Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis
Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis
Fei-Juan Kong 0 1 2
Lei-Lei Ma 0 1
Ge Li 0 1 2
Yi-Xin Chen 0 1 2
Jia-Qiang Zhou 0 1 2
☯ These authors contributed equally to this work. 0 1
@zju.edu.cn 0 1
0 Natural Science Foundation of China (No. 81301608), National Natural Science Foundation of China (No. 81401633), Zhejiang Provincial Natural Science Foundation of China (No. LY14H150005) and Zhejiang Provincial Medical Technology Foundation of China , No. 2014KYA171
1 Editor: Cheng Hu, Shanghai Diabetes Institute , CHINA
2 Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University , Hangzhou , China , 2 Department of Critical Care Medicine, Zhejiang Provincial People's Hospital , Hangzhou , China , 3 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University , Shanghai , China
The evidences from this meta-analysis indicated that the levels of circulating betatrophin
were significantly elevated among women with GDM compared with women with normal
glucose tolerance, especially with BMI 28 kg/m2 and in the third trimester.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Competing Interests: The authors have declared
that no competing interests exist.
Gestational diabetes mellitus (GDM), one of the most common pregnancy complications, is
described as impaired glucose tolerance that begins or is initially recognized during pregnancy.
As patients suffering from GDM usually do not present any clinical symptom, GDM screening
has become a routine prenatal project during the second trimester of pregnancy nowadays.
During the last few decades, GDM affects up to 14% of all pregnancies depending on different
diagnostic criteria and ethnic origin [
]. GDM not only increases maternal incidence of type 2
diabetes mellitus (T2DM) and metabolic syndrome at follow-up, but also will be associated
with various adverse acute outcomes and long-term metabolic derangements in offspring [2±
5]. However, the underline mechanisms of GDM remain unclear.
Betatrophin, a newly identified circulatory hormone, which is predominantly secreted by
liver and adipose tissue in mice, but primarily expressed in the liver in humans, has been
reported to be involved in glucose and lipid metabolism [6±8]. Betatrophin is attracting
increasing attention due to its role in promoting pancreatic β-cell proliferation and improving
glucose tolerance. Recent study has suggested that overexpression of betatrophin in mouse
liver led to an elevated proliferation of pancreatic β-cell and a compensatory expansion of
βcell mass in an insulin resistance mouse model induced by insulin receptor antagonist S961 [
]. Moreover, observational studies in human beings also demonstrated that the alteration of
betatrophin was linked to several health conditions, including obesity, T2DM [
GDM [13±20]. The scientific evidence linking betatrophin with T2DM or obesity is growing
large, but data investigating the correlation between betatrophin status and GDM are
controversial. In this regard, some studies reported that women with GDM showed higher
concentrations of betatrophin compared to healthy pregnant women [13±18, 20], while Huang et al
showed the contrary [
]. Whereas the potential causes of these conflicting results were poorly
In order to provide a more comprehensive estimation of the association between
betatrophin levels in blood and GDM, we performed a systematic review and meta-analysis on related
studies aiming for getting a more persuasive conclusion.
Our review followed the Meta-Analyses and Systematic Reviews of Observational Studies
(MOOSE) guidelines [
]. The data were presented according to the recommendations of the
PRISMA statement [
A systematic search of studies was performed on the association of betatrophin levels and
GDM in the published databases in English of PubMed, The Cochrane Library, Medline and
in Chinese of CNKI (Chinese National Knowledge Infrastructure) up to August 2016. The
search strategy included key terms that were summarized as follows: ªbetatrophinº,
ªANGPTL8º, ªlipasinº, ªC19ORF80º, ªTD26º, ªRIFLº, ªgestational diabetes mellitusº,
ªGDMº, ªdiabetes pregnancyº, ªinsulin gestationº. References from these relevant studies
were manually searched.
Inclusion and exclusion criteria
Studies were considered eligible if they met the following criteria: (1) case-control studies
comparing circulating betatrophin levels in GDM women and healthy pregnant controls; (2) all
participants did not have a previous history of diabetes or present pregnant complications;
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(3) full-text articles were published in English or Chinese. Studies were excluded if they were
(1) available only as abstracts, review studies, case reports, expert comment, or editor opinion,
(2) experimentation on animals or in vitro; (3) predefined outcome data required for analyses
Data extraction and quality evaluation
Two reviewers (FJ Kong and LL Ma) independently reviewed all searched studies and
extracted data using a predefined form. If there was a discrepancy, a discussion was carried out
to reach an agreement. If a consensus could not be reached, a third experienced investigator
(JQ Zhou) was consulted. The following information of each study was recorded: first author,
year of publication, country of the study, sample source, assay method of betatrophin, sample
size of the case and control group, mean and standard deviation (SD) (part of the data were
converted) of betatrophin levels, trimester of betatrophin level measurement, and mean and
SD of age and body mass index (BMI) of GDM women.
The individual study quality was assessed according to the Cochrane collaboration's tool
for risk of bias, which contains random sequence generation, allocation concealment,
blindness, incomplete outcome data, selective outcome reporting, and other biases.
Standard mean difference (SMD) and 95% confidence interval (95% CI) were calculated to
assess the differences in betatrophin levels between groups. Significance levels were
determined by Z test. Forest plots were used to demonstrate effect sizes and their CI. Heterogeneity
amongst the included studies was assessed by Cochran's Q statistics and I2 statistics. According
to heterogeneity inspection results, corresponding pooled method was chosen: if I2 > 50%,
random effect model was used; while I2 50%, fixed effect model was adapted. We also did
subgroup analyses to explore the potential source of heterogeneity if heterogeneity across
studies was statistically significant. Potential publication bias was evaluated using Begg's test and
Egger's test. Sensitivity analysis was carried out by sequentially omitting one single study each
time to test the robustness of uncertainty in the meta-analysis. All data were analyzed with
Review Manager (RevMan 5.3) statistical software provided by The Cochrane Collaboration
and Stata 12.0 (Stata Corp, College Station, TX, USA). The significance level was set as 0.05,
except Cochran's Q test for heterogeneity as 0.1.
A flow diagram of the included and excluded studies was shown in Fig 1. According to the
search strategy, 25 citations were identified from the four databases. After removing the
duplicates (n = 10), two reviewers screened the titles and abstracts of potentially relevant studies
(n = 15) independently. Finally, a total of 8 studies were included for meta-analysis [13±20].
Characteristics and quality assessment of study
All included studies published from 2015 to 2016 were designed as case-control studies
including 401 GDM patients and 421 healthy pregnant women. The characteristics of the studies
included in the present meta-analysis were shown in Table 1. Of the 8 included studies, three
were carried out in Turkey [
13, 17, 20
], two in China [
], one in Austria , one in
Poland  and one in German [
]. The sample size of these studies ranged from 21 to 97.
Three of the included studies involved in the GDM women with BMI < 28 kg/m2 [
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Fig 1. Flow diagram of study recruiting.
the rest five with BMI 28 kg/m2 [13, 15±18]. Blood samples for betatrophin measurement
were collected in the second [
13, 17, 19, 20
] or third [14±16, 18] trimester of gestation. Except
for the study conducted in German that used the American Diabetes Association criteria to
carry out GDM diagnosis, all studies used the criteria suggested by International Association
for Diabetes in Pregnancy Study Group to diagnose GDM.
The assessment on the quality of the included studies was shown in Fig 2.
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Fig 2. Risk of bias graph. The Cochrane collaboration's tool was used to evaluate risk of bias.
As indicated in Fig 3, the overall levels of circulating betatrophin in GDM patients were higher
than that in the healthy controls with statistical significance (SMD = 1.05; 95% CI: 0.41±1.68,
P = 0.001). The SMDs from the individual studies were analyzed using random-effects models,
as the heterogeneity was considered significant (P < 0.001, I2 = 94%).
No significant publication bias was found in our meta-analysis as indicated in Fig 4 (Begg's
test: P = 0.170; Egger's test: P = 0.190). Sensitivity analysis was performed to explore potential
sources of heterogeneity and assess relevant changes on the combined results. As suggested in
Figs 5 and 6, the estimates effects indicated relevant changes on the combined results by study
Fig 3. Forest plot of circulating betatrophin levels in GDM or healthy pregnant women. The random
effect model (Inverse Variance method) was applied.
Fig 4. Begg's funnel plot of included studies for potential publication bias.
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Fig 5. Sensitivity analysis of the circulating betatrophin levels in GDM or healthy pregnant women.
removals and the study carried out by Huang et al [
] may contribute to the methodological
heterogeneity, ranging the heterogeneity from 94% (P < 0.001) for inclusion to 52% (P =
0.050) for exclusion. After strict screening again, we found that the study did meet the
To investigate the possible sources of heterogeneity and obtain thorough information from
this meta-analysis, subgroup analysis was further carried out. Subgroup analysis was
conducted by geographic site, the trimester of betatrophin measurement, sample and mean of age
and BMI in women with GDM. The comprehensive results were shown in Table 2 and Figs 7
When stratifying by the trimester of betatrophin measurement, these studies were classified
as the second trimester and the third trimester. Four studies conducted in the second and the
rest in third presented a conclusion of heterogeneity (second: P < 0.001, I2 = 97%; third:
P = 0.130, I2 = 47%), and the random effect model was chosen to do the pooled analysis. The
results in Fig 7 revealed that the circulating betatrophin levels measured in the third trimester
were higher in women with GDM than that in controls (SMD = 1.3, 95% CI: 1±1.61, P <
0.001). However, the index of betatrophin levels in the second trimester demonstrated no
statistical significance (SMD = 0.73; 95% CI: -0.7±2.16, P = 0.320).
In the subgroup analysis depending on BMI in Fig 8, the random effect model was chosen
to do the pooled analysis because significant heterogeneity was observed (BMI < 28 kg/m2:
Fig 6. Forest plot of the circulating betatrophin levels in GDM or healthy pregnant women after the
extraction of one study. The random effect model (Inverse Variance method) was applied.
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P values in subgroups.
bP values for Cochran's Q statistic test used to assess the heterogeneity.
BMI: body mass index; CI: con®dential interval; SMD: standard mean difference.
P < 0.001, I2 = 98%; BMI 28 kg/m2: P = 0.310, I2 = 16%). For women with BMI 28 kg/m2,
the circulating betatrophin levels increased in the GDM women (SMD = 1.53; 95% CI: 1.3±
1.75, P < 0.001); however, for women with BMI < 28 kg/m2, the difference was not significant
(SMD = 0.22; 95% CI: -1.56 to 2, P = 0.810).
When stratifying by geographic site, these studies were classified as the European group
and the Asian group. For the European group, the betatrophin levels increased in the GDM
patients (SMD = 1.53; 95% CI: 1.29±1.78, P < 0.010); however, for the Asian group, the
difference was not significant (SMD = -0.61; 95% CI: -3.87±2.65, P = 0.710). The studies were
classified to two subgroups according to the average age of the GDM cut-off of 30 years. The results
indicated that both the two groups showed higher betatrophin levels in women with GDM
( 30 years: SMD = 0.96; 95% CI: 0.12±1.8, P = 0.020; < 30 years: SMD = 1.29; 95% CI: 0.84±
Fig 7. Subgroup analysis of circulating betatrophin levels in GDM or healthy pregnant women based
on different trimester. The fixed effect model (Inverse Variance method) was applied.
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Fig 8. Subgroup analysis of circulating betatrophin levels in GDM or healthy pregnant women based
on BMI. The fixed effect model (Inverse Variance method) was applied.
1.74, P < 0.010). In the subgroup analysis of sample source of betatrophin, the difference of
betatrophin levels between the GDM participants and controls was not statistically significant
for the measurement of betatrophin from serum (SMD = 0.72; 95% CI: -0.18±1.63, P = 0.120);
however, the difference was considered significant for the measurement of betatrophin from
plasma (SMD = 1.5; 95% CI: 1±1.99, P < 0.010).
This systematic review and meta-analysis found that circulating betatrophin levels were
significantly higher in women with GDM than healthy pregnant controls. The conclusion was also
available in the subgroups of participants with BMI 28 kg/m2 and in the third trimester. The
changes of betatrophin levels in GDM patients had been already suggested by other authors,
however, to our knowledge no meta-analysis has been performed to date.
GDM is identified as any degree impairment of glucose tolerance with onset or first
recognition during pregnancy. Pregnancy is typically accompanied by physiological insulin
resistance that begins the second trimester and progresses through the third trimester, leading to
an increase in maternal insulin secretion to maintain blood glucose levels as a consequence of
adaptive pancreatic β-cell proliferation. Dysfunction in exacerbation of pancreatic β-cell or
impairment of compensatory increases in insulin secretion from these cells or both leads to
]. The precise mechanisms of insulin resistance underlying GDM remain unknown. It
is probably as a result of upregulation of insulin antagonist hormones.
In view of the prevalence of GDM, an increasing number of studies have involved in
exploring the physiological and pathological mechanisms of GDM in animal models and human
beings [23±28]. As a novel glucolipid metabolic regulation factor, betatrophin is getting more
and more attention, which has been investigated in humans, particularly in the patients of DM
and obesity. Previous studies focuses on the relationship between betatrophin and T2DM or
obesity, while the focus shifts to GDM in recent two year. Several studies revealed that GDM
women showed higher levels of betatrophin than control subjects [13±18, 20], indicating that
augmented insulin resistance and enhanced insulin demand in GDM may contribute to the
upregulation of betatrophin levels. In addition, Natalia et al and Wang et al suggested that not
only maternal but also cord blood betatrophin levels were increased in the patients with GDM
16, 18, 29
]. Furthermore, the three studies mentioned above found an interesting
phenomenon that betatrophin concentration in cord blood was higher than that in maternal serum,
which might suggest its role in promoting β-cell proliferation during intrauterine life. The
alteration of betatrophin has been reported to be influenced by multiple factors, such as age,
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sex, duration of diabetes and BMI, as well as environmental and genetic factors [
11, 12, 18
et al indicated that betatrophin levels were elevated in obesity and were positively correlated
with BMI . However, Fenzl et al revealed that circulating betatrophin did not correlate with
]. While in GDM patients, Yilmaz et al demonstrated that betatrophin levels
increased with age and BMI, demonstrating that obesity and old age may be contributing
factors for increased betatrophin levels in GDM . Taken together, current population-based
studies indicated that circulating betatrophin levels could be a biomarker candidate of GDM.
Conversely, Huang et al suggested that betatrophin levels were much lower in women with
GDM than that in the corresponding controls, although the difference did not reach statistical
]. However, the potential mechenisms are not clear because of the insufficient
The current meta-analysis showed that the pooled value of mean [95% CI] was of statistical
significance, revealing increased circulating levels of betatrophin in GDM. However, according
to the over all forest plot in Fig 3, substantial heterogeneity (I2 = 94%) was observed among the
studies. To find the sources of heterogeneity, subgroup analysis and sensitivity analysis was
performed. Subgroup analysis was depended on geographic site, sample source, the trimester
of betatrophin measurement and group mean of age and BMI in women with GDM. In the
subgroup of Europe participants, the betatrophin levels of GDM patients were relatively higher
than that in healthy pregnant women, while the trend was not available in the subgroup
analysis of Asia patients. The dietary habits in different locations may explain the results. Western
eating habits are more likely to cause obesity and insulin resistance. Previous research
indicated that the circulating betatrophin levels were associated with the BMI and age [
our meta-analysis, subgroup analysis indicated that betatrophin levels were elevated in GDM
patients with BMI 28 kg/m2 and during the third trimester, while not in women with
BMI < 28 kg/m2 or during the second trimester. And the betatrophin levels in GDM
participants were higher than women with normal glucose tolerance regardless of age. The higher
tendency of insulin resistance and increasing level of lipid profiles in the third trimester and in
obesity patients may contribute to the above results. When the subgroup analysis of different
countries, BMI, age and measurement time was carried out, we found that the heterogeneity
was decreased. The results indicated that the source of heterogeneity may be partly from
clinical heterogeneity. Additionally, sensitivity analysis was performed by excluding articles one by
one before reanalyzing statistically. The results showed that the final meta-analysis results were
stable with remove of any study, which provided more credibility to our interpretation of
results. More important, the results of sensitivity analysis indicated that the study performed
by Huang et al  probably contributed to the methodological heterogeneity.
Giving the acute adverse outcomes and long-term effects on pregnant women and
offspring, GDM is drawing increasing attention in recent years. The topic is therefore of
relevance from the public health perspective and the present meta-analysis can contribute to
clarify some of pathophysiological mechanisms of GDM by providing statistical assessment.
However, there are some limitations to this meta-analysis. First, the publication bias cannot be
avoided absolutely, as only published studies in English and Chinese in the selected databases
were included. Second, the absolute value of betatrophin was widely different among included
studies. Third, only fasting circulating betatrophin was detected. As a food intake-induced
hormone, postprandial betatrophin after standard diet could be more meaningful in further
investigation. Fourth, we have no access to get the original data of the included literature, so
we cannot guarantee the accuracy of the data. Therefore, the results should be interpreted with
In conclusion, the current meta-analysis revealed increased circulating levels of betatrophin
in patients with GDM. Women with GDM generally have few obvious related symptoms, then
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betatrophin might be a potential predictor for assessing GDM. This result could help clinical
staff to instruct women with GDM to prevent the progression of GDM. However, the
regulation and metabolism of betatrophin remained unclear in human. For further studies,
welldesigned epidemiological studies with large sample sizes and strict stratification of potential
confounding factors should be performed. It will be meaningful and interesting to explore the
potential role of betatrophin in GDM prediction and therapeutics.
S1 Table. PRISMA 2009 checklist.
Conceptualization: FJK JQZ.
Data curation: FJK LLM JQZ.
Formal analysis: FJK LLM.
Funding acquisition: FJK LLM.
Investigation: GL YXC.
Software: FJK LLM.
Writing ± original draft: FJK LLM.
Writing ± review & editing: JQZ.
We would like to thank professor Yun-Xian Yu for reviewing the statistical methods of this
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