Attenuated metabolic effect of waist measurement in Japanese female patients with type 2 diabetes mellitus

diabetes research and clinical practice 82 (2008) 66–72

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Attenuated metabolic effect of waist measurement in Japanese female patients with type 2 diabetes mellitus Yuji Tajiri a,b,*, Ryoko Takei b, Kazuo Mimura b, Fumio Umeda b a b

Endocrinology and Metabolism Division, Kurume University School of Medicine, Kurume 830-0011, Japan Fukuoka Medical Association Hospital, Fukuoka 814-8522, Japan

article info

abstract

Article history:

Waist circumference (WC) was measured in 200 Japanese patients with type 2 diabetes

Received 2 May 2007

mellitus (T2DM: male 106, female 94, mean age 61 years old) who had been admitted in

Received in revised form

our hospital, and relationship with various risk factors to predict future cardiovascular disease

12 May 2008

(CVD) was analyzed. There was a positive and statistically significant trend in WC levels with

Accepted 26 May 2008

an increasing number of CVD risk factors in male patients, whereas no significant trend of WC was observed in female patients. The receiver operator characteristic (ROC) curve for WC to predict the presence of two or more risk factors of CVD depicted greater area under the curve in

Keywords:

male patients (0.732) than that in female patients (0.571). Apart from positive correlation with

Waist circumference

fasting serum C-peptide (S-CPR) and log-transformed high-sensitivity C-reactive protein (log

Type 2 diabetes mellitus

HS-CRP) in both genders, WC was positively correlated with log-transformed triglyceride (log

Risk factors

TG), systolic and diastolic blood pressure (SBP and DBP) and negatively with HDL-cholesterol

Cardiovascular disease

(HDL-C) in male patients, whereas it was negatively correlated with HbA1c and fasting plasma glucose (FPG) in female patients. The change of WC after administration (DWC) was correlated with DS-CPR, DLDL-C, DSBP and DDBP in male patients, while no relationship was observed in female patients. In conclusion, WC is a reliable marker to predict future CVD events at least in Japanese male, but not female patients with T2DM. # 2008 Published by Elsevier Ireland Ltd.

1.

Introduction

It has been reported that metabolic syndrome (MetS) is associated with a greatly increased risk of coronary heart disease (CHD) [1] and recognized as pro-atherogenic condition. Diagnosis of MetS is thus crucial for the prognosis of those patients who are at risk of cardiovascular disease (CVD). A number of expert groups have attempted to develop a unifying definition for the MetS. The most widely accepted definitions have been produced by the World Health Organization (WHO), The European Group for the Study of Insulin Resistance (EGIR) and the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP ATP III) [2–4]. All groups agree on the core components of the MetS such as obesity, high blood glucose, dyslipidemia and high blood pressure based on

insulin resistance. Recently, The International Diabetes Federation (IDF) convened a workshop held in 2004, and the consensus statement of MetS criteria to be used for worldwide clinical practice was documented [5]. According to the new definition, central obesity is an essential factor which can be expressed as waist circumference (WC) measurement with ethnic group-specific cut-points. Japanese data indicate cutpoints of 85 cm in men and 90 cm in women based on correlations with visceral fat mass [6], although using these figures has produced odd results in relation to cardiovascular risk and prevalence [7]. The IDF recommendations are therefore including the use of Asian values (male 90 cm; female 80 cm) until more data have been obtained. Indeed, central obesity expressed as WC is acceptable for the diagnosis of MetS because of its simplicity and

* Corresponding author. Tel.: +81 942 317563; fax: +81 942 358943. E-mail address: [email protected] (Y. Tajiri). 0168-8227/$ – see front matter # 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2008.05.015

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diabetes research and clinical practice 82 (2008) 66–72

convenience. However, there must be a careful interpretation to evaluate a WC as an essential factor for the prediction of CVD. Many studies have shown that excess fat in the upper part of the body (i.e. central or abdominal) is often observed in men and that in lower part (i.e. peripheral or subcutaneous) is in women [8]. Whether fat deposit is intra-abdominal or subcutaneous, waist measurement does not distinguish between accumulations of visceral abdominal fat and subcutaneous abdominal fat. Therefore, clinical implication of WC measurement to predict future CVD events has not been elucidated yet. The aim of the current study is to investigate the relevance of WC measurement as a predictor of future CVD events in Japanese patients with type 2 diabetes mellitus (T2DM). For this purpose, the relationship between WC and various risk factors of CVD such as high blood pressure, abnormal lipid profile, insulin resistance and inflammation expressed by high sensitivity C-reactive protein (HS-CRP) [9] was analyzed.

2.

Patients and methods

2.1.

Patients

Two hundred Japanese patients (106 men and 94 women, 61  13 years old, mean  S.D.) with T2DM who had been admitted to the metabolic ward of our hospital from April of 2005 to December of 2006 were enrolled in the present study. They had been in suboptimal blood glucose control (hemoglobin A1c; HbA1c level was 9.9  2.5%) and were admitted for 2.2  0.3 weeks. The diagnosis of T2DM was confirmed

according to the criteria of Japan Diabetes Society [10] or medical history of diabetes. All of them were confirmed that their antiglutamic acid decarboxylase antibody test were negative. Patients with severe liver dysfunction (viral hepatitis or liver cirrhosis), renal dysfunction (serum creatinine concentration over 1.5 mg/dl), known malignant disease, or chronic inflammatory disease (e.g., rheumatoid arthritis) were excluded from the study. The study was performed in accordance with the Declaration of Helsinki and approved by the ethics committee of our hospital. Written informed consent was obtained from each patient. Characteristics of patients were shown in Table 1. Patients who had the habit of regular smoking at the time of admission were defined as current smokers. Patients who were drinking alcohol more than 3 days/week and more than 25 g/day of ethanol were defined as drinkers. Following cut-off points are based on the definition of MetS in Japanese population [11]. High blood pressure was diagnosed according to the criteria of systolic BP (SBP) over 130 mm Hg and/or diastolic BP (DBP) over 85 mm Hg, or medication for hypertension. Hypertriglyceridemia and/or hypo HDL-cholesterolemia was diagnosed according to the criteria of triglyceride (TG) over 150 mg/dl and/or, high-density lipoprotein cholesterol (HDL-C) less than 40 mg/dl or medication to reduce TG. In addition, hypercholesterolemia was diagnosed according to the criteria of lowdensity lipoprotein cholesterol (LDL-C) over 120 mg/dl and/or medication to reduce LDL-C. Retinopathy was diagnosed by ophthalmologists. Neuropathy was diagnosed according to the following criteria: symptoms such as numbness or paresthesia of the foot and/or retardation of deep tendon reflex and/or decrease of variation of R–R wave interval in

Table 1 – Characteristics of diabetic patients

Age (years old) Duration of diabetes (years) Current smoking (+) Drinking (+) Family history (+) Retinopathy (+) Neuropathy (+) Nephropathy (+) Hypertension (+) Raised TG and/or reduced HDL-C (+) Raised T-Chol (+) BMI Waist (cm) FPG (mg/dl) HbA1c (%) S-CPR (ng/ml) HS-CRP mg/l) log HS-CRP LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) log TG SBP (mm Hg) DBP (mm Hg)

Total (n = 200)

Male (n = 106)

Female (n = 94)

61  13 9.1  8.1 52 57 113 56 70 64 124 77 91 24.7  4.5 89.4  11.2 170  52 9.9  2.1 2.13  1.03 2.26  4.04 2.97  0.56 124  42 56.0  16.0 150  100 2.1  0.3 138  19 78  12

58  14 9.5  8.6 45 56 60 32 40 39 63 51 39 24.1  4.4 87.9  10.9 177  55 8.0  0.7 2.16  1.08 2.23  3.64 2.96  0.57 121  43 52.0  14.6 168  105 2.2  0.3 139  19 80  13

64  11 b 8.5  7.5 7b 1b 53 24 30 25 61 26 b 52 a 25.4  4.5 91.2  11.4 a 162  48 9.4  1.4 a 2.11  0.97 2.29  4.45 2.98  0.56 128  40 60.6  16.4 b 131  90 b 2.1  0.2 b 137  19 77  11

Descriptions for each abbreviation are given in text. Data are presented as means  S.D. or number of patients. Student’s t-test or chi-square test was used for the comparison between values of male and female patients. aP < 0.05, bP < 0.01 vs. the value in male patients.

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diabetes research and clinical practice 82 (2008) 66–72

electrocardiogram (coefficient of variation less than 1.0% during 1 min of bed rest). Nephropathy was diagnosed by the presence of microalbuminuria or overt proteinuria but without increase of serum creatinine levels over 1.5 mg/dl.

2.2.

Protocol

During hospital stay, an energy restriction protocol was induced (25 kcal/kg ideal body weight, content of fat less than 25%) and exercise training (more than 3 h/week, mainly walking) was performed. Doses of oral hypoglycemic agents or insulin were changed according to blood glucose data, which were checked 6 times per day (before and after meals) 3 days per week with the goal of attaining favorable blood glucose control. A favorable blood glucose control was defined as both fasting plasma glucose (FPG) less than 140 mg/dl and postprandial plasma glucose less than 200 mg/dl. No severe hypoglycemic episode, e.g., faintness, unrest, or blood glucose level less than 50 mg/dl, was reported during admission. At the end of hospital day, 28 patients were not given any medication for diabetes, 80 patients were treated with sulfonylurea, 113 with biganide, 16 with thiazolidinedione, 60 with a-glucosidase inhibitor, and 20 with insulin. There was no significant difference in the proportion of glucose-lowering therapy between male and female. At the beginning and at the end of admission, patients had blood samples drawn after overnight fasting, without taking insulin or glucose-lowering agents to measure HS-CRP, FPG, HbA1c, fasting serum C-peptide (S-CPR), or lipid profile. FPG, HbA1c, total cholesterol (T-Chol), HDL-C and TG levels were measured according to the standard procedures. LDL-C levels were calculated by using the Friedewald formula [12]. S-CPR was measured by radio immunoassay. HS-CRP was measured by latex-enhanced immunonephelometric assay (Dade Behring Co., Marburg, Germany). SBP and DBP were measured twice with an automatic electronic sphygmomanometer (BP103i II; Colin Medical Technology Co., Komaki, Japan) with the patient in the sitting position after rest for at least 5 min. WC was measured in a horizontal plane, midway between the inferior margin of the ribs and the superior border of the iliac crest according to the guideline of IDF [5] at two points during admission.

2.3.

Statistical analysis

All tests were performed using SPSS 11.0J for windows (SPSS, Chicago, IL). Because HS-CRP and TG values did not show normal distribution according to Kolmogorov–Smirnov test, logarithm of these values were used for further analysis instead of HS-CRP and TG. For comparisons of baseline values between male and female, Student’s unpaired t-test was used for parametric data and Chi-square test for non-parametric data. For the comparison between values at the beginning and at the end of admission, Student’s paired t-test was used. Simple regression analyses of each parameter with baseline WC or the change of each parameter (Dparameter) with the change of WC (DWC) during admission were performed using Pearson’s correlation coefficient. For multivariate analyses of each parameter with WC or each Dparameter with DWC, multiple step-wise regression analyses were used. To further elucidate the relevance of WC to the future prediction of CVD in Japanese patients with T2DM, patients were divided into four groups according to the number of risk factors of CVD such as the existence of hypertension, raised TG and/or reduced HDL-C, raised LDL-C and raised HS-CRP level. Cut-off value of 0.8 mg/L was adopted to diagnose raised HS-CRP because it was based on the median level from apparently healthy subjects [13]. WC was compared among those groups using one-way ANOVA with Bonferroni/Dunntype multiple comparison test. The receiver operator characteristic (ROC) curve for WC to predict the presence of two or more risk factors above mentioned was plotted to clarify the close relationship of WC with the cluster of risk factors of CVD. P < 0.05 was considered statistically significant.

3.

Results

3.1. Baseline characteristics and changes of parameters during admission As shown in Table 1, differences between genders were observed regarding a few parameters. Female patients were older and had smaller proportion of current smokers and

Table 2 – Change of each parameter after admission Parameter

WC (cm) BMI FPG (mg/dl) S-CPR (ng/ml) log HS-CRP LDL-C (mg/dl) HDL-C (mg/dl) log TG SBP (mm Hg) DBP (mm Hg)

Total

Male

Female

Before

After

Before

After

Before

89.4  11.2 24.7  4.5 170  52 2.13  1.03 2.97  0.56 124  42 56.0  16.0 2.10  0.25 138  19 78  12

87.3  10.7 b 24.0  4.3 b 124  28 b 2.16  1.0 2.75  0.6 b 112  38 b 48.5  12.8 b 2.06  0.17 b 123  16 b 70  9 b

87.9  10.9 24.1  4.4 170  52 2.16  1.08 2.96  0.57 121  43 52.0  14.6 2.15  0.26 139  19 80  13

85.9  10.4 b 23.3  4.8 b 124  28 b 2.24  1.12 2.64  0.54 b 113  41 a 45.5  11.4 b 2.07  0.18 b 125  16 b 72  10 b

91.2  11.4 25.4  4.5 170  52 2.11  0.97 2.98  0.56 128  40 60.6  16.4 2.05  0.24 137  19 77  11

After 88.8  10.9 b 24.6  4.3 b 124  28 b 2.06  0.93 2.87  0.65 a 112  34 b 51.9  13.5 b 2.04  0.16 121  15 b 68  9 b

Descriptions for each abbreviation are given in text. ‘‘before’’ means the value at the beginning of admission and ‘‘after’’ at the end of admission. Data are presented as means  S.D. Student’s paired t-test was used for the comparison. aP < 0.05, bP < 0.01 vs. the value of ‘‘before’’.

diabetes research and clinical practice 82 (2008) 66–72

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drinkers than male. Female patients were more obese expressed as body mass index (BMI), but not significant, and had significantly larger WC than male. Mean value of WC in both genders were higher than that in the criteria of MetS in Japanese population [11], that is over 85 cm in male and over 90 cm in female. HbA1c, LDL-Chol and HDL-C levels were higher, and TG level was lower in female than in male. Table 2 shows the change of each parameter after admission in total, male and female patients. Value of each parameter except for S-CPR significantly decreased in total and male patients. In female patients, however, log TG value did not significantly change after admission.

3.2. Comparison of waist circumference according to the number of CVD risk factors

3.3. Correlation between waist circumference and other parameters

Fig. 1 – Comparison of WC values according to the numbers of risk factors of CVD as defined in text. According to the number of these components, patients were divided into four groups. Open bar indicates patients who have no risk factor (group 0), hatched bar; one risk factor (group 1), dotted bar; two risk factors (group 2) and closed bar; three or four risk factors (group3). Numbers of patients in each group are indicated below each bar. Data are presented as means W S.D. One-way ANOVA with Bonferroni/Dunntype multiple comparison tests were used for the comparison of WC among these groups. aP < 0.01, bP < 0.01 and cP < 0.01 vs. the value of group 0, group 1 and group 2, respectively.

Results of simple regression analyses between basal WC and other parameters were shown in Table 3. In male patients, WC was positively correlated with S-CPR, log HS-CRP, HDL-C, log TG, SBP, DBP, and negatively correlated with HDL-C. On the other hand, WC was positively correlated with S-CPR and log HS-CRP, and negatively correlated with HbA1c and FPG in female patients. In female patients, the relationship of WC with S-CPR was much weaker than in male patients, and no relationship was observed with lipid profile and blood pressure. In multiple stepwise regression analysis, HDL-C and DBP were selected in addition to S-CPR and log HS-CRP as significant explanatory variables accounting for WC in male

patients. These four parameters well accounted for WC (R2 of this model was 0.445). In female patients, however, FPG was selected together with S-CPR and log HS-CRP as a negative indicator for WC (Table 4). The change of WC (DWC) during admission was analyzed as a function of the change of other parameters (Dparameters). DWC was significantly correlated with DS-CPR, DLDL-C, DSBP and DDBP in male patients, whereas no relationship of DWC with D parameters was observed in female patients (Table 5). In multiple stepwise regression analysis, DS-CPR and DSBP were selected as significant explanatory variables accounting for

We analyzed WC values according to the number of risk factors for CVD. As shown in Fig. 1, there was a positive and statistically significant trend in WC levels with an increasing number of risk factors in male patients (F = 9.643, P < 0.0001). On the other hand, there was such a similar trend, but the trend was not significant in female patients (F = 1.821, P = 0.1489). ROC curve for WC to predict the cluster of risk factors was depicted in Fig. 2. Apparently greater area under the curve was denoted in male patients (0.732) than that in female patients (0.571).

Fig. 2 – The ROC curves for WC to predict the presence of two or more risk factors of CVD as defined in text. AUC means area under the curve.

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diabetes research and clinical practice 82 (2008) 66–72

Table 3 – Univariate analysis on waist circumference as an dependent variable

Table 5 – Univariate analysis on Dwaist circumference as an dependent variable

Independent variable

Independent variable

Male r

HbA1c FPG S-CPR log HS-CRP LDL-C HDL-C log TG SBP DBP

0.108 0.042 0.636 0.291 0.066 0.302 0.391 0.227 0.238

Female P NS NS <0.01 <0.01 NS <0.01 <0.01 <0.05 <0.05

r 0.224 0.239 0.324 0.336 0.185 0.124 0.015 0.158 0.141

P <0.05 <0.05 <0.01 <0.01 NS NS NS NS NS

Simple regression analyses of each parameter with baseline WC were performed using Pearson’s correlation coefficient. NS: not significant.

Table 4 – Multiple step-wise regression analysis on waist circumference as a dependent variable Independent variable

b

S.E.

t-Value

P-value

a

Male S-CPR log-HS-CRP HDL-C DBP

0.505 0.175 0.181 0.181

0.831 1.480 0.057 0.067

6.208 2.195 2.288 2.312

<0.0001 0.0306 0.0244 0.0229

Femaleb S-CPR log HS-CRP FPG

0.202 0.319 0.264

1.132 1.981 0.022

2.080 3.267 2.785

0.0404 0.0015 0.0065

b: standard regression coefficient. R2 in this model is 0.255. a R2 in this model is 0.445. b R2 in this model is 0.234.

DWC in male patients (R2 = 0.123). In contrast, no Dparameter was selected in female patients to account for DWC.

4.

Discussion

MetS is diagnosed with WC as an essential component according to the criteria of IDF. However, careful interpretation is necessary for the application of WC because measurement of WC does not exactly distinguish between accumulations of visceral abdominal fat and subcutaneous abdominal fat. In the present study, WC was significantly correlated with several metabolic components such as hyperinsulinemia, dyslipidemia or hypertension together with inflammation marker in male patients. In female patients, however, no relationship was observed with dyslipidemia or hypertension apart from hyperinsulinemia or inflammation. Moreover, the change of WC was significantly correlated with that of S-CPR or blood pressure only in male patients, not in female patients. WC was significantly related to increasing the number of CVD risk factors in male, but not in female diabetic patients. ROC curve analysis also revealed the validity of WC measurement

Male r

DFPG DS-CPR Dlog HS-CRP DLDL-C DHDL-C Dlog TG DSBP DDBP

Female

P 0.066 0.254 0.152 0.121 0.039 0.161 0.202 0.213

r NS <0.05 NS <0.05 NS NS <0.05 <0.05

P 0.026 0.007 0.091 0.065 0.088 0.101 0.104 0.081

NS NS NS NS NS NS NS NS

Simple regression analyses of each parameter with D WC were performed using Pearson’s correlation coefficient. NS: not significant. D: the change of each parameter.

to predict the cluster of CVD risk factors only in male patients. Thus, measurement of WC seems to be less relevant to risk factors for CVD at least in Japanese female patients than in male patients with T2DM. The negative correlation between WC and HbA1c or FPG in female patients is partly attributable to the enhancement of endogenous insulin secretion because WC is positively related with S-CPR. It is speculated that much weaker correlation between WC and HbA1c or FPG in male patients is possibly due to the existence of insulin resistance because the positive correlation of WC with S-CPR is rather stronger in male patients. There have been some arguments regarding WC in Japanese female. Hara et al. reported that optimal cutoff points of WC for the diagnosis of MetS in the Japanese population were 85 cm in men and 78 cm in women, yielding the maximal sensitivity plus specificity in more than 600 subjects who enrolled themselves for a routine health examination [14]. In another study using health examination data of more than 3500 subjects by Miyawaki et al., cutoff points of visceral fat area (VFA) for the diagnosis of multiple risk factors were 100 cm2 in men and 65 cm2 in women, which means 86 cm and 77 cm of WC, respectively [15]. The cutoff values of WC for the diagnosis of Japanese MetS are simply based on 100 cm2 of VFA in each gender [6]. So far, there has been no evidence regarding the definition of central obesity as VFA 100 cm2 in both genders of Japanese population. Reevaluation of WC as a marker of central obesity seems to be necessary, especially in Japanese women. It is well known that the amount of visceral fat increases with age in both genders, and this increase is more evident in men than in women [16,17]. In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age [18]. Although this correlation was also present in women, the slope was very gentle in the pre-menopausal condition. It became steeper in post-menopausal subjects [18]. In this context, 85 post-menopausal patients (90% of female patients) were extracted from our subjects, and the relationship of WC with MetS was further analyzed. Even in post-menopausal state, WC was correlated only to FPG (r = 0.301, P < 0.05), but not to other metabolic or inflammatory markers. The contribution of WC measurement to CVD risk factors was much different between both genders in the present study. The

diabetes research and clinical practice 82 (2008) 66–72

possible explanation for this matter is the difference of fat distribution between both genders. From the published data [16,17], it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes, but while abdominal subcutaneous adipose tissue decreases after the age of 50-year in obese men, it increases in women up to the age of 60–70-year, at which point it starts to decline [19]. Because visceral fat is correlated with insulin-resistant state [20,21] or plasma lipoprotein-lipid levels [22–24], visceral fat is an important link between CVD risk factors. Lemieux et al. [25] have indicated that the gender difference in visceral adipose tissue accumulation was an important factor in explaining the gender differences in CVD risk profile. Interestingly, our female patients of WC less than 90 cm showed significant correlation between WC and S-CPR, CRP and HDL-C same as male patients, while no relationship with WC was observed in female patients of WC over 90 cm (data not shown). In this regard, WC measurement does not seem relevant to predict future CVD events at least in Japanese female diabetic patients especially with WC over 90 cm, so called ‘‘central obesity’’ defined from Japanese criteria [6]. There are some limitations in our study. Computed Tomography (CT) can be considered the gold standard not only for adipose tissue evaluation but also for multicompartment body measurement [26,27]. In the present study, visceral fat area has not been accurately differentiated from subcutaneous fat area to account for abdominal adiposity. Another limitation is that our female subjects were more obese than male subjects. Indeed, WC of female patients was significantly larger than that of male patients. Nevertheless, WC was not related to CVD risk factors in female patients. BMI is another authorized marker for the evaluation of obesity. In the current diabetic subjects, BMI showed the similar correlation as WC with metabolic components in male, but not in female patients (data not shown). BMI was significantly related to increasing the number of CVD risk factors only in male patients (F = 7.236, P = 0.0002), while the relevance was weaker compared with that of WC. ROC curve analysis also showed the smaller, but significant AUC (0.697) of BMI compared with WC to predict the cluster of CVD risk factors only in male patients. In this aspect, BMI is less relevant to CVD risk factors than WC, whereas the validity is verified only in male diabetic patients same as WC measurement. In conclusion, WC measurement is not useful item for the prediction of future CVD risk at least in Japanese female patients with T2DM. Further investigation is necessary to develop the alternative criteria or technique for the evaluation of visceral adiposity especially in Japanese female diabetic patients.

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There are no conflict of interest.

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