Clinica Chimica Acta 430 (2014) 104–108
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High adiponectin level in late postmenopausal women with normal renal function Sumika Matsui a,⁎, Toshiyuki Yasui b, Kaoru Keyama a, Anna Tani a, Takeshi Kato a, Hirokazu Uemura c, Akira Kuwahara a, Toshiya Matsuzaki a, Minoru Irahara a a b c
Department of Obstetrics and Gynecology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan Department of Reproductive Technology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan Department of Preventive Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan
a r t i c l e
i n f o
Article history: Received 18 September 2013 Received in revised form 9 December 2013 Accepted 23 December 2013 Available online 2 January 2014 Keywords: Adiponectin Renal function Late postmenopause Insulin resistance Lipid profiles
a b s t r a c t Background: We examined whether high circulating adiponectin level is associated with renal function and is favorable for lipid and glucose metabolism in late postmenopausal women with normal renal function. Methods: We conducted a cross-sectional study in 115 postmenopausal women and divided the subjects into 2 groups (early postmenopausal women and late postmenopausal women). Serum levels of adiponectin, blood urea nitrogen, creatinine (Cr), glucose, insulin and lipid profiles were measured. Glomerular filtration rate (GFR) was estimated by age and Cr. Results: Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women, and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women. Adiponectin level showed a negative correlation with eGFR and tended to have a negative correlation with eGFR after adjustments for age, BMI and bioavailable testosterone in all subjects, but adiponectin level did not show a significant correlation with eGFR in late postmenopausal women. Adiponectin level in late postmenopausal women showed a significant negative correlation with triglyceride (TG) and a positive correlation with high-density lipoprotein cholesterol (HDL-C) after adjustments for age and BMI. Conclusion: In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Adiponectin, which is an anti-inflammatory protein mainly secreted by adipocytes, has been reported to play an important role in protection against insulin resistance and atherosclerosis [1,2]. It has been reported that hypoadiponectinemia was correlated with the clinical phenotype of metabolic syndrome such as hypertension, impaired glucose tolerance and dyslipidemia [3]. High-density lipoprotein cholesterol (HDL-C) level, which plays an important role in protection against atherosclerosis, has been reported to be positively correlated with adiponectin level [4]. Matsuura et al. reported that adiponectin protected against atherosclerosis due to increase in HDL assembly through enhancing the pathway of ATP-binding cassette transporters and apoA-1 synthesis in the liver [5].
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Course of Human Development, Human Development and Health Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Tel.: +81 88 633 7177; fax: +81 88 631 2630. E-mail address: [email protected] (S. Matsui). 0009-8981/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.037
Previous studies demonstrated that adiponectin level in postmenopausal women was higher than that in premenopausal women [6–9]. We also reported that total adiponectin level and high molecular weight (HMW) adiponectin level were increased in late postmenopausal women for whom N 5 y had passed since menopause and adiponectin levels were associated with levels of free and bioavailable testosterone in postmenopausal women [10,11]. Since estrogen deficiency after natural and surgical menopause has been associated with increases in insulin resistance and dyslipidemia, high adiponectin level after menopause is paradoxical and its clinical significance has not been fully clarified. On the other hand, an association of adiponectin with renal function has been demonstrated. It has been reported that serum adiponectin levels in hemodialysis patients and patients with chronic kidney disease (CKD) were elevated compared to the level in healthy subjects [4,12]. Adiponectin has been shown to be negatively correlated with estimated glomerular filtration rate (eGFR) in patients with early stages of CKD [13]. Therefore, high adiponectin level in postmenopausal women with renal dysfunction may be due to decrease in adiponectin clearance in the kidney. However, the relationship between adiponectin level and renal function in the healthy subjects without renal dysfunction has been controversial [14–16].
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2. Subjects and methods
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Tokyo, Japan). Glomerular filtration rate was estimated using the following equation: eGFR = 194 × age−0.287 × Cr−1.094 × 0.739 [21].
2.1. Subjects The subjects of this study were recruited from patients visiting the outpatient clinic of the Department of Obstetrics and Gynecology, Tokushima University Hospital. We conducted a cross-sectional study in 115 postmenopausal women. Based on the 2001 Stages of Reproductive Aging (STRAW) criteria, early postmenopause was defined as a period of less than 5 years since menopause and late postmenopause was defined as a period of more than 5 years since menopause. We divided subjects into two groups based on previous study [17]. Sixty women in early postmenopause were women for whom b 5 y had passed since menopause, and 55 women in late postmenopause were women for whom N 5 y had passed since menopause. Before recruitment in the study, women underwent gynecological and biochemical examinations. Reviews of medical histories and the results of physical examinations and blood chemistry tests showed that all of the women were in good health. Exclusion criteria in the study were a history of any cardiovascular disease, diabetes mellitus, CKD, or liver disease. CKD is defined as eGFR b60 ml/min/1.73 m2 for 3 months or more regardless of the cause [18]. Women who had received hormone replacement therapy in the past and women taking any medication known to influence lipoprotein metabolism were not included in the study. Venous blood samples for measurements of hormones were drawn into BD vacutainer tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) between 8 AM and 10 AM after 12-h fasting. Blood samples obtained were frozen at − 70 °C until used for analysis. Informed consent for participation in this study was obtained from each woman. The Ethics Committee of Tokushima University Hospital approved the study. 2.2. Measurement of serum adiponectin concentration Serum total adiponectin concentration was measured by an enzyme-linked immunosorbent assay using a commercially available kit (Otsuka Pharmaceuticals, Tokyo, Japan) after the samples had been diluted 5100-fold with the sample buffer as previously reported [19]. Intra- and inter-assay CVs were b 10.0%, and the sensitivity of the assay was 23.4 pg/ml. 2.3. Measurements of serum concentrations of hormones Serum estradiol concentration was measured by a chemiluminescent immunoassay using a commercially available kit (Abbott Co., Tokyo, Japan). The intra- and inter-assay CVs were b 7%, and the sensitivity of the assay was 10 pg/ml. Serum concentrations of luteinizing hormone and follicle-stimulating hormone were measured by a chemiluminescent immunoassay using a commercially available kit (Abbott Co.). The intra- and inter-assay CVs were b7% and b10%, respectively. Serum total testosterone level was measured by an electrochemiluminescence immunoassay using a commercially available kit (Roche Diagnostics). Intra- and inter-assay CVs were 2.2–3.2% and 3.6–4.6%, respectively. The sensitivity of the assay was 0.05 ng/ml. Serum SHBG concentration was measured by a solid-phase immunoradiometric assay (Siemens Medical Solutions Diagnostics). Intra- and inter-assay CVs were 2.8–5.3% and 7.9–8.5%, respectively, and the sensitivity of the assay was 1 nmol/l. Serum free testosterone and bioavailable testosterone were calculated using total testosterone, albumin and SHBG by a previously described method [20]. 2.4. Measurement of renal function Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured by using an automated clinical analyzer system (Hitachi,
2.5. Measurements of concentrations of glucose, insulin and lipids Plasma glucose level was measured by using the glucose oxidase method on an Automated Glucose Analyzer GA04 (A&T). The intraand inter-assay CVs ranged from 0.8 to 1.3% and 0.6 to 1.3%, respectively. Serum insulin level was measured by using an enzyme immunoassay on AIA2000 (TOSOH Co., Tokyo, Japan). The intra- and inter-assay CVs ranged from 1.1 to 3.2% and 1.9 to 3.3%, respectively, and the sensitivity of the assay was 1.0 μIU/ml. Insulin resistance was evaluated with homeostasis model assessment of insulin resistance (HOMA-IR), which was calculated for all subjects by the following formula: fasting serum insulin (μIU/ml) × fasting plasma glucose (mg/dl) / 405. Serum total cholesterol (TC), HDL-C and triglyceride (TG) levels were measured by using a chemistry system (Hitachi, Tokyo, Japan). Low-density lipoprotein cholesterol (LDL-C) was estimated by the Friedewald equation (LDL-C = TC − TG / 5 − HDL-C). 3. Statistical analysis Data are presented as medians with 25th to 75th percentile ranges. The Mann–Whitney U test was used to compare differences between the 2 groups. The Kruskal–Wallis rank test was used to compare differences between multi-groups. Correlations between variables were determined using Spearman's rank order analysis. Age and body mass index (BMI)-adjusted partial correlation analysis was performed to determine the relationships of serum adiponectin concentration with renal function, insulin resistance and lipid parameters. We also considered the effects of hormones including testosterone on the correlation between adiponectin and eGFR and the correlations between adiponectin and insulin resistance and lipid parameters because we previously reported that circulating adiponectin levels were associated with levels of free and bioavailable testosterone in postmenopausal women [10]. Age, BMI and bioavailable testosterone-adjusted partial correlation analysis was performed because bioavailable testosterone showed a significant and strong correlation with free testosterone (r = 0.997, p b 0.001). All statistical analyses were carried out using Statview ver 8.2 (SAS Institute Inc.) and SPSS statistics version 20.0 (IBM, Armonk). All p values reported were 2-sided and a p b 0.05 were considered statistically significant. We performed statistical analysis by using one-half of the value of sensitivity when the values were below the sensitivity level. 4. Results 4.1. Total adiponectin level and renal function Background characteristics of all 115 subjects and those of early postmenopausal women and late postmenopausal women are shown in Table 1. Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women (p = 0.009). Serum levels of Cr and BUN in late postmenopausal women were significantly higher than those in early postmenopausal women (p b 0.001 and p = 0.004, respectively), and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women (p b 0.001). 4.2. Levels of glucose, insulin and lipid profiles As can be seen in Table 1, lipid profiles did not show significant differences between the 2 groups. Plasma glucose level in late postmenopausal women tended to be higher than that in early postmenopausal women.
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Table 1 Levels of hormones, eGFR, adiponectin, lipid profiles and HOMA-IR in postmenopausal women.
Age BMI Estradiol LH FSH Testosterone Free T Bioavailable T SHBG BUN Cr eGFR Adiponectin TC TG HDL LDL Glucose Insulin HOMA-IR
Years kg/m2 pg/ml mIU/ml mIU/ml ng/ml ng/dl ng/dl nmol/l mg/dl mg/dl ml/min/1.73 m2 μg/ml mg/dl mg/dl mg/dl mg/dl mg/dl μIU/ml
All women (n = 115)
Early postmenopausal women (n = 60)
Late postmenopausal women (n = 55)
p value
55.0 (51.0–60.0) 21.6 (19.9–24.5) 12.5 (12.5–29.5) 29.8 (20.0–40.1) 94.8 (69.4–122.7) 0.21 (0.13–0.28) 0.20 (0.11–0.31) 4.42 (2.88–7.39) 71.3 (50.7–91.9) 13.0 (11.0–17.0) 0.59 (0.52–0.66) 80.8 (71.9–91.9) 11.4 (8.4–16.4) 224.5 (204.5–241.0) 95.0 (72.0–124.0) 70.5 (60.0–87.8) 130.0 (109.7–144.1) 97.0 (91.0–101.3) 4.79 (3.16–6.97) 1.14 (0.70–1.62)
52.0 (48.3–54.8) 21.8 (19.9–25.0) 19.5 (12.5–32.0) 34.5 (21.1–47.6) 101.3 (74.7–138.4) 0.21 (0.12–0.31) 0.21 (0.11–0.33) 4.85 (2.98–8.24) 67.8 (48.8–87.8) 13.0 (11.0–14.0) 0.58 (0.50–0.64) 84.7 (78.2–99.1) 10.2 (7.3–15.3) 226.0 (205.0–249.0) 95.0 (68.5–125.5) 71.5 (63.0–88.8) 131.7 (107.5–144.2) 96.0 (88.3–100.0) 4.91 (3.43–6.97) 1.17 (0.74–1.52)
61.0 (56.0–63.0) 21.5 (20.2–24.2) 12.5 (5.5–23.5) 25.0 (19.4–34.2) 86.1 (62.0–105.5) 0.20 (0.14–0.28) 0.19 (0.10–0.28) 4.34 (2.41–6.77) 73.6 (65.3–99.8) 16.0 (12.0–18.0) 0.60 (0.55–0.67) 75.4 (68.0–84.0) 12.6 (9.7–18.4) 223.0 (200.8–238.0) 94.5 (72.0–123.3) 70.5 (58.3–85.8) 125.5 (110.1–143.8) 98.0 (93.0–102.0) 4.39 (2.84–7.13) 1.07 (0.68–1.73)
b0.001 NS 0.006 0.006 0.011 NS NS NS NS b0.001 0.004 b0.001 0.009 NS NS NS NS NS NS NS
Values are medians with 25–75th percentile ranges in parentheses. SHBG: sex hormone-binding globulin, HOMA-IR: homeostasis model assessment of insulin resistance. p value: early postmenopausal women vs late postmenopausal women.
significant positive correlation with HDL-C (r = 0.416, p b 0.001). After adjustments for age and BMI, the correlations of adiponectin with TG and HDL-C remained significant (r = − 0.275, p = 0.007 and r = 0.400, p b 0.001, respectively). After adjustments for age, BMI and bioavailable testosterone, the positive correlation between adiponectin and HDL-C remained significant (r = 0.432, p b 0.001, respectively) and the correlation between adiponectin and TG showed a negative tendency (r = − 0.241, p = 0.064). Adiponectin level in all subjects also showed significant negative correlations with insulin and HOMA-IR (r = − 0.322, p = 0.001 and r = − 0.305, p = 0.003, respectively). After adjustments for age and BMI, these correlations remained significant (r = − 0.215, p = 0.036 and r = − 0.239, p = 0.023, respectively). After adjustments for age, BMI and bioavailable testosterone, the correlations were not significant. In late postmenopausal women, adiponectin level showed a significant negative correlation with TG (r = −0.423, p = 0.002, respectively) and a significant positive correlation with HDL-C (r = 0.382, p = 0.005, respectively) (Table 3). These correlations remained significant after adjustments for age and BMI (r = −0.400, p = 0.005 and r = 0.380, p = 0.007, respectively). After adjustments for age, BMI and bioavailable testosterone, the negative correlation between adiponectin and TG remained significant (r = −0.590, p = 0.005) and showed a positive tendency with HDL-C (r = 0.430, p = 0.052). Adiponectin level
4.3. Association of total adiponectin and renal function As can be seen in Table 2, adiponectin level in all subjects showed a negative correlation with eGFR level (r = − 0.237, p = 0.012). After adjustments for age and BMI, the correlation was not significant. After adjustments for age, BMI and bioavailable testosterone, the correlation between adiponectin and eGFR showed a negative tendency (r = −0.216, p = 0.070). In late postmenopausal women, adiponectin level did not show a significant correlation with eGFR. 4.4. Adiponectin levels categorized by eGFR groups Based on eGFR level, all subjects were divided into three groups: 60–80 ml/min/1.73 m2, 80–90 ml/min/1.73 m2, and N 90 ml/min/ 1.73 m2. As can be seen in Fig. 1, total adiponectin level showed a tendency to increase with a decrease in eGFR, but the trend was not significant. 4.5. Associations of total adiponectin with lipid profiles and insulin resistance Table 3 shows that the adiponectin level in all subjects showed significant negative correlations with TG and LDL-C (r = − 0.345, p = 0.001 and r = − 0.210, p = 0.040, respectively) and a
Table 2 Correlations of adiponectin with age, BMI and parameters of renal function. All women
Age BMI BUN Cr eGFR
r p r p r p r p r p
Early postmenopausal women
Late postmenopausal women
M1
M2
M3
M4
M1
M2
M3
M4
M1
M2
M3
M4
0.156 0.095 −0.258 0.005 0.279 0.004 0.232 0.014 −0.237 0.012
– – – – 0.190 0.055 0.161 0.092 −0.142 0.138
– – – – 0.215 0.081 0.226 0.059 −0.216 0.070
– – – – 0.138 0.268 0.222 0.066 −0.226 0.062
−0.408 0.001 −0.479 b0.001 0.037 0.792 0.211 0.115 −0.137 0.308
– – – – 0.046 0.750 0.053 0.703 −0.054 0.697
– – – – 0.106 0.495 0.137 0.357 −0.133 0.374
– – – – 0.067 0.670 0.139 0.356 −0.141 0.349
0.398 0.003 −0.001 0.997 0.350 0.012 0.145 0.290 −0.180 0.189
– – – – 0.224 0.121 0.152 0.275 −0.136 0.330
– – – – 0.118 0.622 0.285 0.211 −0.313 0.168
– – – – 0.065 0.790 0.246 0.310 −0.280 0.246
M1: unadjusted, M2: adjusted for age and BMI, M3: adjusted for age, BMI and bioavailable testosterone, M4: adjusted for age, BMI, bioavailable testosterone and estradiol.
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associated with favorable lipid metabolism and insulin sensitivity in postmenopausal women. In a cohort of young and elderly twins, adiponectin receptor gene expression level in skeletal muscle in elderly twins was lower than that in young twins, while circulating adiponectin level in elderly twins was significantly higher than that in young twins [22]. Adiponectin in late postmenopausal women may not act on adiponectin receptors compared to adiponectin in early postmenopausal women. It has been reported that high adiponectin level after menopause may be due to reduction in adiponectin clearance associated with renal function [4,12,13]. A relationship between adiponectin level and renal function has been demonstrated even in subjects without severe renal dysfunction. Isobe et al. showed that adiponectin level increased sharply until the age of 50 y and thereafter gradually increased and that the pattern of change in adiponectin was similar to that in BUN in women without severe renal dysfunction [14]. Doumatey et al. reported that adiponectin showed an inverse relationship with eGFR in nondiabetic postmenopausal women whose eGFR levels were more than 30 [16]. We showed that adiponectin level in late postmenopausal women was higher than that in early postmenopausal women and that eGFR in late postmenopausal women was lower than that in early postmenopausal women. In addition, adiponectin level in all subjects showed a negative correlation with eGFR. However, the correlation between eGFR and adiponectin level was not significant after adjustment for age and BMI and there was no significant difference among the subgroups categorized by eGFR. Adiponectin level did not show a significant correlation with eGFR even in early postmenopausal women. High adiponectin level after menopause may be involved in not only eGFR but also other factors in healthy postmenopausal women. The differences between previous results and our results may be due to the difference in subjects. We excluded subjects whose eGFR level was b60 ml/min/1.73 m2. In previous studies, decrease in GFR might have affected adiponectin level since mean serum Cr level was relatively high (0.85 mg/dl) [14] and women whose eGFR was 30–60 ml/min/1.73 m2 were included [16]. Recently, it has been reported that a higher level of HMW adiponectin was associated with a reduced odds ratio of mild renal dysfunction in a general population without CKD [15]. Circulating adiponectin has been classified into three forms of low-molecular weight (LMW) trimer, medium-molecular weight (MMW) hexamer and HMW multimers [23]. The HMW isoform level and the ratio of HMW/total adiponectin have been reported to be better predictors of insulin sensitivity and metabolic syndrome than total adiponectin level [24,25]. Therefore, the conflicting results may be caused by the difference in total adiponectin or HMW adiponectin. Further studies on HMW adiponectin are needed.
Adiponectin (µg/ml)
p=0.09 10.2 (8.0-16.5)
12.5 (9.2-18.4)
30.0
10.6 (7.1-15.2)
20.0
10.0
0.0
60-80
80-90
eGFR
107
>90
(ml/min/1.73m2)
eGFR: estimated glomerular filtration rate Fig. 1. Serum adiponectin levels categorized by eGFR. eGFR: estimated glomerular filtration rate. Total adiponectin level showed a tendency to increase with decrease in eGFR, but the trend was not significant (p = 0.09).
in late postmenopausal women did not show significant correlations with glucose, insulin and HOMA-IR. 5. Discussion We previously reported that adiponectin level was increased in women in the late postmenopausal stage [10], but we could not demonstrate its clinical significance. In the present study, we showed that adiponectin level was positively correlated with HDL-C and negatively correlated with TG and insulin resistance, suggesting that a high adiponectin level is favorable for lipid profiles and insulin sensitivity in postmenopausal women. In addition we showed that adiponectin level was positively correlated with HDL-C and negatively correlated with TG even if only in late postmenopausal women. However, adiponectin level was high in late postmenopausal women, while levels of HDL-C, TG and HOMA-IR were not different between early and late postmenopausal women. Tamakoshi et al. reported that adiponectin level was negatively correlated with HOMA-IR [8]. However, adiponectin level in postmenopausal women was significantly higher than that in premenopausal women, although HOMA-IR in postmenopausal women was significantly higher than that in premenopausal women. These results seem to be paradoxical. Adiponectin resistance may be a reason for the paradoxical results of high adiponectin level
Table 3 Correlations of adiponectin with lipid profiles and HOMA-IR. All women
TC TG HDL-C LDL-C Glucose Insulin HOMA-IR
r p r p r p r p r p r p r p
Early postmenopausal women
Late postmenopausal women
M1
M2
M3
M4
M1
M2
M3
M4
M1
M2
M3
M4
−0.046 0.652 −0.345 0.001 0.416 b0.001 −0.210 0.040 −0.060 0.546 −0.322 0.001 −0.305 0.003
0.011 0.913 −0.275 0.007 0.400 b0.001 −0.150 0.149 −0.059 0.563 −0.215 0.036 −0.239 0.023
−0.027 0.834 −0241 0.064 0.432 b0.001 −0.184 0.164 −0.060 0.635 −0.166 0.198 −0.221 0.096
0.108 0.414 0.198 0.137 0.362 0.006 0.230 0.085 0.061 0.638 0.103 0.436 0.156 0.250
0.006 0.969 −0.284 0.058 0.532 b0.001 −0.259 0.089 −0.161 0.275 −0.402 0.004 −0.399 0.006
0.099 0.522 0.138 0.379 0.279 0.073 −0.153 0.335 0.077 0.610 −0.297 0.040 −0.257 0.091
0.017 0.919 0.318 0.059 0.130 0.456 −0.269 0.118 0.300 0.060 −0.167 0.292 −0.107 0.524
−0.003 0.985 0.298 0.082 0.122 0.493 −0.280 0.109 0.267 0.101 −0.125 0.436 −0.082 0.627
−0.066 0.642 −0.423 0.002 0.382 0.005 −0.219 0.119 −0.024 0.864 −0.219 0.139 −0.211 0.154
−0.001 0.992 −0.400 0.005 0.380 0.007 −0.148 0.306 −0.011 0.938 −0.192 0.206 −0.177 0.245
−0.193 0.402 −0.590 0.005 0.430 0.052 −0.298 0.190 −0.204 0.374 −0.462 0.062 −0.480 0.051
−0.406 0.085 −0.540 0.017 0.322 0.179 −0.366 0.123 −0.183 0.452 −0.561 0.030 −0.587 0.022
HOMA-IR: homeostasis model assessment of insulin resistance. M1: unadjusted, M2: adjusted for age and BMI, M3: adjusted for age, BMI and bioavailable testosterone, M4: adjusted for age, BMI, bioavailable testosterone and estradiol.
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There are several limitations in the present study. First, this study was a cross-sectional design. Therefore, the causal relationship of adiponectin with renal function was not clear. Second, we defined eGFR on the basis of a single assessment of serum creatinine, which may introduce a misclassification bias. Finally, we did not exclude subjects with hypertension. Some kinds of angiotensin II receptor blocker will increase adiponectin levels [26]. Further studies on confounding factors may be needed. 6. Conclusion In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women. Conflict of interest There is no ethical problem or conflict of interest with regard to this manuscript. Acknowledgment This study was supported in part by a Grant-in-Aid for Scientific Research (C: 25462596) from the Japan Society for the Promotion of Science. References [1] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochem Biophys Res Commun 1996;221(2):286–9. [2] Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003;148(3):293–300. [3] Ryo M, Nakamura T, Kihara S, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004;68(11):975–81. [4] Zoccali C, Mallamaci F, Tripepi G, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13(1):134–41. [5] Matsuura F, Oku H, Koseki M, et al. Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver. Biochem Biophys Res Commun 2007;358(4):1091–5. [6] Gavrila A, Chan JL, Yiannakouris N, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab 2003;88(10):4823–31.
[7] Leung KC, Xu A, Craig ME, Martin A, Lam KS, O'Sullivan AJ. Adiponectin isoform distribution in women–relationship to female sex steroids and insulin sensitivity. Metabolism 2009;58(2):239–45. [8] Tamakoshi K, Yatsuya H, Wada K, et al. The transition to menopause reinforces adiponectin production and its contribution to improvement of insulin-resistant state. Clin Endocrinol (Oxf) 2007;66(1):65–71. [9] Lee CG, Carr MC, Murdoch SJ, et al. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. J Clin Endocrinol Metab 2009;94(4):1104–10. [10] Matsui S, Yasui T, Tani A, et al. Association of circulating adiponectin with testosterone in women during the menopausal transition. Maturitas 2012;73(3):255–60. [11] Matsui S, Yasui T, Tani A, et al. Associations of estrogen and testosterone with insulin resistance in pre- and postmenopausal women with and without hormone therapy. Int J Endocrinol Metab 2013;11(2):65–70. [12] Huang JW, Yen CJ, Chiang HW, Hung KY, Tsai TJ, Wu KD. Adiponectin in peritoneal dialysis patients: a comparison with hemodialysis patients and subjects with normal renal function. Am J Kidney Dis 2004;43(6):1047–55. [13] Guebre-Egziabher F, Bernhard J, Funahashi T, Hadj-Aissa A, Fouque D. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant 2005;20(1):129–34. [14] Isobe T, Saitoh S, Takagi S, et al. Influence of gender, age and renal function on plasma adiponectin level: the Tanno and Sobetsu study. Eur J Endocrinol 2005;153(1):91–8. [15] Kawamoto R, Tabara Y, Kohara K, et al. Serum high molecular weight adiponectin is associated with mild renal dysfunction in Japanese adults. J Atheroscler Thromb 2010;17(11):1141–8. [16] Doumatey AP, Zhou J, Huang H, et al. Circulating adiponectin is associated with renal function independent of age and serum lipids in west Africans. Int J Nephrol 2012:730920. [17] Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Climacteric 2001;4(4):267–72. [18] Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67(6):2089–100. [19] Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257(1):79–83. [20] Vermeulen A, Verdonck L, Kaufman JM. A criteria evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72. [21] Imai E, Horio M, Watanabe T, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol 2009;13(6):621–30. [22] Storgaard H, Poulsen P, Ling C, Groop L, Vaag AA. Relationships of plasma adiponectin level and adiponectin receptors 1 and 2 gene expression to insulin sensitivity and glucose and fat metabolism in monozygotic and dizygotic twins. J Clin Endocrinol Metab 2007;92(7):2835–9. [23] Waki H, Yamauchi T, Kamon J, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 2003;278(41):40352–63. [24] Hara K, Horikoshi M, Yamauchi T, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 2006;29(6):1357–62. [25] Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006;55(1):249–59. [26] Furuhashi M, Ura N, Higashiura K, et al. Blockade of the renin–angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 2003;42(1):76–81.
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High adiponectin level in late postmenopausal women with normal renal function Sumika Matsui a,⁎, Toshiyuki Yasui b, Kaoru Keyama a, Anna Tani a, Takeshi Kato a, Hirokazu Uemura c, Akira Kuwahara a, Toshiya Matsuzaki a, Minoru Irahara a a b c
Department of Obstetrics and Gynecology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan Department of Reproductive Technology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan Department of Preventive Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan
a r t i c l e
i n f o
Article history: Received 18 September 2013 Received in revised form 9 December 2013 Accepted 23 December 2013 Available online 2 January 2014 Keywords: Adiponectin Renal function Late postmenopause Insulin resistance Lipid profiles
a b s t r a c t Background: We examined whether high circulating adiponectin level is associated with renal function and is favorable for lipid and glucose metabolism in late postmenopausal women with normal renal function. Methods: We conducted a cross-sectional study in 115 postmenopausal women and divided the subjects into 2 groups (early postmenopausal women and late postmenopausal women). Serum levels of adiponectin, blood urea nitrogen, creatinine (Cr), glucose, insulin and lipid profiles were measured. Glomerular filtration rate (GFR) was estimated by age and Cr. Results: Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women, and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women. Adiponectin level showed a negative correlation with eGFR and tended to have a negative correlation with eGFR after adjustments for age, BMI and bioavailable testosterone in all subjects, but adiponectin level did not show a significant correlation with eGFR in late postmenopausal women. Adiponectin level in late postmenopausal women showed a significant negative correlation with triglyceride (TG) and a positive correlation with high-density lipoprotein cholesterol (HDL-C) after adjustments for age and BMI. Conclusion: In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Adiponectin, which is an anti-inflammatory protein mainly secreted by adipocytes, has been reported to play an important role in protection against insulin resistance and atherosclerosis [1,2]. It has been reported that hypoadiponectinemia was correlated with the clinical phenotype of metabolic syndrome such as hypertension, impaired glucose tolerance and dyslipidemia [3]. High-density lipoprotein cholesterol (HDL-C) level, which plays an important role in protection against atherosclerosis, has been reported to be positively correlated with adiponectin level [4]. Matsuura et al. reported that adiponectin protected against atherosclerosis due to increase in HDL assembly through enhancing the pathway of ATP-binding cassette transporters and apoA-1 synthesis in the liver [5].
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Course of Human Development, Human Development and Health Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Tel.: +81 88 633 7177; fax: +81 88 631 2630. E-mail address: [email protected] (S. Matsui). 0009-8981/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.037
Previous studies demonstrated that adiponectin level in postmenopausal women was higher than that in premenopausal women [6–9]. We also reported that total adiponectin level and high molecular weight (HMW) adiponectin level were increased in late postmenopausal women for whom N 5 y had passed since menopause and adiponectin levels were associated with levels of free and bioavailable testosterone in postmenopausal women [10,11]. Since estrogen deficiency after natural and surgical menopause has been associated with increases in insulin resistance and dyslipidemia, high adiponectin level after menopause is paradoxical and its clinical significance has not been fully clarified. On the other hand, an association of adiponectin with renal function has been demonstrated. It has been reported that serum adiponectin levels in hemodialysis patients and patients with chronic kidney disease (CKD) were elevated compared to the level in healthy subjects [4,12]. Adiponectin has been shown to be negatively correlated with estimated glomerular filtration rate (eGFR) in patients with early stages of CKD [13]. Therefore, high adiponectin level in postmenopausal women with renal dysfunction may be due to decrease in adiponectin clearance in the kidney. However, the relationship between adiponectin level and renal function in the healthy subjects without renal dysfunction has been controversial [14–16].
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2. Subjects and methods
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Tokyo, Japan). Glomerular filtration rate was estimated using the following equation: eGFR = 194 × age−0.287 × Cr−1.094 × 0.739 [21].
2.1. Subjects The subjects of this study were recruited from patients visiting the outpatient clinic of the Department of Obstetrics and Gynecology, Tokushima University Hospital. We conducted a cross-sectional study in 115 postmenopausal women. Based on the 2001 Stages of Reproductive Aging (STRAW) criteria, early postmenopause was defined as a period of less than 5 years since menopause and late postmenopause was defined as a period of more than 5 years since menopause. We divided subjects into two groups based on previous study [17]. Sixty women in early postmenopause were women for whom b 5 y had passed since menopause, and 55 women in late postmenopause were women for whom N 5 y had passed since menopause. Before recruitment in the study, women underwent gynecological and biochemical examinations. Reviews of medical histories and the results of physical examinations and blood chemistry tests showed that all of the women were in good health. Exclusion criteria in the study were a history of any cardiovascular disease, diabetes mellitus, CKD, or liver disease. CKD is defined as eGFR b60 ml/min/1.73 m2 for 3 months or more regardless of the cause [18]. Women who had received hormone replacement therapy in the past and women taking any medication known to influence lipoprotein metabolism were not included in the study. Venous blood samples for measurements of hormones were drawn into BD vacutainer tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) between 8 AM and 10 AM after 12-h fasting. Blood samples obtained were frozen at − 70 °C until used for analysis. Informed consent for participation in this study was obtained from each woman. The Ethics Committee of Tokushima University Hospital approved the study. 2.2. Measurement of serum adiponectin concentration Serum total adiponectin concentration was measured by an enzyme-linked immunosorbent assay using a commercially available kit (Otsuka Pharmaceuticals, Tokyo, Japan) after the samples had been diluted 5100-fold with the sample buffer as previously reported [19]. Intra- and inter-assay CVs were b 10.0%, and the sensitivity of the assay was 23.4 pg/ml. 2.3. Measurements of serum concentrations of hormones Serum estradiol concentration was measured by a chemiluminescent immunoassay using a commercially available kit (Abbott Co., Tokyo, Japan). The intra- and inter-assay CVs were b 7%, and the sensitivity of the assay was 10 pg/ml. Serum concentrations of luteinizing hormone and follicle-stimulating hormone were measured by a chemiluminescent immunoassay using a commercially available kit (Abbott Co.). The intra- and inter-assay CVs were b7% and b10%, respectively. Serum total testosterone level was measured by an electrochemiluminescence immunoassay using a commercially available kit (Roche Diagnostics). Intra- and inter-assay CVs were 2.2–3.2% and 3.6–4.6%, respectively. The sensitivity of the assay was 0.05 ng/ml. Serum SHBG concentration was measured by a solid-phase immunoradiometric assay (Siemens Medical Solutions Diagnostics). Intra- and inter-assay CVs were 2.8–5.3% and 7.9–8.5%, respectively, and the sensitivity of the assay was 1 nmol/l. Serum free testosterone and bioavailable testosterone were calculated using total testosterone, albumin and SHBG by a previously described method [20]. 2.4. Measurement of renal function Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured by using an automated clinical analyzer system (Hitachi,
2.5. Measurements of concentrations of glucose, insulin and lipids Plasma glucose level was measured by using the glucose oxidase method on an Automated Glucose Analyzer GA04 (A&T). The intraand inter-assay CVs ranged from 0.8 to 1.3% and 0.6 to 1.3%, respectively. Serum insulin level was measured by using an enzyme immunoassay on AIA2000 (TOSOH Co., Tokyo, Japan). The intra- and inter-assay CVs ranged from 1.1 to 3.2% and 1.9 to 3.3%, respectively, and the sensitivity of the assay was 1.0 μIU/ml. Insulin resistance was evaluated with homeostasis model assessment of insulin resistance (HOMA-IR), which was calculated for all subjects by the following formula: fasting serum insulin (μIU/ml) × fasting plasma glucose (mg/dl) / 405. Serum total cholesterol (TC), HDL-C and triglyceride (TG) levels were measured by using a chemistry system (Hitachi, Tokyo, Japan). Low-density lipoprotein cholesterol (LDL-C) was estimated by the Friedewald equation (LDL-C = TC − TG / 5 − HDL-C). 3. Statistical analysis Data are presented as medians with 25th to 75th percentile ranges. The Mann–Whitney U test was used to compare differences between the 2 groups. The Kruskal–Wallis rank test was used to compare differences between multi-groups. Correlations between variables were determined using Spearman's rank order analysis. Age and body mass index (BMI)-adjusted partial correlation analysis was performed to determine the relationships of serum adiponectin concentration with renal function, insulin resistance and lipid parameters. We also considered the effects of hormones including testosterone on the correlation between adiponectin and eGFR and the correlations between adiponectin and insulin resistance and lipid parameters because we previously reported that circulating adiponectin levels were associated with levels of free and bioavailable testosterone in postmenopausal women [10]. Age, BMI and bioavailable testosterone-adjusted partial correlation analysis was performed because bioavailable testosterone showed a significant and strong correlation with free testosterone (r = 0.997, p b 0.001). All statistical analyses were carried out using Statview ver 8.2 (SAS Institute Inc.) and SPSS statistics version 20.0 (IBM, Armonk). All p values reported were 2-sided and a p b 0.05 were considered statistically significant. We performed statistical analysis by using one-half of the value of sensitivity when the values were below the sensitivity level. 4. Results 4.1. Total adiponectin level and renal function Background characteristics of all 115 subjects and those of early postmenopausal women and late postmenopausal women are shown in Table 1. Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women (p = 0.009). Serum levels of Cr and BUN in late postmenopausal women were significantly higher than those in early postmenopausal women (p b 0.001 and p = 0.004, respectively), and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women (p b 0.001). 4.2. Levels of glucose, insulin and lipid profiles As can be seen in Table 1, lipid profiles did not show significant differences between the 2 groups. Plasma glucose level in late postmenopausal women tended to be higher than that in early postmenopausal women.
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Table 1 Levels of hormones, eGFR, adiponectin, lipid profiles and HOMA-IR in postmenopausal women.
Age BMI Estradiol LH FSH Testosterone Free T Bioavailable T SHBG BUN Cr eGFR Adiponectin TC TG HDL LDL Glucose Insulin HOMA-IR
Years kg/m2 pg/ml mIU/ml mIU/ml ng/ml ng/dl ng/dl nmol/l mg/dl mg/dl ml/min/1.73 m2 μg/ml mg/dl mg/dl mg/dl mg/dl mg/dl μIU/ml
All women (n = 115)
Early postmenopausal women (n = 60)
Late postmenopausal women (n = 55)
p value
55.0 (51.0–60.0) 21.6 (19.9–24.5) 12.5 (12.5–29.5) 29.8 (20.0–40.1) 94.8 (69.4–122.7) 0.21 (0.13–0.28) 0.20 (0.11–0.31) 4.42 (2.88–7.39) 71.3 (50.7–91.9) 13.0 (11.0–17.0) 0.59 (0.52–0.66) 80.8 (71.9–91.9) 11.4 (8.4–16.4) 224.5 (204.5–241.0) 95.0 (72.0–124.0) 70.5 (60.0–87.8) 130.0 (109.7–144.1) 97.0 (91.0–101.3) 4.79 (3.16–6.97) 1.14 (0.70–1.62)
52.0 (48.3–54.8) 21.8 (19.9–25.0) 19.5 (12.5–32.0) 34.5 (21.1–47.6) 101.3 (74.7–138.4) 0.21 (0.12–0.31) 0.21 (0.11–0.33) 4.85 (2.98–8.24) 67.8 (48.8–87.8) 13.0 (11.0–14.0) 0.58 (0.50–0.64) 84.7 (78.2–99.1) 10.2 (7.3–15.3) 226.0 (205.0–249.0) 95.0 (68.5–125.5) 71.5 (63.0–88.8) 131.7 (107.5–144.2) 96.0 (88.3–100.0) 4.91 (3.43–6.97) 1.17 (0.74–1.52)
61.0 (56.0–63.0) 21.5 (20.2–24.2) 12.5 (5.5–23.5) 25.0 (19.4–34.2) 86.1 (62.0–105.5) 0.20 (0.14–0.28) 0.19 (0.10–0.28) 4.34 (2.41–6.77) 73.6 (65.3–99.8) 16.0 (12.0–18.0) 0.60 (0.55–0.67) 75.4 (68.0–84.0) 12.6 (9.7–18.4) 223.0 (200.8–238.0) 94.5 (72.0–123.3) 70.5 (58.3–85.8) 125.5 (110.1–143.8) 98.0 (93.0–102.0) 4.39 (2.84–7.13) 1.07 (0.68–1.73)
b0.001 NS 0.006 0.006 0.011 NS NS NS NS b0.001 0.004 b0.001 0.009 NS NS NS NS NS NS NS
Values are medians with 25–75th percentile ranges in parentheses. SHBG: sex hormone-binding globulin, HOMA-IR: homeostasis model assessment of insulin resistance. p value: early postmenopausal women vs late postmenopausal women.
significant positive correlation with HDL-C (r = 0.416, p b 0.001). After adjustments for age and BMI, the correlations of adiponectin with TG and HDL-C remained significant (r = − 0.275, p = 0.007 and r = 0.400, p b 0.001, respectively). After adjustments for age, BMI and bioavailable testosterone, the positive correlation between adiponectin and HDL-C remained significant (r = 0.432, p b 0.001, respectively) and the correlation between adiponectin and TG showed a negative tendency (r = − 0.241, p = 0.064). Adiponectin level in all subjects also showed significant negative correlations with insulin and HOMA-IR (r = − 0.322, p = 0.001 and r = − 0.305, p = 0.003, respectively). After adjustments for age and BMI, these correlations remained significant (r = − 0.215, p = 0.036 and r = − 0.239, p = 0.023, respectively). After adjustments for age, BMI and bioavailable testosterone, the correlations were not significant. In late postmenopausal women, adiponectin level showed a significant negative correlation with TG (r = −0.423, p = 0.002, respectively) and a significant positive correlation with HDL-C (r = 0.382, p = 0.005, respectively) (Table 3). These correlations remained significant after adjustments for age and BMI (r = −0.400, p = 0.005 and r = 0.380, p = 0.007, respectively). After adjustments for age, BMI and bioavailable testosterone, the negative correlation between adiponectin and TG remained significant (r = −0.590, p = 0.005) and showed a positive tendency with HDL-C (r = 0.430, p = 0.052). Adiponectin level
4.3. Association of total adiponectin and renal function As can be seen in Table 2, adiponectin level in all subjects showed a negative correlation with eGFR level (r = − 0.237, p = 0.012). After adjustments for age and BMI, the correlation was not significant. After adjustments for age, BMI and bioavailable testosterone, the correlation between adiponectin and eGFR showed a negative tendency (r = −0.216, p = 0.070). In late postmenopausal women, adiponectin level did not show a significant correlation with eGFR. 4.4. Adiponectin levels categorized by eGFR groups Based on eGFR level, all subjects were divided into three groups: 60–80 ml/min/1.73 m2, 80–90 ml/min/1.73 m2, and N 90 ml/min/ 1.73 m2. As can be seen in Fig. 1, total adiponectin level showed a tendency to increase with a decrease in eGFR, but the trend was not significant. 4.5. Associations of total adiponectin with lipid profiles and insulin resistance Table 3 shows that the adiponectin level in all subjects showed significant negative correlations with TG and LDL-C (r = − 0.345, p = 0.001 and r = − 0.210, p = 0.040, respectively) and a
Table 2 Correlations of adiponectin with age, BMI and parameters of renal function. All women
Age BMI BUN Cr eGFR
r p r p r p r p r p
Early postmenopausal women
Late postmenopausal women
M1
M2
M3
M4
M1
M2
M3
M4
M1
M2
M3
M4
0.156 0.095 −0.258 0.005 0.279 0.004 0.232 0.014 −0.237 0.012
– – – – 0.190 0.055 0.161 0.092 −0.142 0.138
– – – – 0.215 0.081 0.226 0.059 −0.216 0.070
– – – – 0.138 0.268 0.222 0.066 −0.226 0.062
−0.408 0.001 −0.479 b0.001 0.037 0.792 0.211 0.115 −0.137 0.308
– – – – 0.046 0.750 0.053 0.703 −0.054 0.697
– – – – 0.106 0.495 0.137 0.357 −0.133 0.374
– – – – 0.067 0.670 0.139 0.356 −0.141 0.349
0.398 0.003 −0.001 0.997 0.350 0.012 0.145 0.290 −0.180 0.189
– – – – 0.224 0.121 0.152 0.275 −0.136 0.330
– – – – 0.118 0.622 0.285 0.211 −0.313 0.168
– – – – 0.065 0.790 0.246 0.310 −0.280 0.246
M1: unadjusted, M2: adjusted for age and BMI, M3: adjusted for age, BMI and bioavailable testosterone, M4: adjusted for age, BMI, bioavailable testosterone and estradiol.
S. Matsui et al. / Clinica Chimica Acta 430 (2014) 104–108
associated with favorable lipid metabolism and insulin sensitivity in postmenopausal women. In a cohort of young and elderly twins, adiponectin receptor gene expression level in skeletal muscle in elderly twins was lower than that in young twins, while circulating adiponectin level in elderly twins was significantly higher than that in young twins [22]. Adiponectin in late postmenopausal women may not act on adiponectin receptors compared to adiponectin in early postmenopausal women. It has been reported that high adiponectin level after menopause may be due to reduction in adiponectin clearance associated with renal function [4,12,13]. A relationship between adiponectin level and renal function has been demonstrated even in subjects without severe renal dysfunction. Isobe et al. showed that adiponectin level increased sharply until the age of 50 y and thereafter gradually increased and that the pattern of change in adiponectin was similar to that in BUN in women without severe renal dysfunction [14]. Doumatey et al. reported that adiponectin showed an inverse relationship with eGFR in nondiabetic postmenopausal women whose eGFR levels were more than 30 [16]. We showed that adiponectin level in late postmenopausal women was higher than that in early postmenopausal women and that eGFR in late postmenopausal women was lower than that in early postmenopausal women. In addition, adiponectin level in all subjects showed a negative correlation with eGFR. However, the correlation between eGFR and adiponectin level was not significant after adjustment for age and BMI and there was no significant difference among the subgroups categorized by eGFR. Adiponectin level did not show a significant correlation with eGFR even in early postmenopausal women. High adiponectin level after menopause may be involved in not only eGFR but also other factors in healthy postmenopausal women. The differences between previous results and our results may be due to the difference in subjects. We excluded subjects whose eGFR level was b60 ml/min/1.73 m2. In previous studies, decrease in GFR might have affected adiponectin level since mean serum Cr level was relatively high (0.85 mg/dl) [14] and women whose eGFR was 30–60 ml/min/1.73 m2 were included [16]. Recently, it has been reported that a higher level of HMW adiponectin was associated with a reduced odds ratio of mild renal dysfunction in a general population without CKD [15]. Circulating adiponectin has been classified into three forms of low-molecular weight (LMW) trimer, medium-molecular weight (MMW) hexamer and HMW multimers [23]. The HMW isoform level and the ratio of HMW/total adiponectin have been reported to be better predictors of insulin sensitivity and metabolic syndrome than total adiponectin level [24,25]. Therefore, the conflicting results may be caused by the difference in total adiponectin or HMW adiponectin. Further studies on HMW adiponectin are needed.
Adiponectin (µg/ml)
p=0.09 10.2 (8.0-16.5)
12.5 (9.2-18.4)
30.0
10.6 (7.1-15.2)
20.0
10.0
0.0
60-80
80-90
eGFR
107
>90
(ml/min/1.73m2)
eGFR: estimated glomerular filtration rate Fig. 1. Serum adiponectin levels categorized by eGFR. eGFR: estimated glomerular filtration rate. Total adiponectin level showed a tendency to increase with decrease in eGFR, but the trend was not significant (p = 0.09).
in late postmenopausal women did not show significant correlations with glucose, insulin and HOMA-IR. 5. Discussion We previously reported that adiponectin level was increased in women in the late postmenopausal stage [10], but we could not demonstrate its clinical significance. In the present study, we showed that adiponectin level was positively correlated with HDL-C and negatively correlated with TG and insulin resistance, suggesting that a high adiponectin level is favorable for lipid profiles and insulin sensitivity in postmenopausal women. In addition we showed that adiponectin level was positively correlated with HDL-C and negatively correlated with TG even if only in late postmenopausal women. However, adiponectin level was high in late postmenopausal women, while levels of HDL-C, TG and HOMA-IR were not different between early and late postmenopausal women. Tamakoshi et al. reported that adiponectin level was negatively correlated with HOMA-IR [8]. However, adiponectin level in postmenopausal women was significantly higher than that in premenopausal women, although HOMA-IR in postmenopausal women was significantly higher than that in premenopausal women. These results seem to be paradoxical. Adiponectin resistance may be a reason for the paradoxical results of high adiponectin level
Table 3 Correlations of adiponectin with lipid profiles and HOMA-IR. All women
TC TG HDL-C LDL-C Glucose Insulin HOMA-IR
r p r p r p r p r p r p r p
Early postmenopausal women
Late postmenopausal women
M1
M2
M3
M4
M1
M2
M3
M4
M1
M2
M3
M4
−0.046 0.652 −0.345 0.001 0.416 b0.001 −0.210 0.040 −0.060 0.546 −0.322 0.001 −0.305 0.003
0.011 0.913 −0.275 0.007 0.400 b0.001 −0.150 0.149 −0.059 0.563 −0.215 0.036 −0.239 0.023
−0.027 0.834 −0241 0.064 0.432 b0.001 −0.184 0.164 −0.060 0.635 −0.166 0.198 −0.221 0.096
0.108 0.414 0.198 0.137 0.362 0.006 0.230 0.085 0.061 0.638 0.103 0.436 0.156 0.250
0.006 0.969 −0.284 0.058 0.532 b0.001 −0.259 0.089 −0.161 0.275 −0.402 0.004 −0.399 0.006
0.099 0.522 0.138 0.379 0.279 0.073 −0.153 0.335 0.077 0.610 −0.297 0.040 −0.257 0.091
0.017 0.919 0.318 0.059 0.130 0.456 −0.269 0.118 0.300 0.060 −0.167 0.292 −0.107 0.524
−0.003 0.985 0.298 0.082 0.122 0.493 −0.280 0.109 0.267 0.101 −0.125 0.436 −0.082 0.627
−0.066 0.642 −0.423 0.002 0.382 0.005 −0.219 0.119 −0.024 0.864 −0.219 0.139 −0.211 0.154
−0.001 0.992 −0.400 0.005 0.380 0.007 −0.148 0.306 −0.011 0.938 −0.192 0.206 −0.177 0.245
−0.193 0.402 −0.590 0.005 0.430 0.052 −0.298 0.190 −0.204 0.374 −0.462 0.062 −0.480 0.051
−0.406 0.085 −0.540 0.017 0.322 0.179 −0.366 0.123 −0.183 0.452 −0.561 0.030 −0.587 0.022
HOMA-IR: homeostasis model assessment of insulin resistance. M1: unadjusted, M2: adjusted for age and BMI, M3: adjusted for age, BMI and bioavailable testosterone, M4: adjusted for age, BMI, bioavailable testosterone and estradiol.
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There are several limitations in the present study. First, this study was a cross-sectional design. Therefore, the causal relationship of adiponectin with renal function was not clear. Second, we defined eGFR on the basis of a single assessment of serum creatinine, which may introduce a misclassification bias. Finally, we did not exclude subjects with hypertension. Some kinds of angiotensin II receptor blocker will increase adiponectin levels [26]. Further studies on confounding factors may be needed. 6. Conclusion In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women. Conflict of interest There is no ethical problem or conflict of interest with regard to this manuscript. Acknowledgment This study was supported in part by a Grant-in-Aid for Scientific Research (C: 25462596) from the Japan Society for the Promotion of Science. References [1] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochem Biophys Res Commun 1996;221(2):286–9. [2] Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003;148(3):293–300. [3] Ryo M, Nakamura T, Kihara S, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004;68(11):975–81. [4] Zoccali C, Mallamaci F, Tripepi G, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13(1):134–41. [5] Matsuura F, Oku H, Koseki M, et al. Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver. Biochem Biophys Res Commun 2007;358(4):1091–5. [6] Gavrila A, Chan JL, Yiannakouris N, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab 2003;88(10):4823–31.
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