http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–8 ! 2015 Informa UK Ltd. DOI: 10.3109/09513590.2015.1005594
REVIEW ARTICLE
Circulating retinol-binding protein 4 levels in gestational diabetes mellitus: a meta-analysis of observational studies Qi-Tao Huang1,2, Qiong Huang1, Wei Luo1, Fei Li1, Li-Lin Hang1, Yan-Hong Yu1, and Mei Zhong1 Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China and 2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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1
Abstract
Keywords
Retinol-binding protein 4 (RBP4) is a novel adipocyte-derived cytokine playing an important role in the regulation of energy metabolism and insulin sensitivity. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of gestational diabetes mellitus (GDM) have yielded inconclusive results. We performed a meta-analysis to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women. PubMed, Web of Science and EMBASE were searched up to 1 August 2014. A total of 14 studies comprised of 884 women with GDM and 1251 normglycemic pregnant women were included. The overall results suggested that maternal circulating RBP4 levels were significantly higher in GDM than their normal controls (SMD: 0.49 mg/ml, 95% CI: 0.23–0.75 mg/ml, p50.001, random effect model). However, stratified results indicated that this significant difference only existed in the second/third trimester and was limited to Asian populations. Furthermore, subgroup analysis according to matched maternal age and BMI still demonstrated that GDM had higher circulating RBP4 levels than the normal controls. Our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester.
Diabetes, gestational diabetes mellitus, insulin resistance, pregnancy, retinol-binding protein 4
Introduction Gestational diabetes mellitus (GDM), characterized by glucose intolerance with onset or first recognition during pregnancy, is one of the most common obstetrical complications. It is estimated that GDM affects 1–14% of all pregnancies depending on the population and the diagnostic criteria [1–3]. Although extensive research was performed, the precise mechanism responsible for the pathogenesis of GDM is still not completely understood. Mounting evidence demonstrated that enhanced systemic insulin resistance played a crucial role in the etiology of GDM [4,5]. Previous studies also suggested that women with obesity, metabolic syndrome or polycystic ovary syndrome had a significantly higher risk of developing GDM when they were pregnant [6–8]. Furthermore, it is generally accepted that women with previous history of GDM were more likely to experience increased subsequent risk for developing impaired glucose tolerance, type 2 diabetes mellitus, metabolic syndrome as well as cardiovascular diseases [9,10]. Currently, a growing body of research found that a novel adipocyte-derived cytokine known as retinol-binding protein 4 (RBP4) might play an important role in the regulation of energy metabolism and insulin sensitivity [11,12]. Previous evidence from animal experiments and clinical studies showed that increased circulating RBP4 levels could lead to impaired skeletal muscular glucose uptake and increased hepatic glucose Address for correspondence: Mei Zhong, Professor of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, P.R. China. Fax: +86-020-62787-560. E-mail: [email protected]
History Received 18 October 2014 Revised 20 December 2014 Accepted 6 January 2015 Published online 23 February 2015
production through insulin receptor subtrate-1 and phosphoinositide 3-kinase activation [13]. Recently, mounting evidence demonstrated higher circulating levels of RBP4 in patients with obesity, metabolic syndrome as well as type 2 diabetes [14,15]. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of GDM have yielded inconclusive results [16–29]. For instance, several studies suggested significantly enhanced serum levels of RBP4 in GDM [16,17,19,20,23,25–29], while some reports showed decreased or no different RBP4 concentrations between GDM serum specimen compared with those of controls [18,21,22,24,29]. As the association between RBP4 and GDM were far from clear, we performed a meta-analysis to systematically review the current literature to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women.
Methods The present meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) guidelines [30]. Search strategy and data sources Three electronic databases (PubMed, Web of Science and EMBASE) were searched up to August 1st, 2014 using the combinations of terms ‘‘GDM’’ or ‘‘gestational diabetes’’ or ‘‘diabetes’’ or ‘‘pregnancy’’ and ‘‘RBP4’’ or ‘‘retinol-binding protein’’ or ‘‘adipokine’’. We sifted through potentially relevant articles, firstly by titles and abstracts, and then we retrieved the
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full texts of articles for detailed review. Further, we scanned the reference lists of the articles that met the inclusion criteria in our analysis, and searched for those articles or citations in Google Scholar and Google to obtain additional studies. Inclusion and exclusion criteria Original case-control or cohort studies comparing serum/plasma RBP4 levels in pregnant women with GDM as well as healthy pregnant women were included. Studies which did not report the absolute RBP4 concentrations and/or an indication of the variation (demonstrated as standard error, standard deviation or interquartile range) in their original data were excluded from this meta-analysis. For multiple publications based on the same population, only the study with the latest or the most complete data were selected.
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Data extraction A form designed a priori was used to extract the information from the included studies. Two independent investigators performed the data extraction. Concentrations of serum/plasma RBP4 were the main exposure and GDM was the primary outcome. The following information was recorded: first author’s last name; year of publication; study location; number of GDM and controls; covariates adjusted for in the analysis. Assessment of methodological quality Two independent investigators assessed the quality of each study included using the Newcastle-Ottawa Quality Assessment Scale (NOS) (Table S1) [31]. Studies of low, intermediate and high quality were defined with NOS scores of 1–3, 4–6 and 7–9 in the meta-analysis, respectively. Statistical analysis The results were presented as the standardized mean difference (SMD) and 95% confident interval (95% CI) to estimate the size of the effect. Studies were weighted with consideration of both the sample size and the standard deviation. The SMDs were combined in a meta-analysis using a fixed-effects model when heterogeneity observed among studies was absent to moderate. When heterogeneity was high (I2450%), a random-effects model was used. Heterogeneity among these studies was evaluated by two parameters. p50.10 for the Cochran’s Q test or I2450% for Higgins statistic were regarded statistically significant heterogeneity [32]. The publication bias was investigated by two methods. Visual detection was used to analyze the funnel plots. Quantitative analysis was performed by the Begg’s regression asymmetry test [33]. Subgroup analysis was performed with respect to study type, diagnostic criteria of GDM, countries, maternal age as well as maternal BMI in order to explore the influence of these factors on the association.
Results Selection flow and Study characteristics The detailed search procedures were demonstrated in Figure 1. Full texts of 19 identified articles were retrieved for further assessment. Five of these articles were excluded because 2 studies explored serum RBP4 concentrations between women with previous history of GDM and their normal controls and three studies investigated the cord blood, adipose tissues or placental other than circulating concentrations in women with GDM as well as their controls (Figure 2). Finally, the remaining 14 independent articles were used for this meta-analysis. The main characteristics of the included studies are presented in Table 1. According to the NOS scoring, three of the 14 studies selected in this meta-analysis
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were of intermediate quality [21,24,26], and 11 studies were of high quality [16–20,22,23,25,27–29]. None of the studies included were of low quality (Table S1). Main results A total of 14 studies comprised of 884 women with GDM and 1251 normoglycemic pregnant women were included. In a pooled analysis of all studies, the results indicated that maternal circulating level of RBP4 was significantly higher in women with GDM than their normal controls (SMD: 0.49 mg/ml, 95% CI: 0.23–0.75 mg/ml, p50.001, random effect model) with significant heterogeneity among these studies (Q ¼ 89.17, I2 ¼ 85%, p50.001) Subgroup analysis An analysis of the results according to study type (cohort [16,18,19,22–25,29], case-control [20,26–28] or Cross-section [17,21]), diagnostic criteria of GDM (ADA [16,22–24,28], WHO [17,21,25–27], Carpenter & Coustan [18,29] or NDDG [19,20]), countries (Asia [16,19,20,23,26,29], Europe [17,21,22,25,27] or North America [18,24,28]), maternal age (matched [16–20,22, 23,25,27,29] or higher in GDM [21,24,26,29]), maternal BMI (matched [16–20,22,23,25] or higher in GDM [21,24,26–29]) and gestational weeks of RBP4 measurement (first trimester [27] or second or early third trimesters [16–26,28,29]) are summarized in Table 2. Stratification by countries indicated that circulating RBP4 levels were higher in patients with GDM in Asia than their normal controls (SMD: 0.78 mg/ml, 95%CI: 0.30–1.26 mg/ml), while no significant difference of circulating RBP4 levels were observed when patients with GDM were compared to their normal controls in non-Asian population. Moreover, subgroup analysis according to matched maternal age and BMI still demonstrated that women with GDM had higher circulating RBP4 levels than their normal controls (SMD: 0.67 mg/ml, 95%CI: 0.37– 0.97 mg/ml) and (SMD: 0.80 mg/ml, 95%CI: 0.50–1.10 mg/ml), respectively. Publication bias The publication bias was investigated by Begg’s funnel plot (Figure S1). The shape of this funnel plot was symmetrical, indicating a low probability of publication bias (p ¼ 0.381).
Discussion While elevated maternal circulating RBP4 levels has been associated with increased rate of obstetrical complications such as preeclampsia and fetal growth restriction [34,35], one intriguing observation was regarding the occurrence of GDM. Previous reports on the association between circulating RBP4 levels and the risk of GDM have yielded inconsistent results. Although the overall pooled results indicated that circulating levels of RBP4 were significantly higher in women with GDM than their normal controls, these results should be interpreted with caution, since subgroup analysis with respect to studies locations suggested that this observation was limited to Asian population [16,19,20,23,26,29]. And no significant differences of serum RBP4 levels were found between women with GDM and their control from European [17,21,22,25,27] or North American countries [18,24,28]. Previously, several studies reported elevated plasma RBP4 was associated with increased risk of insulin resistance and type 2 diabetes in Asian population [36–38], whereas some clinical studies demonstrated lack of association between plasma RBP4 levels and increased risk of insulin resistance as well as type 2 diabetes in non-Asian population [39,40]. Previous studies
RBP4 levels and GDM
Idenficaon
DOI: 10.3109/09513590.2015.1005594
Records idenfied through database searching (n =527)
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Addional records idenfied through other sources (n =4)
Eligibility
Records screened (n = 62)
Records excluded (n =43)
Full-text arcles assessed for eligibility (n =19)
Full-text arcles excluded with reasons* (n =5)
Studies included in qualitave synthesis (n =14)
Included
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Screening
Records aer duplicates removed (n =208)
Studies included in quantave synthesis (meta-analysis) (n =14)
Exclusions *Reasons:
Serum RBP4 levels in women with previous history of GDM (N=2). Cord blood, adipose ssues or placenta levels of RBP4 in women with GDM (N=3)
Figure 1. Flow chart of the literature search and article selection.
Figure 2. Forest plot of standardized mean differences in circulating RBP4 between women with gestational diabetes mellitus and normal controls for all the studies included in the meta-analysis.
suggested GDM has a strong genetic basis [41]. Under the influence of environment, lifestyles, and genetic factors, the association between RBP4 and the pathophysiology of GDM might vary in different regions [42,43]. A very recent meta-analysis
investigated the association between RBP4 and polycystic ovary syndrome (PCOS), which [44] seemed to support our hypothesis by demonstrating that RBP4 levels were higher in PCOS patients in Asian countries, but not in European countries. Since GDM
Year
2008
2008
2010
2007
2014
2008
2010
2010
Author
Kim et al. [16]
Lewandowski et al. [17]
Tepper et al. [18]
Chan et al. [19]
Liang et al. [20]
Krzyzanowska et al. [21]
Klein et al. [22]
Su et al. [23]
Retrospective cohort
China
Austria
Austria
China
China
USA
UK
South Korea
Location
63/58
63/38
42/45
35/35
20/20
12/10
15/20
10/9
24–29
24–28
29
24–27
24 28
24–28
28
24–28
Gestation age for RBP4 measurement (weeks)
GDM: 28.8 ± 1.8 Control: 28.4 ± 2.4
GDM: 32.7 ± 5.2 Control: 33.3 ± 4.8
GDM: 33.0 (29.0–35.0) Control: 28 (24–34)
GDM: 29.0 ± 2.5 Control: 29.3 ± 3.1
GDM: 32.7 ± 5.0 Control: 32.7 ± 5.0
GDM: 28.6 ± 4.9 Control: 28.8 ± 6.2
GDM: 34.0 (29.0–36.0) Control: 32.0 (29.0–35.0)
GDM: 32.6 ± 3.0 Control: 32.6 ± 3.3
Age* (years)
ADA
ADA
ADA
ELISA
ELISA GDM: 25.5 ± 2.6 Control: 24.9 ± 2.1
GDM: 27.7 ± 5.6 Control: 28.1 ± 6.2
Serum GDM: 41.6 ± 12.2 Control: 34.5 ± 9.8
Serum GDM: 18.0 ± 3.7 Control: 16.9 ± 5.1
Serum GDM: 25.1 ± 3.6 Control: 26.6 ± 2.1
WB GDM: 34.0 (29.0–38.0) Control: 29.0(25.0–31.0)
NDDG
ELISA
Serum GDM: 22.9 ± 3.1 Control: 17.9 ± 3.9 GDM#: 20.2 ± 1.5 Control#: 20.3 ± 1.5
NDDG
ELISA
Serum GDM: 42.4 ± 13.8## Control: 32.0 ± 8.7##
Carpenter & Coustan
GDM: 26.1 ± 4.7 Control: 25.9 ± 2.9
EIA
WHO
Serum GDM: 44.1 ± 8.4 Control: 37.8 ± 12.6
NR
Serum GDM: 53.9 ± 17.9 Control: 29.7 ± 13.9
GDM: 26.3 (24.9–30.1) Control: 25.1 (23.5–28.2)
ADA
GDM diagnostic criterion
GDM: 31.1 ± 0.6 Control: 31.1 ± 0.9
ELISA
Assay
Serum GDM: 39.1 ± 6.3 Control: 30.0 ± 10.0
RBP4 levels* (mg/l)
NR
Pregnancy BMI* (kg/m2)
NR
Insulin therapy
Diet control and/or insulin therapy
NR
NR
NR
NR
Diet control
GDM treatments
Age, BMI, BP
Age, BMI, parity
BP, fasting insulin, 1 h insulin, 2 h insulin
Age, pre-pregnant BMI, gestational week, glycosylated hemoglobin
Age, BMI, parity
Age, BMI, ethnicity
Age, BMI
Age, BMI, gestational week
Adjustment
Qi-Tao Huang et al.
Retrospective cohort
Cross-sectional
Case-control
Prospective cohort
Prospective cohort
Cross-sectional
Retrospective cohort
Study type
GDM/ Control
Table 1. Characteristics of studies of GDM versus control on RBP4.
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2011
2010
2013
2013
2012
Kuzmicki et al. [25]
Maghbooli et al. [26]
Nanda et al. [27]
Abetew et al. [28]
Khovidhunkit et al.[29]
Retrospective cohort
Case-control
Case-control
Case-control
Prospective cohort
Prospective cohort
Thailand
USA
UK
Iran
Poland
Mexico
171/361
173/187
60/240
92/100
68/68
60/60
24–32
13–19
11–13
24–28
24–30
30
GDM: 33.0 (29.0–37.0) Control: 33.0 (28.0–36.0)
GDM: 34.2 ± 4.6 Control: 33.0 ± 4.3
GDM: 32.0 (28.5–35.6) Control: 33.0 (27.3–35.9)
GDM: 32.5 ± 5.2** Control: 27.9 ± 7.1
GDM: 29.5 (27.0–33.0) Control: 29.5 (27.0–31.5)
GDM: 31.9 ± 5.6** Control: 24.8 ± 6.4
GDM#: 23.1 (20.6–26.2) Control#: 21.9 (19.9–25.3)
GDM#: 26.6 ± 6.5 Control#: 23.4 ± 5.1 Serum GDM: 36.0 ± 10.4 Control: 35.6 ± 10.9
Serum GDM: 47.1 ± 30.0 Control: 41.4 ± 21.3
Serum GDM: 13.8 ± 2.4 Control: 12.6 ± 2.2
ELISA
ELISA
ELISA
Carpenter & Coustan
ADA
WHO
WHO
ELISA
Serum GDM: 0.5 ± 0.1 Control: 0.4 ± 0.1
GDM#: 28.2 ± 4.1 Control#: 25.2 ± 3.7 GDM: 28.6 (24.6–34.2) Control: 23.8 (21.7–26.2)
WHO
ADA
EIA
RIA
Serum GDM: 58.1 ± 12.3 Control: 51.0 ± 12.6
Serum GDM: 4.7 ± 1.9 Control: 5.3 ± 1.8
GDM: 27.2 (25.2–30.1) Control: 27.3 (23.1–29.4)
GDM: 30.2 ± 4.9 Control: 28.4 ± 7.3
NR
NR
NR
NR
Diet control or insulin therapy
NR
Age, gestational week, history of macrosomia
Education, smoking, parity, gestational week
Age, parity
None
Age, BMI, parity
Height
GDM: gestational diabetes mellitus; RBP4: retinol-binding protein-4; UK: the United Kingdom; BMI: body Mass Index; EIA: enzyme immunometric assay; ELISA: enzyme linked immuno-sorbent assay; RIA: radio immunoassay; WB: western blot; ADA: American Diabetes Association; WHO: World Health Organization; NDDG: National Diabetes Data Group; BP: blood pressure; GCT: glucose challenge test. * Values are given as mean ± SD or media (interquartile ranges); # Pre-pregnancy BMI; ## ng/ml.
2011
Saucedo et al. [24]
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Table 2. Subgroup analysis of the association between GDM and RBP4.
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Studies Study type Cohort 8 Case-control 4 Cross-sectional 2 Diagnostic criteria of GDM ADA 6 WHO 4 Carpenter & Coustan 2 NDDG 2 Countries Asia 6 Europe 5 North America 3 Maternal age Matched 10 Higher in GDM 4 Maternal BMI Matched 8 Higher in GDM 6 Gestational weeks of RBP4 measurement First trimester 1 Second or early third trimesters 13
GDM
Control
SMD
95%CI
I2
467 360 57
624 562 65
0.37 0.72 0.47
0.07 to 0.67 0.28 to 1.15 1.50 to 2.44
76% 88% 95%
411 235 183 55
397 428 371 55
0.15 0.76 0.06 1.20
0.21 0.46 0.12 0.72
to 0.51 to 1.05 to 0.24 to 1.67
81% 60% 31% 25%
391 248 245
583 411 257
0.78 0.42 0.08
0.30 to 1.26 0.06 to 0.89 0.38 to 0.54
89% 85% 75%
517 367
859 392
0.67 0.08
0.37 to 0.97 0.48 to 0.64
80% 92%
286 598
258 993
0.80 0.16
0.50 to 1.10 0.18 to 0.50
60% 89%
60 824
240 1011
0.53 0.49
0.25 to 0.82 0.21 to 0.77
– 86%
GDM: gestational diabetes mellitus; RBP4: retinol-binding protein-4; BMI: body Mass Index; ADA: American Diabetes Association; WHO: World Health Organization; NDDG: National Diabetes Data Group; SMD: standardized mean difference. Bold values indicate SMD is significant between GDM and the controls (p50.05).
shares several common risk factors including obesity, decreased insulin sensitivity and/or increased insulin resistance with PCOS, women with PCOS also have a greater risk of developing GDM [45]. These data indicated that the two diseases may have similar pathogenesis. Therefore, our observed results of stratification by regions raised the possibility that RBP4 may have a role in the racial differences that exist with GDM. A growing body of evidence suggested that higher circulating concentrations of RBP4 were closely associated with obesity and advanced age [11,14,15,46]. Moreover, several studies showed serum RBP4 levels were increased and positively correlated with body mass index (BMI) in obese non-diabetic and diabetic subjects [47–49]. Prior studies indicated that higher pre-pregnancy maternal BMI and advanced maternal age were associated with increased risk for GDM [50,51]. Therefore, it was proposed that women with GDM were more likely have a higher BMI status and/or advanced age, which might be important confounders in the current study. It should be noted that several studies included in this meta-analysis also reported a higher BMI status and/or older maternal age among the GDM cases [21,24,27,29]. Our findings could avoid these biases, since subgroup analysis of all the studies with matched maternal BMI as well as maternal age still demonstrated higher circulating RBP4 levels in women with GDM when compared with their normal controls. Mounting evidence demonstrated that enhanced systemic insulin resistance played a crucial role in the etiology of GDM [4,5]. Prior studies suggested that women with previous history of GDM were more likely to experience increased subsequent risk for developing type 2 diabetes mellitus in their future life time [52]. One recent study investigated the correlation between serum RBP4 level and various risk factors related to cardiovascular diseases (CVD) and found a strong association between circulating RBP4 levels and various well-established CVD risk factors and suggested RBP4 might serve as an independent predictor of CVD in women [53]. Therefore, it was reasonable to propose that RBP4 might serve as a link between the metabolic dysfunction and increased risk of GDM.
Regarding diagnostic criteria of GDM, the pooled results using the ADA criteria [16,22–24,28] suggested no significant difference between GDM and their normal controls, while the WHO criteria [17,21,25–27] demonstrated that an increased circulating levels of RBP4 in GDM. Although the ADA criteria had higher sensitivity and less strict inclusion criteria when compared with the WHO criteria [54], it also meant that the ADA criteria may contain more mild GDM cases than those diagnosed by the WHO criteria. Since higher levels of RBP4 could be associated with more severe glycemic metabolic dysfunction [11,14,15,46], this may partially explain why the higher circulating levels of RBP4 in GDM were not obvious when using the ADA criteria. As for the Carpenter and Coustan [18,29] as well as the NDDG criteria [19,20], the results seemed still inconclusive, since both the studies number and the sample sizes were limited. In this meta-analysis, although we observed significantly higher levels of RBP4 in women with GDM in the second/third trimesters of pregnancy, only one study investigated this relationship in the first trimester [27], which suggested no significant association between RBP4 concentrations and subsequent increased risk of GDM. Since insufficient data on the first trimester was available, it was still inconclusive whether there was significant difference of circulating RBP4 levels between GDM and their normal controls. Another issue which should be taken into account was that the methods used for RBP4 determination and the possible influences on results. A prior study found that different assays could yield significant different absolute values and magnitudes of serum RBP4 [55]. In this meta-analysis, different methods used for RBP4 determination might contribute to the moderate to high heterogeneity observed among these studies. Therefore, large prospective cohorts were performed in the first trimester, with standardized assays required to confirm whether elevated circulating RBP4 levels during early gestational age were associated with subsequent increased risk of GDM in the future. To the best of our knowledge, this is the first comprehensive systematic review to explore whether women with GDM had
RBP4 levels and GDM
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higher circulating RBP4 levels than the normglycemic pregnant women. Our meta-analysis had some strengths. First of all, both case-control and cohort studies were included to explore the relationships between RBP4 concentrations and risk of GDM, and the significant associations were not influenced by the study designs. Second, our findings could avoid some important potential bias, since results of stratification according to confounders such as maternal age and BMI still demonstrated significantly higher RBP4 concentrations in women with GDM. However, several limitations should also be addressed. First, there were limited studies on the maternal circulating levels of RBP4 in the first trimesters of pregnancy. Thus, we could not address adequately the time course of the alteration in circulating RBP4 levels. Second, heterogeneity among the studies was significant, this could be partly explained by the various assay used for the measurement of RBP4 concentrations in different studies. Third, women with GDM had a higher incidence of developing a series of adverse pregnancy outcomes such as preeclampsia, preterm labor, stillbirth as well as dystocia due to macrosomia [56,57]. However, none of the studies in the current meta-analysis explored whether elevated circulating RBP4 levels were associated with adverse pregnancy outcomes in these population. In conclusion, our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester of pregnancy. In future, prospective cohorts with standardized assay measurement beginning from the first trimester of pregnancy are needed to ascertain the causality between changes in RBP4 concentrations and subsequent increased risk of GDM.
Declaration of interest The authors have no competing interests to declare. This work was supported by the President Grant from Nanfang Hospital (2012C026) to Dr. Qi Tao, Huang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Ethical approval The study was approved by the local Institutional Review Board.
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hyperglycaemia first detected in pregnancy. Diabetes Res Clin Pract 2014;103:364–72. Mutsaerts MA, Groen H, Buiter-Van der Meer A, et al. Effects of paternal and maternal lifestyle factors on pregnancy complications and perinatal outcome. A population-based birth-cohort study: the GECKO Drenthe cohort. Hum Reprod 2014;29:824–34. Carpenter MW. Gestational diabetes, pregnancy hypertension, and late vascular disease. Diabetes Care 2007;30:S246–50. Verier-Mine O. Outcomes in women with a history of gestational diabetes. Screening and prevention of type 2 diabetes: literature review. Diabetes Metab 2010;36:595–616. Ng TW, Watts GF, Barrett PH, et al. Effect of weight loss on LDL and HDL kinetics in the metabolic syndrome: associations with changes in plasma retinol-binding protein-4 and adiponectin levels. Diabetes Care 2007;30:2945–50. Lim S, Choi SH, Jeong IK, et al. Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. J Clin Endocrinol Metab 2008; 93:2263–8. Ost A, Danielsson A, Lide´n M, et al. Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB J 2007;21:3696–704. Reinehr T, Stoffel-Wagner B, Roth CL. Retinol-binding protein 4 and its relation to insulin resistance in obese children before and after weight loss. J Clin Endocrinol Metab 2008;93:2287–93. Yildizhan R, Ilhan GA, Yildizhan B, et al. Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertil Steril 2011;96:246–50. Kim SH, Choi HJ, Im JA. Retinol-binding protein 4 responses during an oral glucose tolerance testing in women with gestational diabetes mellitus. Clin Chim Acta 2008;391:123–5. Lewandowski KC, Stojanovic N, Bienkiewicz M, et al. Elevated concentrations of retinol-binding protein-4 (RBP-4) in gestational diabetes mellitus: negative correlation with soluble vascular cell adhesion molecule-1 (sVCAM-1). Gynecol Endocrinol 2008;24: 300–5. Tepper BJ, Kim YK, Shete V, Shabrova E, Quadro L. Serum retinolbinding protein 4 (RBP4) and retinol in a cohort of borderline obese women with and without gestational diabetes. Clin Biochem 2010; 43:320–3. Chan TF, Chen HS, Chen YC, et al. Increased serum retinol-binding protein 4 concentrations in women with gestational diabetes mellitus. Reprod Sci 2007;14:169–74. Zhaoxia L, Mengkai D, Qin F, Danqing C. Significance of RBP4 in patients with gestational diabetes mellitus: a case-control study of Han Chinese women. Gynecol Endocrinol 2014;30:161–4. Krzyzanowska K, Zemany L, Krugluger W, et al. Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Diabetologia 2008;51:1115–22. Klein K, Bancher-Todesca D, Leipold H, et al. Retinol-binding protein 4 in patients with gestational diabetes mellitus. J Womens Health (Larchmt) 2010;19:517–21. Su YX, Hong J, Yan Q, et al. Increased serum retinol-binding protein-4 levels in pregnant women with and without gestational diabetes mellitus. Diabetes Metab 2010;36:470–5. Saucedo R, Zarate A, Basurto L, et al. Relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in women with gestational diabetes. Arch Med Res 2011; 42:318–23. Kuzmicki M, Telejko B, Wawrusiewicz-Kurylonek N, et al. Retinolbinding protein 4 in adipose and placental tissue of women with gestational diabetes. Gynecol Endocrinol 2011;27:1065–9. Maghbooli Z, Hossein-Nezhad A, Mirzaei K, et al. Association between retinol-binding protein 4 concentrations and gestational diabetes mellitus and risk of developing metabolic syndrome after pregnancy. Reprod Sci 2010;17:196–201. Nanda S, Nikoletakis G, Markova D, et al. Maternal serum retinolbinding protein-4 at 11-13 weeks’ gestation in normal and pathological pregnancies. Metabolism 2013;62:814–9. Abetew DF, Qiu C, Fida NG, et al. Association of retinol binding protein 4 with risk of gestational diabetes. Diabetes Res Clin Pract 2013;99:48–53. Khovidhunkit W, Pruksakorn P, Plengpanich W, Tharavanij T. Retinol-binding protein 4 is not associated with insulin resistance in pregnancy. Metabolism 2012;61:65–9.
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30. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:W65–9425. 31. Wells G, Shea B, O’Connell J, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalysis. [updated 2011]. Available from: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp. 32. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60. 33. Egger M, Smith GD. Bias in location and selection of studies. BMJ 1998;316:61–8. 34. Fruscalzo A, Biasioli A, Londero AP, et al. Retinol binding protein as early marker of fetal growth restriction in first trimester maternal serum. Gynecol Endocrinol 2013;29:323–6. 35. Masuyama H, Inoue S, Hiramatsu Y. Retinol-binding protein 4 and insulin resistance in preeclampsia. Endocr J 2011;58:47–53. 36. Deng W, Zhang Y, Zheng Y, et al. Serum retinol-binding protein 4 levels are elevated but do not contribute to insulin resistance in newly diagnosed Chinese hypertensive patients. Diabetol Metab Syndr 2014;6:72. 37. Sun L, Qi Q, Zong G, et al. Elevated plasma retinol-binding protein 4 is associated with increased risk of type 2 diabetes in middle-aged and elderly Chinese adults. J Nutr 2014;144:722–8. 38. Yan H, Chang X, Xia M, et al. Serum retinol binding protein 4 is negatively related to beta cell function in Chinese women with nonalcoholic fatty liver disease: a cross-sectional study. Lipids Health Dis 2013;12:157. 39. Go´mez-Ambrosi J, Rodrı´guez A, Catala´n V, et al. Serum retinolbinding protein 4 is not increased in obesity or obesity-associated type 2 diabetes mellitus, but is reduced after relevant reductions in body fat following gastric bypass. Clin Endocrinol (Oxf) 2008;69: 208–15. 40. Takebayashi K, Suetsugu M, Wakabayashi S, et al. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin Endocrinol Metab 2007;92:2712–19. 41. Lucarini N, Gerlini G, Palmarino R, et al. Is there a genetic basis for gestational diabetes? Hum Biol 1994;66:715–23. 42. Kim C. Gestational diabetes mellitus in Korean women: similarities and differences from other racial/ethnic groups. Diabetes Metab J 2014;38:1–12. 43. Kim SY, Sappenfield W, Sharma AJ, et al. Racial/ethnic differences in the prevalence of gestational diabetes mellitus and maternal overweight and obesity, by nativity, Florida, 2004–2007. Obesity (Silver Spring) 2013;21:E33–40. 44. Jia J, Bai J, Liu Y, et al. Association between retinol-binding protein 4 and polycystic ovary syndrome: a meta-analysis. Endocr J 2014;61:995–1002.
45. Toulis KA, Goulis DG, Kolibianakis EM, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril 2009;92: 667–77. 46. Luft VC, Pereira M, Pankow JS, et al.; ARIC Investigators. Retinol binding protein 4 and incident diabetes—the Atherosclerosis Risk in Communities Study (ARIC Study). Rev Bras Epidemiol 2013;16: 388–97. 47. Friebe D, Neef M, Erbs S, et al. Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. Int J Pediatr Obes 2011;6:e345–52. 48. Chiba M, Saitoh S, Ohnishi H, et al. Associations of metabolic factors, especially serum retinol-binding protein 4 (RBP4), with blood pressure in Japanese – the Tanno and Sobetsu study. Endocr J 2010;57:811–7. 49. Goodman E, Graham TE, Dolan LM, et al. The relationship of retinol binding protein 4 to changes in insulin resistance and cardiometabolic risk in overweight black adolescents. J Pediatr 2009;154:67–73. 50. Di Cianni G, Volpe L, Lencioni C, et al. Prevalence and risk factors for gestational diabetes assessed by universal screening. Diabetes Res Clin Pract 2003;62:131–7. 51. Shirazian N, Emdadi R, Mahboubi M, et al. Screening for gestational diabetes: usefulness of clinical risk factors. Arch Gynecol Obstet 2009;280:933–7. 52. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995;44:586–91. 53. Alkharfy KM, Al-Daghri NM, Vanhoutte PM, et al. Serum retinolbinding protein 4 as a marker for cardiovascular disease in women. PLoS One 2012;7:e48612. 54. Santos-Ayarzagoitia M, Salinas-Martı´nez AM, Villarreal-Pe´rez JZ. Gestational diabetes: Validity of ADA and WHO diagnostic criteria using NDDG as the reference test. Diabetes Res Clin Pract 2006;74: 322–8. 55. Graham TE, Wason CJ, Blu¨her M, Kahn BB. Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects. Diabetologia 2007;50:814–23. 56. Hartling L, Dryden DM, Guthrie A, et al. Benefits and harms of treating gestational diabetes mellitus: a systematic review and metaanalysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med 2013;159:123–9. 57. Schneider S, Freerksen N, Ro¨hrig S, et al. Gestational diabetes and preeclampsia – similar risk factor profiles? Early Hum Dev 2012;88: 179–84.
Supplementary material available online Supplementary Figure S1 and Table S1
REVIEW ARTICLE
Circulating retinol-binding protein 4 levels in gestational diabetes mellitus: a meta-analysis of observational studies Qi-Tao Huang1,2, Qiong Huang1, Wei Luo1, Fei Li1, Li-Lin Hang1, Yan-Hong Yu1, and Mei Zhong1 Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China and 2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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Abstract
Keywords
Retinol-binding protein 4 (RBP4) is a novel adipocyte-derived cytokine playing an important role in the regulation of energy metabolism and insulin sensitivity. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of gestational diabetes mellitus (GDM) have yielded inconclusive results. We performed a meta-analysis to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women. PubMed, Web of Science and EMBASE were searched up to 1 August 2014. A total of 14 studies comprised of 884 women with GDM and 1251 normglycemic pregnant women were included. The overall results suggested that maternal circulating RBP4 levels were significantly higher in GDM than their normal controls (SMD: 0.49 mg/ml, 95% CI: 0.23–0.75 mg/ml, p50.001, random effect model). However, stratified results indicated that this significant difference only existed in the second/third trimester and was limited to Asian populations. Furthermore, subgroup analysis according to matched maternal age and BMI still demonstrated that GDM had higher circulating RBP4 levels than the normal controls. Our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester.
Diabetes, gestational diabetes mellitus, insulin resistance, pregnancy, retinol-binding protein 4
Introduction Gestational diabetes mellitus (GDM), characterized by glucose intolerance with onset or first recognition during pregnancy, is one of the most common obstetrical complications. It is estimated that GDM affects 1–14% of all pregnancies depending on the population and the diagnostic criteria [1–3]. Although extensive research was performed, the precise mechanism responsible for the pathogenesis of GDM is still not completely understood. Mounting evidence demonstrated that enhanced systemic insulin resistance played a crucial role in the etiology of GDM [4,5]. Previous studies also suggested that women with obesity, metabolic syndrome or polycystic ovary syndrome had a significantly higher risk of developing GDM when they were pregnant [6–8]. Furthermore, it is generally accepted that women with previous history of GDM were more likely to experience increased subsequent risk for developing impaired glucose tolerance, type 2 diabetes mellitus, metabolic syndrome as well as cardiovascular diseases [9,10]. Currently, a growing body of research found that a novel adipocyte-derived cytokine known as retinol-binding protein 4 (RBP4) might play an important role in the regulation of energy metabolism and insulin sensitivity [11,12]. Previous evidence from animal experiments and clinical studies showed that increased circulating RBP4 levels could lead to impaired skeletal muscular glucose uptake and increased hepatic glucose Address for correspondence: Mei Zhong, Professor of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, P.R. China. Fax: +86-020-62787-560. E-mail: [email protected]
History Received 18 October 2014 Revised 20 December 2014 Accepted 6 January 2015 Published online 23 February 2015
production through insulin receptor subtrate-1 and phosphoinositide 3-kinase activation [13]. Recently, mounting evidence demonstrated higher circulating levels of RBP4 in patients with obesity, metabolic syndrome as well as type 2 diabetes [14,15]. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of GDM have yielded inconclusive results [16–29]. For instance, several studies suggested significantly enhanced serum levels of RBP4 in GDM [16,17,19,20,23,25–29], while some reports showed decreased or no different RBP4 concentrations between GDM serum specimen compared with those of controls [18,21,22,24,29]. As the association between RBP4 and GDM were far from clear, we performed a meta-analysis to systematically review the current literature to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women.
Methods The present meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) guidelines [30]. Search strategy and data sources Three electronic databases (PubMed, Web of Science and EMBASE) were searched up to August 1st, 2014 using the combinations of terms ‘‘GDM’’ or ‘‘gestational diabetes’’ or ‘‘diabetes’’ or ‘‘pregnancy’’ and ‘‘RBP4’’ or ‘‘retinol-binding protein’’ or ‘‘adipokine’’. We sifted through potentially relevant articles, firstly by titles and abstracts, and then we retrieved the
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full texts of articles for detailed review. Further, we scanned the reference lists of the articles that met the inclusion criteria in our analysis, and searched for those articles or citations in Google Scholar and Google to obtain additional studies. Inclusion and exclusion criteria Original case-control or cohort studies comparing serum/plasma RBP4 levels in pregnant women with GDM as well as healthy pregnant women were included. Studies which did not report the absolute RBP4 concentrations and/or an indication of the variation (demonstrated as standard error, standard deviation or interquartile range) in their original data were excluded from this meta-analysis. For multiple publications based on the same population, only the study with the latest or the most complete data were selected.
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Data extraction A form designed a priori was used to extract the information from the included studies. Two independent investigators performed the data extraction. Concentrations of serum/plasma RBP4 were the main exposure and GDM was the primary outcome. The following information was recorded: first author’s last name; year of publication; study location; number of GDM and controls; covariates adjusted for in the analysis. Assessment of methodological quality Two independent investigators assessed the quality of each study included using the Newcastle-Ottawa Quality Assessment Scale (NOS) (Table S1) [31]. Studies of low, intermediate and high quality were defined with NOS scores of 1–3, 4–6 and 7–9 in the meta-analysis, respectively. Statistical analysis The results were presented as the standardized mean difference (SMD) and 95% confident interval (95% CI) to estimate the size of the effect. Studies were weighted with consideration of both the sample size and the standard deviation. The SMDs were combined in a meta-analysis using a fixed-effects model when heterogeneity observed among studies was absent to moderate. When heterogeneity was high (I2450%), a random-effects model was used. Heterogeneity among these studies was evaluated by two parameters. p50.10 for the Cochran’s Q test or I2450% for Higgins statistic were regarded statistically significant heterogeneity [32]. The publication bias was investigated by two methods. Visual detection was used to analyze the funnel plots. Quantitative analysis was performed by the Begg’s regression asymmetry test [33]. Subgroup analysis was performed with respect to study type, diagnostic criteria of GDM, countries, maternal age as well as maternal BMI in order to explore the influence of these factors on the association.
Results Selection flow and Study characteristics The detailed search procedures were demonstrated in Figure 1. Full texts of 19 identified articles were retrieved for further assessment. Five of these articles were excluded because 2 studies explored serum RBP4 concentrations between women with previous history of GDM and their normal controls and three studies investigated the cord blood, adipose tissues or placental other than circulating concentrations in women with GDM as well as their controls (Figure 2). Finally, the remaining 14 independent articles were used for this meta-analysis. The main characteristics of the included studies are presented in Table 1. According to the NOS scoring, three of the 14 studies selected in this meta-analysis
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were of intermediate quality [21,24,26], and 11 studies were of high quality [16–20,22,23,25,27–29]. None of the studies included were of low quality (Table S1). Main results A total of 14 studies comprised of 884 women with GDM and 1251 normoglycemic pregnant women were included. In a pooled analysis of all studies, the results indicated that maternal circulating level of RBP4 was significantly higher in women with GDM than their normal controls (SMD: 0.49 mg/ml, 95% CI: 0.23–0.75 mg/ml, p50.001, random effect model) with significant heterogeneity among these studies (Q ¼ 89.17, I2 ¼ 85%, p50.001) Subgroup analysis An analysis of the results according to study type (cohort [16,18,19,22–25,29], case-control [20,26–28] or Cross-section [17,21]), diagnostic criteria of GDM (ADA [16,22–24,28], WHO [17,21,25–27], Carpenter & Coustan [18,29] or NDDG [19,20]), countries (Asia [16,19,20,23,26,29], Europe [17,21,22,25,27] or North America [18,24,28]), maternal age (matched [16–20,22, 23,25,27,29] or higher in GDM [21,24,26,29]), maternal BMI (matched [16–20,22,23,25] or higher in GDM [21,24,26–29]) and gestational weeks of RBP4 measurement (first trimester [27] or second or early third trimesters [16–26,28,29]) are summarized in Table 2. Stratification by countries indicated that circulating RBP4 levels were higher in patients with GDM in Asia than their normal controls (SMD: 0.78 mg/ml, 95%CI: 0.30–1.26 mg/ml), while no significant difference of circulating RBP4 levels were observed when patients with GDM were compared to their normal controls in non-Asian population. Moreover, subgroup analysis according to matched maternal age and BMI still demonstrated that women with GDM had higher circulating RBP4 levels than their normal controls (SMD: 0.67 mg/ml, 95%CI: 0.37– 0.97 mg/ml) and (SMD: 0.80 mg/ml, 95%CI: 0.50–1.10 mg/ml), respectively. Publication bias The publication bias was investigated by Begg’s funnel plot (Figure S1). The shape of this funnel plot was symmetrical, indicating a low probability of publication bias (p ¼ 0.381).
Discussion While elevated maternal circulating RBP4 levels has been associated with increased rate of obstetrical complications such as preeclampsia and fetal growth restriction [34,35], one intriguing observation was regarding the occurrence of GDM. Previous reports on the association between circulating RBP4 levels and the risk of GDM have yielded inconsistent results. Although the overall pooled results indicated that circulating levels of RBP4 were significantly higher in women with GDM than their normal controls, these results should be interpreted with caution, since subgroup analysis with respect to studies locations suggested that this observation was limited to Asian population [16,19,20,23,26,29]. And no significant differences of serum RBP4 levels were found between women with GDM and their control from European [17,21,22,25,27] or North American countries [18,24,28]. Previously, several studies reported elevated plasma RBP4 was associated with increased risk of insulin resistance and type 2 diabetes in Asian population [36–38], whereas some clinical studies demonstrated lack of association between plasma RBP4 levels and increased risk of insulin resistance as well as type 2 diabetes in non-Asian population [39,40]. Previous studies
RBP4 levels and GDM
Idenficaon
DOI: 10.3109/09513590.2015.1005594
Records idenfied through database searching (n =527)
3
Addional records idenfied through other sources (n =4)
Eligibility
Records screened (n = 62)
Records excluded (n =43)
Full-text arcles assessed for eligibility (n =19)
Full-text arcles excluded with reasons* (n =5)
Studies included in qualitave synthesis (n =14)
Included
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Screening
Records aer duplicates removed (n =208)
Studies included in quantave synthesis (meta-analysis) (n =14)
Exclusions *Reasons:
Serum RBP4 levels in women with previous history of GDM (N=2). Cord blood, adipose ssues or placenta levels of RBP4 in women with GDM (N=3)
Figure 1. Flow chart of the literature search and article selection.
Figure 2. Forest plot of standardized mean differences in circulating RBP4 between women with gestational diabetes mellitus and normal controls for all the studies included in the meta-analysis.
suggested GDM has a strong genetic basis [41]. Under the influence of environment, lifestyles, and genetic factors, the association between RBP4 and the pathophysiology of GDM might vary in different regions [42,43]. A very recent meta-analysis
investigated the association between RBP4 and polycystic ovary syndrome (PCOS), which [44] seemed to support our hypothesis by demonstrating that RBP4 levels were higher in PCOS patients in Asian countries, but not in European countries. Since GDM
Year
2008
2008
2010
2007
2014
2008
2010
2010
Author
Kim et al. [16]
Lewandowski et al. [17]
Tepper et al. [18]
Chan et al. [19]
Liang et al. [20]
Krzyzanowska et al. [21]
Klein et al. [22]
Su et al. [23]
Retrospective cohort
China
Austria
Austria
China
China
USA
UK
South Korea
Location
63/58
63/38
42/45
35/35
20/20
12/10
15/20
10/9
24–29
24–28
29
24–27
24 28
24–28
28
24–28
Gestation age for RBP4 measurement (weeks)
GDM: 28.8 ± 1.8 Control: 28.4 ± 2.4
GDM: 32.7 ± 5.2 Control: 33.3 ± 4.8
GDM: 33.0 (29.0–35.0) Control: 28 (24–34)
GDM: 29.0 ± 2.5 Control: 29.3 ± 3.1
GDM: 32.7 ± 5.0 Control: 32.7 ± 5.0
GDM: 28.6 ± 4.9 Control: 28.8 ± 6.2
GDM: 34.0 (29.0–36.0) Control: 32.0 (29.0–35.0)
GDM: 32.6 ± 3.0 Control: 32.6 ± 3.3
Age* (years)
ADA
ADA
ADA
ELISA
ELISA GDM: 25.5 ± 2.6 Control: 24.9 ± 2.1
GDM: 27.7 ± 5.6 Control: 28.1 ± 6.2
Serum GDM: 41.6 ± 12.2 Control: 34.5 ± 9.8
Serum GDM: 18.0 ± 3.7 Control: 16.9 ± 5.1
Serum GDM: 25.1 ± 3.6 Control: 26.6 ± 2.1
WB GDM: 34.0 (29.0–38.0) Control: 29.0(25.0–31.0)
NDDG
ELISA
Serum GDM: 22.9 ± 3.1 Control: 17.9 ± 3.9 GDM#: 20.2 ± 1.5 Control#: 20.3 ± 1.5
NDDG
ELISA
Serum GDM: 42.4 ± 13.8## Control: 32.0 ± 8.7##
Carpenter & Coustan
GDM: 26.1 ± 4.7 Control: 25.9 ± 2.9
EIA
WHO
Serum GDM: 44.1 ± 8.4 Control: 37.8 ± 12.6
NR
Serum GDM: 53.9 ± 17.9 Control: 29.7 ± 13.9
GDM: 26.3 (24.9–30.1) Control: 25.1 (23.5–28.2)
ADA
GDM diagnostic criterion
GDM: 31.1 ± 0.6 Control: 31.1 ± 0.9
ELISA
Assay
Serum GDM: 39.1 ± 6.3 Control: 30.0 ± 10.0
RBP4 levels* (mg/l)
NR
Pregnancy BMI* (kg/m2)
NR
Insulin therapy
Diet control and/or insulin therapy
NR
NR
NR
NR
Diet control
GDM treatments
Age, BMI, BP
Age, BMI, parity
BP, fasting insulin, 1 h insulin, 2 h insulin
Age, pre-pregnant BMI, gestational week, glycosylated hemoglobin
Age, BMI, parity
Age, BMI, ethnicity
Age, BMI
Age, BMI, gestational week
Adjustment
Qi-Tao Huang et al.
Retrospective cohort
Cross-sectional
Case-control
Prospective cohort
Prospective cohort
Cross-sectional
Retrospective cohort
Study type
GDM/ Control
Table 1. Characteristics of studies of GDM versus control on RBP4.
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2011
2010
2013
2013
2012
Kuzmicki et al. [25]
Maghbooli et al. [26]
Nanda et al. [27]
Abetew et al. [28]
Khovidhunkit et al.[29]
Retrospective cohort
Case-control
Case-control
Case-control
Prospective cohort
Prospective cohort
Thailand
USA
UK
Iran
Poland
Mexico
171/361
173/187
60/240
92/100
68/68
60/60
24–32
13–19
11–13
24–28
24–30
30
GDM: 33.0 (29.0–37.0) Control: 33.0 (28.0–36.0)
GDM: 34.2 ± 4.6 Control: 33.0 ± 4.3
GDM: 32.0 (28.5–35.6) Control: 33.0 (27.3–35.9)
GDM: 32.5 ± 5.2** Control: 27.9 ± 7.1
GDM: 29.5 (27.0–33.0) Control: 29.5 (27.0–31.5)
GDM: 31.9 ± 5.6** Control: 24.8 ± 6.4
GDM#: 23.1 (20.6–26.2) Control#: 21.9 (19.9–25.3)
GDM#: 26.6 ± 6.5 Control#: 23.4 ± 5.1 Serum GDM: 36.0 ± 10.4 Control: 35.6 ± 10.9
Serum GDM: 47.1 ± 30.0 Control: 41.4 ± 21.3
Serum GDM: 13.8 ± 2.4 Control: 12.6 ± 2.2
ELISA
ELISA
ELISA
Carpenter & Coustan
ADA
WHO
WHO
ELISA
Serum GDM: 0.5 ± 0.1 Control: 0.4 ± 0.1
GDM#: 28.2 ± 4.1 Control#: 25.2 ± 3.7 GDM: 28.6 (24.6–34.2) Control: 23.8 (21.7–26.2)
WHO
ADA
EIA
RIA
Serum GDM: 58.1 ± 12.3 Control: 51.0 ± 12.6
Serum GDM: 4.7 ± 1.9 Control: 5.3 ± 1.8
GDM: 27.2 (25.2–30.1) Control: 27.3 (23.1–29.4)
GDM: 30.2 ± 4.9 Control: 28.4 ± 7.3
NR
NR
NR
NR
Diet control or insulin therapy
NR
Age, gestational week, history of macrosomia
Education, smoking, parity, gestational week
Age, parity
None
Age, BMI, parity
Height
GDM: gestational diabetes mellitus; RBP4: retinol-binding protein-4; UK: the United Kingdom; BMI: body Mass Index; EIA: enzyme immunometric assay; ELISA: enzyme linked immuno-sorbent assay; RIA: radio immunoassay; WB: western blot; ADA: American Diabetes Association; WHO: World Health Organization; NDDG: National Diabetes Data Group; BP: blood pressure; GCT: glucose challenge test. * Values are given as mean ± SD or media (interquartile ranges); # Pre-pregnancy BMI; ## ng/ml.
2011
Saucedo et al. [24]
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Table 2. Subgroup analysis of the association between GDM and RBP4.
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Studies Study type Cohort 8 Case-control 4 Cross-sectional 2 Diagnostic criteria of GDM ADA 6 WHO 4 Carpenter & Coustan 2 NDDG 2 Countries Asia 6 Europe 5 North America 3 Maternal age Matched 10 Higher in GDM 4 Maternal BMI Matched 8 Higher in GDM 6 Gestational weeks of RBP4 measurement First trimester 1 Second or early third trimesters 13
GDM
Control
SMD
95%CI
I2
467 360 57
624 562 65
0.37 0.72 0.47
0.07 to 0.67 0.28 to 1.15 1.50 to 2.44
76% 88% 95%
411 235 183 55
397 428 371 55
0.15 0.76 0.06 1.20
0.21 0.46 0.12 0.72
to 0.51 to 1.05 to 0.24 to 1.67
81% 60% 31% 25%
391 248 245
583 411 257
0.78 0.42 0.08
0.30 to 1.26 0.06 to 0.89 0.38 to 0.54
89% 85% 75%
517 367
859 392
0.67 0.08
0.37 to 0.97 0.48 to 0.64
80% 92%
286 598
258 993
0.80 0.16
0.50 to 1.10 0.18 to 0.50
60% 89%
60 824
240 1011
0.53 0.49
0.25 to 0.82 0.21 to 0.77
– 86%
GDM: gestational diabetes mellitus; RBP4: retinol-binding protein-4; BMI: body Mass Index; ADA: American Diabetes Association; WHO: World Health Organization; NDDG: National Diabetes Data Group; SMD: standardized mean difference. Bold values indicate SMD is significant between GDM and the controls (p50.05).
shares several common risk factors including obesity, decreased insulin sensitivity and/or increased insulin resistance with PCOS, women with PCOS also have a greater risk of developing GDM [45]. These data indicated that the two diseases may have similar pathogenesis. Therefore, our observed results of stratification by regions raised the possibility that RBP4 may have a role in the racial differences that exist with GDM. A growing body of evidence suggested that higher circulating concentrations of RBP4 were closely associated with obesity and advanced age [11,14,15,46]. Moreover, several studies showed serum RBP4 levels were increased and positively correlated with body mass index (BMI) in obese non-diabetic and diabetic subjects [47–49]. Prior studies indicated that higher pre-pregnancy maternal BMI and advanced maternal age were associated with increased risk for GDM [50,51]. Therefore, it was proposed that women with GDM were more likely have a higher BMI status and/or advanced age, which might be important confounders in the current study. It should be noted that several studies included in this meta-analysis also reported a higher BMI status and/or older maternal age among the GDM cases [21,24,27,29]. Our findings could avoid these biases, since subgroup analysis of all the studies with matched maternal BMI as well as maternal age still demonstrated higher circulating RBP4 levels in women with GDM when compared with their normal controls. Mounting evidence demonstrated that enhanced systemic insulin resistance played a crucial role in the etiology of GDM [4,5]. Prior studies suggested that women with previous history of GDM were more likely to experience increased subsequent risk for developing type 2 diabetes mellitus in their future life time [52]. One recent study investigated the correlation between serum RBP4 level and various risk factors related to cardiovascular diseases (CVD) and found a strong association between circulating RBP4 levels and various well-established CVD risk factors and suggested RBP4 might serve as an independent predictor of CVD in women [53]. Therefore, it was reasonable to propose that RBP4 might serve as a link between the metabolic dysfunction and increased risk of GDM.
Regarding diagnostic criteria of GDM, the pooled results using the ADA criteria [16,22–24,28] suggested no significant difference between GDM and their normal controls, while the WHO criteria [17,21,25–27] demonstrated that an increased circulating levels of RBP4 in GDM. Although the ADA criteria had higher sensitivity and less strict inclusion criteria when compared with the WHO criteria [54], it also meant that the ADA criteria may contain more mild GDM cases than those diagnosed by the WHO criteria. Since higher levels of RBP4 could be associated with more severe glycemic metabolic dysfunction [11,14,15,46], this may partially explain why the higher circulating levels of RBP4 in GDM were not obvious when using the ADA criteria. As for the Carpenter and Coustan [18,29] as well as the NDDG criteria [19,20], the results seemed still inconclusive, since both the studies number and the sample sizes were limited. In this meta-analysis, although we observed significantly higher levels of RBP4 in women with GDM in the second/third trimesters of pregnancy, only one study investigated this relationship in the first trimester [27], which suggested no significant association between RBP4 concentrations and subsequent increased risk of GDM. Since insufficient data on the first trimester was available, it was still inconclusive whether there was significant difference of circulating RBP4 levels between GDM and their normal controls. Another issue which should be taken into account was that the methods used for RBP4 determination and the possible influences on results. A prior study found that different assays could yield significant different absolute values and magnitudes of serum RBP4 [55]. In this meta-analysis, different methods used for RBP4 determination might contribute to the moderate to high heterogeneity observed among these studies. Therefore, large prospective cohorts were performed in the first trimester, with standardized assays required to confirm whether elevated circulating RBP4 levels during early gestational age were associated with subsequent increased risk of GDM in the future. To the best of our knowledge, this is the first comprehensive systematic review to explore whether women with GDM had
RBP4 levels and GDM
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DOI: 10.3109/09513590.2015.1005594
higher circulating RBP4 levels than the normglycemic pregnant women. Our meta-analysis had some strengths. First of all, both case-control and cohort studies were included to explore the relationships between RBP4 concentrations and risk of GDM, and the significant associations were not influenced by the study designs. Second, our findings could avoid some important potential bias, since results of stratification according to confounders such as maternal age and BMI still demonstrated significantly higher RBP4 concentrations in women with GDM. However, several limitations should also be addressed. First, there were limited studies on the maternal circulating levels of RBP4 in the first trimesters of pregnancy. Thus, we could not address adequately the time course of the alteration in circulating RBP4 levels. Second, heterogeneity among the studies was significant, this could be partly explained by the various assay used for the measurement of RBP4 concentrations in different studies. Third, women with GDM had a higher incidence of developing a series of adverse pregnancy outcomes such as preeclampsia, preterm labor, stillbirth as well as dystocia due to macrosomia [56,57]. However, none of the studies in the current meta-analysis explored whether elevated circulating RBP4 levels were associated with adverse pregnancy outcomes in these population. In conclusion, our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester of pregnancy. In future, prospective cohorts with standardized assay measurement beginning from the first trimester of pregnancy are needed to ascertain the causality between changes in RBP4 concentrations and subsequent increased risk of GDM.
Declaration of interest The authors have no competing interests to declare. This work was supported by the President Grant from Nanfang Hospital (2012C026) to Dr. Qi Tao, Huang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Ethical approval The study was approved by the local Institutional Review Board.
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Supplementary material available online Supplementary Figure S1 and Table S1
