.4 (1.1–1.9) 2.4 (1.8–3.1) 3.9 (3.0–5.1)

Odds ratios of the metabolic syndrome according to HOMA and insulin level As shown in Table 4, the odds ratio of the metabolic syndrome increased as HOMA and fasting insulin level increased. As HOMA is calculated from fasting glucose and insulin values, we investigated whether the same trends could be observed if fasting hyperglycaemia was not included as a component of the metabolic syndrome. The odds ratio of the metabolic syndrome in the group with the highest HOMA, according to the ATP III criteria, was 6.8 [95 % CI (confidence interval), 4.4–10.7] and that based on the APC-WC was 5.9 (95 % CI, 4.3–7.9).

HOMA and insulin level according to the number of risk factors of the metabolic syndrome present As the number of ATP III criteria metabolic syndrome risk factors increased, HOMA and fasting insulin levels also increased. The same trends were observed when fasting hyperglycaemia was not included as a component of the metabolic syndrome (F = 159.8, P < 0.001). Using a 95 % CI as the borderline value between the metabolic syndrome and normal, HOMA was 2.56 and the fasting insulin level was 9.98 µIU/ml. Significant differences were also obtained by using multiple comparison analysis (Table 5). HOMA and fasting insulin levels also increased as the number of risk factors, as determined by APCWC, of the metabolic syndrome increased. The same trends were also observed when fasting hyperglycaemia were excluded from items of the metabolic syndrome (F = 156.9, P < 0.001). The borderline values between the metabolic syndrome and normal were 2.40 for HOMA and 9.18 µIU/ml for fasting insulin, and significant differences were seen between the groups by multiple comparison analysis. When the subjects were divided in C


Table 5 Comparison of mean values of HOMA and insulin concentration according to the number of components of the metabolic syndrome

Values are means (95 % CI). ∗ Components include high waist circumference, high triacylglycerols, low HDL-C, high blood pressure and high fasting glucose. †Waist circumference determined by ATP III (> 102 cm for men and > 88 cm for women). ‡Waist circumference determined by APC-WC ( 90 cm for men and 80 cm for women). a,b, same letters indicate a non-significant difference between groups by Scheffe’s multiple comparison test (significance, P < 0.01). Number of the components∗ ATP III† 0 1 2 3 4 5 APC-WC‡ 0 1 2 3 4 5

n

HOMA

Fasting insulin (µIU/ml)

2905 2591 1188 307 57 9

1.51 1.79 2.19 2.74 3.62 4.67

(1.49–1.54) (1.76–1.82) (2.12–2.26) (2.56–2.91) (3.13–4.12)a (3.24–6.10)a

7.18 8.21 9.43 10.27 11.51 13.40

(7.09–7.28) (8.08–8.24) (8.91–9.72) (9.98–10.86)a (10.46–12.55)a,b (11.27–18.14)b

2382 2634 1413 490 119 19

1.49 1.75 2.02 2.51 3.29 4.08

(1.46–1.52) (1.73–1.78) (1.96–2.08) (2.40–2.62) (2.93–3.65) (3.26–4.90)

7.11 8.02 8.69 9.49 9.78 11.79

(7.01–7.22) (7.90–8.13) (8.50–8.89) (9.18–9.80)a (9.08–10.47)a,b (9.29–14.48)a,b

two groups around the borderline values between the metabolic syndrome and the normals according to ATP III criteria, i.e. 2.56 for HOMA and 9.98 µIU/ml for the fasting insulin level, the relative risks of metabolic syndrome in subjects with increased HOMA (> 2.56) or an increased fasting insulin level (> 9.98 µIU/ml) were 4.42 (95 % CI, 3.50–5.58) and 2.33 (95 % CI, 1.86–2.92) respectively, after adjusting for age, gender and BMI. The relative risks of the metabolic syndrome in subjects with a HOMA index higher than 2.40 and a fasting insulin level higher than 9.18 µIU/ml, based on the APC-WC, were 4.03 (95 % CI, 3.34–4.87) and 2.38 (95 % CI, 1.99–2.85) respectively (P < 0.001).

DISCUSSION Insulin resistance is widely believed to be a central cause of the metabolic syndrome, with strong associations with visceral obesity and dyslipidaemia. Recent studies reported that ATP III criteria did not provide a sensitive approach to identifying insulin-resistant subjects [13,14]. However the goal of ATP III criteria is to identify individuals at risk of cardiovascular disease rather than identifying insulin-resistant individuals. We hypothesized that more insulin-resistant individuals are likely to be at more risk of the metabolic syndrome and to satisfy more


metabolic syndrome criteria. In view of the therapeutic intervention for metabolic syndrome, if our assumption is reasonable, HOMA or plasma insulin level may provide a helpful guide for management, irrespective of the number of metabolic syndrome criteria satisfied. Thus the primary end point of the present study is not to find the ability of metabolic syndrome criteria to identify insulinresistant subjects, but to analyse the relationship between the metabolic syndrome and the degree of insulin resistance. We observed the cut-off point of the insulin resistance index from which the risk of the metabolic syndrome by the ATP III report rises significantly. In a consensus reached on the causes of insulin resistance, it was reported that obesity and a lack of exercise each account for 25 % of insulin resistance [15]. We confirmed a close relationship between insulin resistance and abdominal obesity by observing that insulin resistance increases with increased abdominal obesity. In the present study, the incidence of the metabolic syndrome was 5.3 % (5.0 % in men and 5.8 % in women) based on the ATP III criteria and 8.9 % (8.1 % in men and 10.3 % in women) based on APC-WC. These results are significantly different from the 23.7 % (24 % in men and 23.4 % in women) reported in American adults [8]. This difference in the incidence of the metabolic syndrome between Korean and American adults is probably due to differences in abdominal obesity, which was reported to be 38.6 % in American adults and 24 % in Korean adults, even after applying the more stringent APC-WC. Since the present study excluded subjects with metabolic disorders, almost all of whom would be classified as having insulin resistance, this low prevalence of the metabolic syndrome is comparable with 9.4 % by the ATP III criteria and 14.8 % by APC-WC among Chinese subjects in the Singapore National Health Survey [16]. Although controversy still exists on the effect of insulin resistance on atherosclerosis [17–21], recent prospective studies reported that insulin resistance increases the risk of cardiovascular disease. In a study of Helsinki policemen, with a prospective 22-year follow-up of adult males older than 34 years of age with no cardiovascular ischaemic disease [22], mortality due to myocardial infarction was found to be 2–5-fold higher in the group with the highest quintile of insulin resistance. Yip et al. [23], after a prospective follow-up of non-obese adults for 4.7 years, observed that one in four subjects developed cardiovascular disease in the highest insulin-resistance tertile, indicating that insulin resistance is an important predictor of cardiovascular disease. According to the Quebec cardiovascular study [24], hyperinsulinaemia in a fasting state is an independent risk factor of cardiovascular ischaemic disease, and they proposed that Type II diabetes could be prevented and the prevalence of cardiovascular disease be reduced by increasing insulin sensitivity through diet control and exercise. We are probably in a position to elucidate the effects of insulin resistance

on the development of cardiovascular disease in Koreans by long-term follow up of our subjects. Although the euglycaemic clamp test is the standard method of measuring insulin resistance, it is complex and requires much manpower and time and, therefore, it has been used for research purposes only [25]. The more convenient HOMA [26,27] and the quantitative insulin sensitivity check index [28,29] are mainly used in largescale epidemiological or clinical studies. One study reported that HOMA is not only effective in the diagnosis of insulin resistance in Type II diabetes, but could also be used as an indicator of treatment outcome and prognosis [30]. Haffner et al. [31] in their prospective cohort study reported that hyperinsulinaemia precedes metabolic impairment in the insulin-resistance syndrome, suggesting that insulin resistance could be the cause of the various risk factors of the metabolic syndrome. Although we could not find a direct cause-and-effect relationship between the metabolic syndrome and insulin resistance, since this was a cross-sectional study, we saw a positive relationship between the number of metabolic syndrome components and HOMA and fasting insulin levels, thus we were able to confirm a close relationship between the two. When subjects were split into two groups according to the borderline values of HOMA and fasting insulin level values for those with and without metabolic syndrome, the relative risks of the metabolic syndrome were increased by more than 4- and 2-fold respectively, for a HOMA value of > 2.56 or a fasting insulin level > 9.98 µIU/ml, even after adjusting for age, gender and BMI. This suggests that insulin resistance is an independent risk factor of the metabolic syndrome. As for the relationship between obesity and insulin resistance, the role of TNFα (tumour necrosis factor α) and NEFAs (non-esterified fatty acids) are important. Increased expression of TNFα in adipose tissue has been reported in obese subjects [32]. TNFα inhibits the action of lipoprotein lipase and stimulates lipolysis. TNFα also impairs the function of the insulin signalling pathway by effects on phosphorylation of both the insulin receptor and IRS-1 (insulin receptor substrate-1). NEFAs released from adipocytes, particularly intra-abdominal adipocytes, can be transported to the liver where they stimulate synthesis of triacylglycerols and assembly and secretion of VLDL (very-LDL). Increased plasma VLDL triacylglycerols exchange with cholesterol esters from HDL, resulting in a lower plasma HDL-C. On the other hand, an increase in circulating NEFAs has been proposed as having an aetiological role in the development of insulin resistance [33]. Multiple potential mechanisms by which insulin resistance may cause hypertension have been proposed [34]. These include resistance to insulinmediated vasodilation, impaired endothelial function, sympathetic nervous system overactivity, sodium retention, increased vascular sensitivity to the vasoconstrictor C


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effect of pressor amines, and enhanced growth factor activity leading to proliferation of smooth muscle walls. In the present study, we also observed inter-relationship between insulin resistance, obesity, dyslipidaemia and hypertension. Early diagnosis, along with intensive management of the overall risk factors, would be a desirable and appropriate treatment for the metabolic syndrome. Incidence of the metabolic syndrome will probably rise steadily in Koreans due to westernization of the diet, excessive food intake, an increase in the elderly population, a change in lifestyle and a lack of exercise. Thus more objective and stricter diagnostic criteria are essential, along with early diagnosis. The application of an appropriate HOMA value and a fasting insulin level could provide a helpful guide for the intensive management of the metabolic syndrome.

ACKNOWLEDGMENTS This study was supported by a Samsung grant (number #SBRI C-A4-115-1).

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Received 17 November 2004/13 January 2005; accepted 26 January 2005 Published as Immediate Publication 26 January 2005, DOI 10.1042/CS20040331

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