Introduction

Insulin resistance and de-compensation of β-cell function are the key determinants of type 2 diabetes mellitus. Obesity is the most common cause for insulin resistance and eventually for diabetes mellitus type 2, which significantly increases the risk of cardiovascular

disease and premature death (DeFronzo & Ferrannini, 1991). It is well known that adipose tissue secreted products, so called adipokines, influence the function of insulin in other tissues (reviewed in Rasouli & Kern, 2008).

One of the fat-derived adipokines, retinol-binding protein 4 (RBP4), has been identified as a modulator of

Archives of Physiology and Biochemistry, 2010; 116(2): 57–62

O R I G I N A L A R T I C L E

Association of serum levels of retinol-binding protein 4 with male sex but not with insulin resistance in obese patients

Fatma Ülgen1, Christian Herder2, Markus C. Kühn1, Holger S. Willenberg1, Matthias Schott1, Werner A. Scherbaum1, and Sven Schinner1

1Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Germany, and 2Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Germany

Abstract

Background: Retinol-binding protein 4 (RBP4) is secreted by adipocytes and by the liver and modulates insulin sensitivity in animal models. However, controversial data exist regarding the association of serum levels of RBP4 with insulin resistance in humans. Obesity confers a major risk to develop insulin resistance.Aim: Therefore, we investigated RBP4 levels in non-diabetic obese patients and analysed the association with insulin sensitivity and other metabolic markers.Subjects and methods: Glucose tolerance was assessed by oral glucose tolerance tests and 70 normal glucose tolerant patients (36 women, 34 men; body mass index >30 kg/m2) were included in our study. We compared the serum level of RBP4 (measured by ELISA) with clinical features (age, sex, BMI, waist-to-hip-ratio, blood pressure) and laboratory findings (total cholesterol, triglycerides, fasting glucose, 2-hour glucose, fasting insulin, HOMA-IR and HOMA-B). The associations between RBP4 and the above mentioned variables were assessed using multiple linear regression models.Results: The mean age (±SD) of the subjects included was 48.1 (± 12.3) years and the mean BMI 41.6 (± 7.4) kg/m2. We found significantly higher RBP4 levels in men (53.0 ± 20.8 µg/ml) than in women (39.7 ± 12.3 µg/ml) (p = 0.0013). However, age and sex-adjusted multiple linear regression models showed no significant associa-tion of serum RBP4 levels with BMI, waist-to-hip-ratio, blood pressure, cholesterol, triglycerides, fasting glucose, 2-hour glucose, insulin resistance (as assessed by HOMA-IR), or insulin secretion (as assessed by HOMA-B).Conclusion: Our data show higher RBP4 levels in obese men than in obese women. However, there was no association of RBP4 levels with insulin resistance or other components of the metabolic syndrome. We conclude that obesity might already be associated with elevated RBP4 levels which then show no additional correlation with metabolic markers.

Keywords: Obesity; insulin resistance RBP4

Address for Correspondence: Sven Schinner MD, Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany. Tel: +49-211-8117810. Fax: +49-211-8117860. E-mail: sven.schinner@uni-duesseldorf.de

(Received 15 September 2009; revised 14 January 2010; accepted 17 January 2010)

ISSN 1381-3455 print/ISSN 1744-4160 online © 2010 Informa UK LtdDOI: 10.3109/13813451003631421 http://www.informahealthcare.com/arp

Archives of Physiology and Biochemistry2010

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1381-34551744-4160© 2010 Informa UK Ltd10.3109/13813451003631421

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insulin sensitivity in animal models (Muoio & Newgard, 2005; Yang et al., 2005; Graham, 2006). Different mouse models of obesity and insulin resistance show elevated levels of RBP4. Consistently, an over-expression of RBP4 generates insulin resistance in mice (Yang et al., 2005). However, controversial data exist regarding the associa-tion of serum levels of RBP4 with insulin resistance in humans. RBP4 is thought to raise blood glucose levels by impairing insulin signalling in muscle and liver (Muoio & Newgard, 2005). Klöting et al. (2007) reported elevated serum RBP4 levels in insulin- resistant subjects and sug-gest RBP4 as a marker of insulin resistance. Previous studies found that plasma RBP4 levels were increased in obese subjects with impaired glucose tolerance and type 2 diabetes (Cho et al., 2006; Takebayashi et al., 2007), whereas Gomez-Ambrosi et al. (2008) reported no change in serum RBP4 levels in obesity-associated type 2 diabetic subjects. Some studies indicated that RBP4 levels are not associated with insulin resist-ance, but with markers of inflammation and features of the metabolic syndrome like total cholesterol, LDL and VLDL-cholesterol (von Eynatten et al., 2007; Yao-Borengasser et al., 2007). Analyses of different adipose tissue depots have shown that elevated serum levels of RBP4 expression correlate with visceral obesity (Kloting et al., 2007; Jia et al., 2007). In order to elucidate the role of RBP4 in highly obese subjects with a mean BMI of >40 kg/m2, we investigated RBP4 levels in a subgroup of non-diabetic obese patients with respect to insulin sensitivity and other metabolic markers.

Participants and Methods

Participants

70 subjects (36 women and 34 men) from the obesity outpatient clinic at the University Hospital Düsseldorf were included in this study. The subjects underwent complete physical examinations and biochemical analysis of metabolic serum markers as well as an oral glucose tolerance test (oGTT). Only normal glucose tolerant subjects were eventually included in our study. The most important inclusion criterion for the subjects in our study was a BMI >30 kg/m2. The mean age (± SD) of the subjects included was 48.1 (± 12.3) years and the mean BMI 41.6 (± 7.4) kg/m2. The study was performed according to the rules of the Declaration of Helsinki, and all study patients gave informed written consent.

Methods

BMI was calculated as weight in kilograms divided by height in meters squared, and the waist-to-hip-ratio was

calculated by assessing the waist circumference located just above the upper hip bone and the hip circumference at its widest part. Blood pressure was measured after resting for 5 minutes in the semi-sitting position. Laboratory values of cholesterol, triglycerides, fasting and 2-hour glucose insulin were measured according to standard laboratory methods. Homeostasis model assessments of insulin resistance (HOMA-IR) and beta cell function (HOMA-B) were performed as described previously (Matthews et al., 1985).

Serum RBP4 levels were measured as described previously (Aeberli et al., 2007; Ingelsson et al., 2009) with an enzyme immunoassay kit (Immundiagnostik, Bensheim, Germany), and inter- and intra-assay variability were 9.7% and 5.0%, respectively.

Statistical analysis

Data for anthropometric and metabolic character-istics of the study subjects were expressed as means ± SD. RBP4 concentrations in men and women were compared using Wilcoxon signed rank test. Univariate associations between variables were described with Pearson correlation coefficients (r). Associations between serum concentrations of RBP4 and metabolic variables were analysed using multiple linear regres-sion models with RBP4 levels as dependent and age and sex as independent variables. For all statistical analyses a p-value less than 0.05 was considered to be statistically significant. Analyses were conducted using SAS (Version 9.1, SAS Institute, Cary, NC).

Results

Patient characteristics

In line with previous studies we found many of the patients included to suffer from insulin resistance, arterial hypertension and dyslipidemia (Table 1) (Bjorntorp, 1991; Cheung, 2008). As expected we found a significant correlation of the BMI with diastolic blood pressure and HDL-cholesterol levels. However, in our population the BMI was not significantly cor-related with waist-to-hip ratio, systolic blood pressure, triglyceride and LDL cholesterol levels, fasting and 2-hour blood glucose (Table 2). This may be due to the fact that the average BMI in this study was >40 kg/m2. Consistently, the waist-to-hip-ratio showed a sig-nificant correlation only with the systolic blood pres-sure, HDL-cholesterol and HOMA-IR, but not with the other metabolic parameters (Table 2). Interestingly, RBP4 levels in our population differed between men and women. We found serum RBP4 levels in men

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Association of serum levels of RBP4 with male sex but not with insulin resistance in obese patients 59

(53.0 ± 20.8 µg/ml) to be significantly higher than in women (39.7 ± 12.3 µg/ml) (P = 0.0013) (Table 1). One third of the female patients was older than 51 years and therefore considered postmenopausal. The mean RBP4 levels were 36.3 vs. 45.8 µg/ml (p = 0.0183) in pre- and postmenopausal women.

Association of RBP4 levels with components of the metabolic syndrome

In previous studies, serum RBP4 levels were associated with features of the metabolic syndrome, which include insulin resistance, fasting glucose, waist-to-hip-ratio, triglyceride and cholesterol levels (Muoio & Newgard, 2005; Cho et al., 2006; von Eynatten et al., 2007; Yao-Borengasser et al., 2007; Lee et al., 2007; Mody et al., 2008). Therefore, we examined serum RBP4 levels from 70 obese subjects with respect to above-mentioned parameters. Covering a wide range of BMI (31–63 kg/m2) with a mean BMI > 40 kg/m2, we found no sig-nificant associations between RBP4 levels and BMI or waist-to-hip-ratio. In addition, we found no correla-tion of RBP4 with blood pressure, cholesterol levels,

triglycerides, fasting glucose, 2-hour glucose, insu-lin resistance (as assessed by HOMA-IR), or insulin secretion (as assessed by HOMA-B) (Table 3).

Discussion

Recently, RBP4 has been identified as a novel adipok-ine. This protein has been shown to impair insulin sensitivity in vitro and in animal models (Moio & Newgard, 2005; Cho et al., 2006; Mody et al., 2008).

Insulin-resistant GLUT4 knockout mice had high levels of RBP4 expression, and over-expression of RBP4 led to insulin resistance. Furthermore, genetic deletion of RBP4 led to increased insulin sensitivity (Yang et al., 2005). Therefore, RBP4 was suggested to mediate insulin resistance (Tamori et al., 2006).

However, in humans the role of RBP4 in glucose metabolism is less clear: A number of studies reported associations of RBP4 levels with insulin resistance (Kloting et al., 2007), glucose intolerance and type 2 diabetes (Cho et al., 2006; Takebayashi et al., 2007), whereas other recent studies failed to demonstrate a correlation of RBP4 levels with insulin resistance (von Eynatten et al., 2007; Yao-Borengasser et al., 2007; Broch et al., 2007). A longitudinal study on RBP4 levels and the onset of insulin resistance suggested that RBP4 was not a predictor for the development of insulin resistance (Lewis et al., 2008).

For a better understanding of the role of RBP4 in humans, we investigated RBP4 levels in non-diabetic obese patients with respect to insulin sensitivity and other metabolic markers. We found that serum RBP4 levels were significantly higher in men than in women. A study by Cho et al. (2006) who investigated the association of RBP4 serum levels with IGT and type 2 diabetes mellitus found a positive correlation of RBP4 with male sex only in subjects <50 years. Consistently, Lee et al. (2007) found a positive cor-relation of RBP4 with male sex in adolescents. These observations are in line with the findings in our study population with a mean age of 48.9 years (females) and 47.4 years (men).

The technical quantification of RBP4 has been a matter of debate as certain ELISA assays appeared to differ from quantification by western blot. We are aware of the questioned validity of RBP4 assays. However, the assay used by us has previously been successfully used by other groups (Aeberli et al., 2007; Ingelsson et al., 2009) and been validated by Western blotting (Aeberli et al., 2007; Graham et al., 2007).

Sex-specific differences in serum levels have been shown for other adipokines. For example, serum levels of leptin are higher in women than in men (Casabiell et al., 2001). In vitro studies suggest that testosterone

Table 1. Baseline characteristics of the patients included in this study. 70 patients from the obesity outpatient clinic at the University Hospital Düsseldorf were included. The inclusion cri-teria were BMI > 30 kg/m2 and normal glucose tolerance in an oral glucose tolerance test (according to ADA criteria).Variable Male (n = 34) Female (n = 36 ) PAge (years) 47.4 ± 13.9 48.9 ± 10.7 0.61BMI (kg/m2) 43.7 ± 8.7 39.6 ± 5.2 0.020Waist–to–hip–ratio 1.06 ± 0.09 0.93 ± 0.09 <0.001Systolic blood presure (mmHg)

145 ± 17 142 ± 19 0.46

Diastolic blood presure (mmHg)

92 ± 11 90 ± 11 0.49

Total cholesterol (mg/dl)

228 ± 32 228 ± 31 0.98

HDL cholesterol (mg/dl)

48 ± 12 64 ± 15 <0.001

LDL cholesterol (mg/dl)

157 ± 33 150 ± 32 0.39

Triglycerides (mg/dl)

225 ± 139 180 ± 120 0.18

Fasting plasma glucose (mmol/l)

98 ± 11 96 ± 10 0.60

2–h post–randial glucose (mmol/l)

119 ± 35 116 ± 31 0.67

Fasting plasma insulin (mU/l)

31.1 ± 14.2 24.1 ± 10.6 0.025

HOMA–IR 7.49 ± 3.45 5.84 ± 2.84 0.020HOMA–B 362 ± 233 270 ± 114 0.15RBP4 (±g/ml) 53.0 ± 20.8 39.7 ± 12.3 0.0013Data are shown as mean ± SD. Significant differences are highlighted using bold print.

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60 F. Ülgen et al.

regulates the secretion of leptin from adipocytes Wabitsch et al., 1997).

In this study we found higher RBP4 levels in men than in women. Given that studies by others indicate that this correlation is restricted to subjects <50 years – which may reflect the onset of menopause – one might speculate that RBP4 secretion might be regulated by female sex steroids. In line with the hypothesis of female sex ster-oids to regulate RBP4 levels we found higher RBP4 levels in post-menopausal than in pre-menopausal women.

In addition, serum levels of RBP4 have been shown to be associated with 17beta-estradiol, testosterone, andros-tendione and DHEA-S in young women with polycystic ovary syndrome (PCOS) and in controls (age 31.4 vs 32.0 years; mean BMI 30.5 vs. 29.3 kg/m2). Furthermore, the regulation of RBP4 expression by 17beta-estradiol in adipocytes has been shown in vitro (Tan et al., 2007). However, Möhlig and colleagues did not find a correla-tion of RBP4 serum levels with hyperandrogenemia or 17beta-estradiol in obese women (mean BMI 31.6 kg/m2) with a PCOS (Mohlig et al., 2008). Further studies using in vitro and in vivo approaches are necessary to

Table 3. Association between RBP4 and metabolic variables. The associations between serum concentrations of RBP4 and metabolic variables were analysed using multiple linear regres-sion models with RBP4 levels as dependent and age and sex as independent variables. In our population there was no signifi-cant association of RBP4 levels with the mentioned metabolic parameters.

Variable β pBMI (kg/m2) –0.00470 0.44Waist-to-hip-ratio (cm) 0.05720 0.90Systolic blood presure (mmHg) –0.00003 0.99Diastolic blood presure (mmHg) –0.00220 0.95Total cholesterol (mmol/l) 0.00140 0.26HDL cholesterol (mg/dl) 0.00330 0.25LDL cholesterol (mg/dl) 0.00001 0.99Triglycerides (mg/dl) 0.08764 0.23Fasting plasma glucose (mg/dl) –0.00170 0.682-h post-prandial glucose (mg/dl) 0.00040 0.76Fasting plasma insulin (mU/l) –0.00460 0.62HOMA-IR –0.04850 0.57HOMA-B –0.00160 0.98

Table 2. Correlation between clinical and biochemical parameters. The mentioned clinical and biochemical variables of the patients were correlated to each other. Pearson correlation coefficients (r) and p–values are given in the table.

Fasting insulin BMI WHR SBP DBP TG

Fasting- gluc 2h-gluc HDL LDL HOMA-IR HOMA-B

Fasting insulin 1 r ± pBMI 0.178 1 r 0.14 ± pWHR 0.29 0.22 1 r 0.0182 0.0805 ± pSBP 0.27 0.21 0.26 1 r 0.0253 0.0829 0.0373 ± pDBP 0.24 0.31 0.12 0.64 1 r 0.0452 0.0091 0.39 <.0001 ± pTG 0.26 –0.02 0.22 0.11 0.02 1 r 0.0345 0.87 0.0776 0.38 0.86 ± pFasting glucose 0.16 0.002 0.34 0.17 0.13 0.03 1 r 0.18 0.98 0.0052 0.15 0.27 0.82 ± p2-h glucose 0.24 –0.15 –0.01 0.18 0.08 0.14 0.22 1 r 0.0473 0.23 0.95 0.13 0.50 0.26 0.0641 ± pHDL –0.25 –0.24 –0.30 0.02 –0.11 –0.37 –0.09 –0.13 1 r 0.0370 0.0432 0.0144 0.88 0.37 0.0020 0.50 0.27 ± pLDL 0.06 –0.04 0.18 0.08 0.20 –0.03 0.25 –0.08 –0.31 1 r 0.63 0.76 0.15 0.52 0.10 0.78 0.0369 0.52 0.0099 ± pHOMA–IR 0.97 0.18 0.36 0.30 0.28 0.24 0.36 0.26 –0.25 0.11 1 r

<0.0001 0.14 0.0034 0.0132 0.0209 0.0511 0.0021 0.0288 0.0407 0.36 ± pHOMA–B 0.75 0.08 0.04 0.13 0.09 0.23 –0.43 0.12 –0.20 –0.08 0.60 1 r <0.0001 0.51 0.76 0.28 0.44 0.0578 0.0002 0.33 0.0958 0.51 <0.0001 ± pAge –0.02 –0.41 –0.07 0.21 –0.01 -0.11 0.22 0.18 0.16 –0.08 0.01 –0.11 r 0.85 0.0005 0.58 0.0835 0.95 0.39 0.0643 0.13 0.20 0.50 0.91 0.36 pSignificant correlations are highlighted using bold print.

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Association of serum levels of RBP4 with male sex but not with insulin resistance in obese patients 61

clarify possible effects of sex steroids on RBP4 expression in adipose tissue and possibly also in the liver.

In our cohort we demonstrated a positive correlation between the BMI and the diastolic blood pressure and a negative correlation for the BMI and HDL-cholesterol levels. The lack of significant correlation of the BMI with waist-to-hip ratio, systolic blood pressure, trig-lyceride and LDL cholesterol levels, and blood glucose levels may be explained by the fact that our popula-tion was very obese (mean BMI 41.6 kg/m2). At such high BMI levels the correlation between the BMI and metabolic parameters appears to be less pronounced. Consistently, there was no significant correlation of RBP4 with HOMA-IR (as a marker for insulin resistance) in our population. As mentioned above, data on RBP4 levels and insulin resistance are controversial. Our findings are in line with previous studies such as those by von Eynatten et al. (2007) and Yao-Borengasser et al. (2007) who found no correlation between RBP4 levels and insulin resistance, but are in contrast to the findings of other studies who reported serum RBP4 levels to be associated with insulin resistance (Graham et al., 2006). It is important to point out that insulin resistance in our study was assessed by the HOMA model (HOMA-IR). This method might overestimate the insulin clearance in the liver as compared to insulin sensitivity in the muscle. This is a limitation of our study compared to clamp-based techniques being the gold standard to quantify insulin resistance. However, in our popula-tion clamp studies were not feasible. Importantly, a major part of the previous studies on RBP4 used the HOMA model to assess insulin resistance. For exam-ple, the studies by Cho et al. (2006), Lee et al. (2007) and Möhlig et al. (2008) used HOMA-IR and found a positive correlation between RBP4 levels and insulin resistance. Therefore, the discrepancies between our findings and these published reports may not be due to differences in technical issues of quantifying insulin resistance.

The reason for the differences between the afore-mentioned studies results is not clear but possibly due to the high BMI in both our study groups. Notably, the obese patients included in the study by Graham et al. (2006) (mean BMI 32.4 kg/m2), Möhlig et al. (2008) (mean BMI 31.6 kg/m2), Lee et al. (2007) (mean BMI 30.8 kg/m2) and Kowalska et al. (2008) (mean BMI 31.1 kg/m2) had a relatively low BMI compared to the obese patients included in our study (mean BMI 41.6 kg/m2). Consistently, the patients in our study were already markedly insulin-resistant (HOMA-IR 7.49 for men and 5.84 for women). Of note, the RBP4 levels in lean controls in other studies were substantially lower (e.g. 25.0 ± 8.9 µg/ml in the study by Tan et al. (2007) and 23.8 ± 1.0 µg/ml in the study by Graham et al. (2006) than in both groups of our obese study population

(53.0 ± 20.8 and 39.7 ± 12.3 µg/ml in men and women, respectively). Therefore, it seems conceivable that there is no additional correlation of RBP4 with BMI or insulin resistance under these pathologic conditions. In other words, there seems to be no further increase in RBP4 levels with increasing BMI once the BMI is above a certain limit. Therefore, we suggest that RBP4, if at all applicable as a marker of insulin resistance, has its limitations at high BMI ranges.

Acknowledgements

This study was supported by the German Federal Ministry of Health and Social Security and the Ministry of Innovation, Science and Research of the State North Rhine-Westphalia. We thank Birgit Mülders-Opgenoorth for excellent technical assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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