Further inflammatory information on metabolic syndrome by adiponectin evaluation

International Journal of Cardiology 124 (2008) 339 – 344 www.elsevier.com/locate/ijcard

Further inflammatory information on metabolic syndrome by adiponectin evaluation Kunihiro Matsushita a,b , Koji Tamakoshi a , Hiroshi Yatsuya a , Keiko Wada a , Rei Otsuka a , Seiko Takefuji c , Yo Hotta c , Takahisa Kondo b , Toyoaki Murohara b , Hideaki Toyoshima a,⁎ a

c

Department of Public Health/Health Information Dynamics, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan b Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Diabetes and Endocrinology, Nagoya University Graduate School of Medicine, Nagoya, Japan Received 12 July 2006; received in revised form 4 January 2007; accepted 16 February 2007 Available online 11 April 2007

Abstract Background: Despite a close association of adiponectin with metabolic syndrome (MetS), its usefulness as an additional MetS factor has not been well investigated. Methods: We studied 2327 apparently healthy Japanese male office workers aged 35 to 66 years old and investigated cross-sectionally whether categorization by serum adiponectin distinguished participants' levels of high-sensitivity C-reactive protein (CRP) beyond the conventional MetS. Results: In a linear regression analysis, adiponectin was associated with CRP independently of all MetS factors (β = −0.192, P < 0.001). Furthermore, a graded decrease in CRP level was observed with elevation of adiponectin in every stratum characterized by the presence or absence of each MetS component (trend P < 0.05 in all strata except those of decreased high-density lipoprotein cholesterol or hyperglycemia). Similarly, geometric means of CRP levels (mg/l) decreased as adiponectin increased from the lowest to the highest tertile in all strata classified by the number of MetS components, though a P value did not reach statistical significance in those with 3 MetS components (the stratum of 0 MetS component: 0.41 [95% confidence interval, 0.34–0.49], 0.32 [0.28–0.37] and 0.26 [0.23–0.30], trend P < 0.001; 1 component: 0.45 [0.39–0.52], 0.38 [0.34–0.43], and 0.32 [0.28–0.36], trend P < 0.001; 2 components: 0.58 [0.50–0.67], 0.51 [0.44–0.60], and 0.46 [0.38–0.55], trend P = 0.043; 3 components: 0.80 [0.66–0.96], 0.69 [0.55–0.87], and 0.58 [0.39–0.85], trend P = 0.139). Conclusions: Adiponectin evaluation provides additional inflammatory information on conventional MetS, supporting the potential of hypoadiponectinemia as an additional MetS component for identifying high-risk individuals for cardiovascular disease. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Adiponectin; Metabolic syndrome; Risk factors; C-reactive protein

1. Introduction An adipocyte-derived protein, adiponectin, has emerged as a key molecule underlying the development of metabolic syndrome (MetS) [1], a syndrome proposed to identify highrisk individuals for cardiovascular disease (CVD), and the ⁎ Corresponding author. Tel.: +81 52 744 2128; fax: +81 52 744 2131. E-mail address: [email protected] (H. Toyoshima). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.015

next target of treatment after low-density lipoprotein cholesterol [2]. Interestingly, serum adiponectin concentration is low in obese subjects even though adiponectin is exclusively produced by adipose tissue [3]. Adiponectin has been shown to improve glucose metabolism and stimulate fatty acid oxidation and nitric oxide synthesis [4–6]. Consistent with these basic observations, decreased serum adiponectin has been known to be associated with each MetS component and hence with MetS itself [7]. In addition,

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adiponectin has been reported to function as an antiinflammatory protein [1]. Given that insulin resistance and atherosclerosis are considered to share a common basis of low-grade inflammation in their development [8], this antiinflammatory function also seems to be an important property of adiponectin. We have recently demonstrated that adiponectin is more strongly associated with MetS than proinflammatory cytokines, e.g., tumor necrosis factor α and interleukin 6, which have been reported to be closely associated with MetS [7]. Recently, the International Diabetes Federation has indicated adiponectin as a potential marker for future MetS criteria [9]. However, this close association of adiponectin with MetS might be a double-edged sword for adiponectin as a clinical MetS factor. Namely, adiponectin might be a comprehensive marker for MetS or otherwise might not add unique prognostic information on MetS. Most previous studies, which have reported that adiponectin could predict future diabetes and cardiac events, could not resolve this issue since they did not control for all MetS factors [10–16]. Of a few studies actually having controlled for all MetS factors [17–19], two supported the concern about adiponectin. One has demonstrated that adiponectin did not predict the incident CVD after adjusting for high-density lipoprotein cholesterol (HDL-C) [17]. Another study demonstrated that plasma adiponectin predicted the incidence of myocardial infarction after simultaneously adjusting for all MetS factors but not after subdividing subjects into those with or without MetS [18]. Thus, it has remained unclear whether evaluation of serum adiponectin provides additional information to the conventional diagnostic criteria of MetS. To evaluate, therefore, the potential of hypoadiponectinemia as an additional component of MetS, we investigated crosssectionally whether evaluation of serum adiponectin adds unique information to the conventional MetS factors in regard to high-sensitivity C-reactive protein (CRP), a novel well-studied CVD predictor. We selected this biomarker on the basis that CRP not only increases linearly with the clustering of MetS components [7,20], but also predicts incident diabetes and CVD independently of MetS factors [8,21]. Consequently, it has been considered applicable for coronary risk stratification in clinical practice [22]. 2. Materials and methods 2.1. Study subjects In 2002, we sent out self-administered questionnaires about lifestyle and medical history to a population of 10,759 civil servants, who were aged 35 years or more and working in Aichi Prefecture, Japan. They were considered to be mainly engaged in desk work. As an annual health check-up, they underwent anthropometric evaluation and blood pressure measurement in the sitting position after a 5-min rest, followed by collection of 8-h or overnight fasting blood samples. Among 10,759 civil servants, 5030 subjects (3942

men and 1088) provided consent to use their physical examination data obtained at an annual health check-up, their information regarding lifestyle and medical history, and offered to donate serum samples remaining after their annual check-up. We first limited ourselves to male subjects, since there were few female subjects available to conduct the undermentioned analyses. Among 3942 eligible male subjects, we obtained all essential data for the present study from 2654 subjects. We also excluded 327 subjects with a medical history of cancer or CVD or currently on medications for hypertension, diabetes mellitus, or hyperlipidemia, leaving 2327 subjects aged 35 to 66 years, who became the final sample for the present analyses. All subjects provided informed consent, and the study was approved by the Ethics Review Committee of Nagoya University Graduate School of Medicine, Nagoya, Japan and complied with the Declaration of Helsinki. 2.2. Definition of MetS We minimally modified the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria for MetS [2] using body mass index (BMI) in place of waist circumference. Obesity was defined by BMI ≥ 25 kg/m2 according to the criteria of the Japan Society for the Study of Obesity [23]. Consequently, those with 3 or more of the following components were considered as having MetS: (1) BMI ≥ 25 kg/m 2 ; (2) low HDL-C defined as HDLC < 40 mg/dl (< 1.036 mmol/l); (3) hypertriglyceridemia defined as triglyceride ≥ 150 mg/dl (≥ 1.695 mmol/l); (4) hyperglycemia defined as fasting glucose ≥ 110 mg/dl (≥ 6.10 mmol/l); and (5) elevated blood pressure defined as blood pressure ≥ 130/85 mm Hg. 2.3. Biochemical analysis The serum samples were stored at − 80 °C until biochemical assay. HDL-C was measured by the phosphotungstate method. Triglyceride was determined enzymatically. Glucose was enzymatically determined by the hexokinase method. High-sensitivity CRP was measured by latex nephelometry (BNII, Dade Behring Co., Ltd.). Adiponectin concentrations were determined by enzymelinked immunosorbent assay (Otsuka Pharmaceutical Co., Ltd., Japan). Inter-assay coefficients of variation of CRP and adiponectin were < 4.0% and < 8.6%, respectively. 2.4. Statistical analyses All statistical analyses were conducted with the SPSS version 12.0 (SPSS Inc., Chicago, IL). CRP and adiponectin were natural-log-transformed to approximate normal distribution for the analysis and shown as geometric means and the 95% confidence intervals (CIs) for those means, whereas other continuous variables were shown as mean (SD). First, linear regression analyses were conducted on the association

K. Matsushita et al. / International Journal of Cardiology 124 (2008) 339–344 Table 1 Characteristics of subjects Characteristics

n = 2327

Age (years) BMI (kg/m2) Current smoker [n (%)] Adiponectin (μg/ml)⁎ High-sensitivity CRP (mg/l)⁎ HDL-C (mg/dl)⁎⁎ Triglyceride (mg/dl)⁎⁎⁎ Glucose (mg/dl)⁎⁎⁎⁎ Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Prevalence of MetS components [n (%)] Obesity (BMI ≥ 25 kg/m2) Low HDL-C (< 40 mg/dl) Hypertriglyceridemia (≥150 mg/dl) Hyperglycemia (≥110 mg/dl) Elevated blood pressure (≥130/85 mm Hg)

48.0 (7.1) 23.1 (2.6) 836 (35.9%) 6.11 (6.00–6.23) 0.41 (0.40–0.43) 58.9 (14.3) 131.0 (91.2) 94.0 (20.0) 127.5 (13.9) 79.1 (10.7) 546 (23.5%) 133 (5.7%) 663 (28.5%) 235 (10.1%) 1192 (51.2%)

Data are expressed as mean (SD), number (%), or geometric mean⁎ (95% confidence interval). To convert to mmol/l, ⁎⁎multiply by 0.0259, ⁎⁎⁎multiply by 0.0113, and ⁎⁎⁎⁎multiply by 0.0555. BMI body mass index; HDL-C high-density lipoprotein cholesterol; CRP C-reactive protein.

between variables of interest with CRP. Subsequently, CRP concentrations were compared among the tertiles of adiponectin after the stratification of subjects according to the presence/absence of each MetS component and then to the number of clustering MetS components by analysis of covariance (ANCOVA) with age and smoking status as covariates. In the latter stratification, those with 4 or 5 MetS components were excluded, since there were too few subjects to be analyzed this way (n = 63 or 4, respectively). The test of trend was performed with a polynomial contrast procedure. We also compared CRP levels between the group with low adiponectin (1st tertile, ≤ 5.0 μg/ml) in the stratum without a MetS component and the group with high adiponectin (3rd tertile, ≥ 7.5 μg/ml) in the stratum with the relevant component by ANCOVA. This comparison was made by replacing the MetS component concerned. Similarly, the CRP levels were compared between the group having low adiponectin together with a certain number of MetS components and the group having high adiponectin

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together with one additional MetS component, e.g., low adiponectin with 2 MetS component group versus high adiponectin with 3 MetS component group. In these comparisons of 2 subgroups, P values were corrected by the Bonferroni method for multiple comparisons. All reported P values were two-sided, and a P value of less than 0.05 was considered statistically significant. 3. Results Demographic characteristics of the study subjects are shown in Table 1. The most prevalent MetS component in the present subjects was elevated blood pressure, whereas the least was low HDL-C. The prevalence of MetS with 3 MetS components in this population was 9.2% (n = 215), with 4 components, 2.7% (n = 63), with 5 components, 0.2% (n = 4), and the total was 12.1% (n = 282). Linear regression analyses revealed that all MetS factors were associated with CRP, though the significant association of glucose was diminished in the multivariate analysis (Table 2). Adiponectin was associated with CRP independently of all MetS factors. In addition, the standardized β of adiponectin showed the third largest value following BMI and HDL-C. From a more practical viewpoint, we evaluated whether the adiponectin tertile distinguished participants' CRP levels beyond the power of each MetS component. Adjusted geometric means of CRP decreased with increasing adiponectin from the lowest to the highest tertile groups, within all strata by the presence/absence of each MetS component, though P values did not reach statistical significance in either stratum with low HDL-C or hyperglycemia (Table 3). When compared the adjusted geometric mean of CRP between the group having low adiponectin (1st tertile) in the stratum without obesity and that of the group having high adiponectin (3rd tertile) in the stratum with obesity, there was no statistical difference between them. No significant difference was observed either in the same analysis using low HDL-C, hypertriglyceridemia, and hyperglycemia in place of obesity. However, the adjusted mean CRP level of the group with low adiponectin in the stratum of normal blood pressure was significantly higher

Table 2 Linear regression analysis of relationship between CRP and age, smoking, MetS factors, and adiponectin Independent variables

Age Smoking BMI HDL-C Triglyceride Glucose Systolic blood pressure Ln adiponectin

Univariate

Multivariate

β

SE

Standardized β

P

β

SE

Standardized β

0.015 0.281 0.107 − 0.724 0.200 0.070 0.010 − 0.497

0.003 0.048 0.009 0.061 0.022 0.021 0.002 0.050

0.097 0.120 0.253 − 0.238 0.183 0.069 0.127 − 0.203

< 0.001

0.011 0.217 0.069 −0.369 0.046 0.014 0.005 −0.192

0.003 0.047 0.009 0.070 0.024 0.021 0.002 0.054

0.070 0.093 0.163 − 0.122 0.043 0.013 0.066 − 0.078

< 0.001 < 0.001 < 0.001 < 0.001

0.001 < 0.001 < 0.001

P 0.001 < 0.001 < 0.001 < 0.001

0.054 0.51 0.001 < 0.001

CRP: C-reactive protein; MetS: metabolic syndrome; BMI: body mass index; HDL-C: high-density lipoprotein cholesterol. Dependent variable is ln CRP.

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Table 3 Age and smoking-adjusted geometric mean of CRP according to tertiles of adiponectin and MetS components 1st Tertile (1.0–5.0 μg/ml)

2nd Tertile (5.1–7.4 μg/ml)

3rd Tertile (7.5–30.4 μg/ml)

n

Mean (95% CI)

n

Mean (95% CI)

n

Mean (95% CI)

Obesity Present Absent

266 502

0.67 (0.59–0.76) 0.46 (0.42–0.51)

173 614

0.63 (0.54–0.74) 0.37 (0.34–0.41)

107 665

0.51 (0.42–0.62) 0.30 (0.28–0.33)

< 0.001

Low HDL-C Present Absent

82 686

0.71 (0.57–0.89) 0.51 (0.47–0.56)

31 756

0.72 (0.50–1.03) 0.41 (0.38–0.44)

20 752

0.61 (0.39–0.95) 0.32 (0.29–0.34)

< 0.001

Hypertriglyceridemia Present 330 Absent 438

0.62 (0.55–0.69) 0.47 (0.43–0.53)

237 550

0.56 (0.49–0.63) 0.37 (0.34–0.40)

96 676

0.49 (0.40–0.59) 0.30 (0.28–0.33)

< 0.001

Hyperglycemia Present Absent

105 663

0.53 (0.42–0.67) 0.53 (0.49–0.58)

74 713

0.45 (0.34–0.59) 0.41 (0.38–0.45)

56 716

0.43 (0.31–0.59) 0.31 (0.29–0.34)

< 0.001

Elevated blood pressure Present 405 Absent 363

0.61 (0.55–0.67) 0.45 (0.40–0.51)

423 364

0.48 (0.44–0.54) 0.35 (0.31–0.39)

364 408

0.36 (0.32–0.40) 0.29 (0.26–0.32)

MetS components

Trend P

0.025

0.53

0.039

0.293

< 0.001 < 0.001

CRP, C-reactive protein; MetS, metabolic syndrome; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol.

than that of the group with high adiponectin in the stratum of elevated blood pressure (0.45 [0.41–0.51] versus 0.36 [0.32–0.40] mg/l, P = 0.046 after the Bonferroni correction). When MetS items are clustered, the risk of developing CVD is reportedly higher than for the total risk when the individual risk items are summed [24]. Thus, we made the same investigations as above on the CRP concentration in the adiponectin tertiles after stratification of each grouping of MetS components (0 to 3 components). As shown in Fig. 1, the adjusted mean of CRP significantly decreased, as the adiponectin concentration rose. However, in the group of 3 MetS components, the P value for such association did not

reach statistical significance (0 or 1 MetS component: trend P < 0.001; 2 components: trend P = 0.043; 3 components: trend P = 0.139). Interestingly, the CRP level of a low adiponectin group with two MetS components, i.e., the group considered as non-MetS nowadays, was as high as that of the MetS group (3 MetS components) with high adiponectin (0.57 [0.50–0.66] versus 0.56 [0.37–0.85] mg/l, P = 1.000 after the Bonferroni correction). Similarly, the CRP value of a low adiponectin group with 0 or 1 MetS components showed no difference from that of a high adiponectin group with 1 or 2 MetS components, respectively. 4. Discussion

Fig. 1. Adjusted geometric means of C-reactive protein (CRP) according to tertiles of adiponectin in each stratum by the number of metabolic syndrome (MetS) components (0 to 3 components). Age and smoking status are adjusted for. Open bars signify geometric means; error bars, 95% confidence intervals of geometric means.

An inverse association between serum adiponectin and CRP was observed in the present study, same as several previous reports [25]. We extended these studies by showing that adiponectin was inversely associated with CRP independently of all MetS factors. Furthermore, the present study showed, for the first time, that categorization according to adiponectin provided additional inflammatory information even on the strata according to the presence/ absence or the number of MetS components. It seems also important that the mean CRP concentrations of those with low adiponectin are as high as or higher than those in whom low adiponectin was replaced with high adiponectin plus one of the MetS components. Specifically, the group with low adiponectin together with 2 MetS components, currently considered the non-MetS group, was demonstrated to have a CRP level equal to that of the MetS individuals with high adiponectin. Given that a dose–response relationship has been consistently observed between the CRP level and a CVD

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risk [8,21] and that the risk of diabetes and coronary events in Japanese–Americans has reportedly started to increase at a CRP level of approximately 0.4 to 0.6 mg/l [26,27], the present results raise the possibility that evaluation of serum adiponectin may well be useful not only for more meticulous risk stratification within the states according to the conventional MetS components but also to identify high-risk individuals in addition to those components. Therefore, further prospective studies are strongly warranted to confirm this hypothesis. If so, the issues regarding the standardized assay of adiponectin and cost effectiveness must be evaluated. Although the P value did not reach statistical significance in the strata of those with low HDL-C, hyperglycemia or 3 MetS components, this might be mainly due to a smaller sample allocated to those conditions and would not necessarily lower the usefulness of adiponectin. Indeed, those in the highest tertile of adiponectin consistently demonstrated the lowest concentrations of CRP within these strata also. Furthermore, CRP levels linearly and significantly decreased with the increase of adiponectin in their opposite strata, i.e., those with normal HDL-C, normoglycemia, and non-MetS. From a different point of view, the fact that there were only a few high adiponectin individuals allocated to these abnormal conditions may reflect the close relationship between low adiponectin and MetS. Thus, only 11.0% (n = 31) of MetS subjects had adiponectin ≥ 7.5 μg/ml. These subjects corresponded to only 4.0% of those in the 3rd tertile of adiponectin, whereas the prevalence of MetS in the 1st tertile was 19.9% (n = 153), suggesting that MetS is very rare in those with high adiponectin. Hence, as previously suggested [7,28], adiponectin could be also useful as a comprehensive marker for estimating one's metabolic condition. Although adiponectin has been intensively investigated, the mechanism of adiponectin regulation has remained to be elucidated. In contrast to other adipokines, the circulating adiponectin level is lower in obese than nonobese people, though adiponectin is exclusively secreted from adipose tissue [3]. The lowering of adiponectin in obesity may be partly ascribed to the fact that other increased adipokines (e.g., tumor necrosis factor α) suppress the adiponectin production of adipose cells [29]. Meanwhile, some investigators attach importance to fat distribution to explain this paradoxical decrease in adiponectin, based on inferences that individuals with abdominal obesity tend to have low adiponectin, since visceral adipose tissue produces less adiponectin than subcutaneous adipose tissue [30]. Smoking may also be a potential link between obesity and low adiponectin, since it has been reported to induce abdominal obesity and to possibly decrease the adiponectin level [31,32]. Nevertheless, given that increase in adiponectin has been a therapeutic strategy of choice against MetS or atherosclerotic diseases [33], further studies are warranted to unravel the regulatory mechanism of adiponectin.

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Some limitations of the present study must be discussed. First, the cross-sectional design of our study does not allow causality to be determined from the present findings, which require confirmation by further prospective studies. Second, the potential of adiponectin as a risk factor was evaluated using high-sensitivity CRP. Therefore, studies with solid endpoints, e.g., cardiac events, must still be conducted. Third, we had to use BMI instead of waist circumference. However, BMI of 25 kg/m2 was equivalent to waist circumference of 85.5 cm, a value similar to the Japanesespecific cutoff point for abdominal obesity [9], as a predictor of the 5-year incidence of diabetes in Japanese–American men [34]. Furthermore, the similarly modified ATP-III criteria have predicted CVD in previous studies [35]. Given these facts, we believe that this modification of MetS criteria would not change the main implications of the present study. Finally, the present results could not be simply extrapolated to a general population, since all subjects in the present study were Japanese male office workers. More specifically, the detailed values of adiponectin and CRP must be interpreted with great care, since both circulating adiponectin and CRP levels have been reported to differ among races and genders [36,37]. In summary, the present study demonstrated that adiponectin measurement provided unique and substantive inflammatory information not only on individual MetS components but also on their clustering states. This result supports the potential of hypoadiponectinemia as an additional MetS component. Acknowledgments The authors wish to express their sincere appreciation to the study participants and to the healthcare personnel of the local government office. This work was supported by Grant Nos. 17390185 (H.T.), 18590594 (K.T.), and 17790384 (H.Y.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, from the Japan Atherosclerosis Prevention Fund (JAPF), and the Aichi D.R.G. Foundation. References [1] Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004;24:29–33. [2] Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Circulation 2002;106:3143–421. [3] Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adiposespecific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83. [4] Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMPactivated protein kinase. Nat Med 2002;8:1288–95. [5] Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocytesecreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947–53.

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