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Higher vaspin levels in subjects with obesity and type 2 diabetes mellitus: A meta-analysis
diabetes research and clinical practice 106 (2014) 88–94
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Higher vaspin levels in subjects with obesity and type 2 diabetes mellitus: A meta-analysis Rennan Feng a,b, Yanchuan Li a,b, Cheng Wang c, Chao Luo e, Liyan Liu a,b, Fuchuan Chuo a,b, Qiang Li d,*, Changhao Sun a,b,** a
Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China c Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, China d Department of Endocrine and metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin, China e STD & AIDS Center, Harbin Center for Disease Control and Prevention, Harbin, China b
article info
abstract
Article history:
Aims: Visceral adipose tissue-derived serpin (vaspin) was identified as a new adipocytokine.
Received 26 February 2014
Many studies reported vaspin concentrations in obese subjects and type 2 diabetes mellitus
Received in revised form
(T2DM) patients. However, large variation in levels of vaspin seen in different studies may be
14 May 2014
attributable to differences of sample size. The aim of this study is to establish an accurate
Accepted 20 July 2014
confidence interval of vaspin levels in obese subjects and T2DM patients using a large-scale
Available online 27 July 2014
meta-analysis. Methods: Publications of the association between vaspin and obesity and T2DM in the
Keywords:
databases of Medline, PubMed and EMBase were collected. The keywords included ‘‘vaspin’’
Vaspin
and ‘‘visceral adipose tissue-derived serpin’’. Review manager 5.0 was used to process the
Obesity
data.
Diabetes
Results: For the analysis of obesity, 6 studies with 1826 participants were included in our
Meta-analysis
meta-analysis; the level of vaspin was 0.52 ng/ml [95% confidence interval (CI)](0.10–0.93, P = 0.02) higher in obese subjects than that in non-obese healthy controls. Eleven studies with 1570 patients were included for the analysis of T2DM; the level of vaspin was 0.36 ng/ml [95%CI] (0.23–0.49, P < 0.00001) higher compared with that in healthy controls. Conclusions: Significantly higher levels of serum vaspin were observed in obese subjects and T2DM patients. # 2014 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Adipose tissue is a highly active endocrine organ that plays critical roles in energy homeostasis through secreting bioactive molecules (adipocytokines) [1]. It interacts with
central and peripheral organs such as brain, liver and skeletal muscles to function in many physical processes [2]. Several adipose tissue-derived hormones, for example leptin [3], were found to be able to improve insulin resistance, metabolic disturbance and reduce the risk of cardiovascular disease [1,4,5].
* Corresponding author. Tel.: +86 0451 87502801; fax: +86 0451 87502885. ** Corresponding author at: Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China. Tel.: +86 0451 87502801; fax: +86 0451 87502885. E-mail addresses: [email protected] (Q. Li), [email protected] (C. Sun). http://dx.doi.org/10.1016/j.diabres.2014.07.026 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice 106 (2014) 88–94
Previously, Hida et al. [6] demonstrated that visceral adipose tissue-derived serpin (vaspin), known as a new adipocytokine, was secreted from visceral adipose tissue. In an animal model of abdominal obesity with T2DM, it was shown to sensitize insulin that targeted on white adipose tissues in obese rats. They also found the expression of vaspin was tissue-specific that the highest level was observed in white adipose tissues. Noticeably, its tissue serum levels showed an increase trend with prediabetic stage, but decreased in diabetes upgrade development along with a sharp body weight loss. In addition, the study showed that further administration of vaspin could help to improve glucose tolerance and insulin sensitivity of obese mice [6]. Convincing evidence indicated that vaspin may also ameliorate atherosclerosis by protecting against the damage of vascular endothelial cells through the mediation of PI-3 kinase/Akt pathway [7]. Recently, Youn et al. [8] investigated the relationship between circulating vaspin and obesity related factors (i.e., BMI and insulin sensitivity). Strong correlations were found for circulating vaspin and BMI and insulin sensitivity. Moreover, the study showed that vaspin levels were increased dramatically after 4 weeks’ physical training. Derosa et al. [9] and Cho et al. [10] reported higher serum vaspin levels in obese subjects compared with those were lean or having normal weight. However, the result could not be replicated by Jeong et al. [11]. The association was inconclusive for T2DM patients as well. Teshigawara et al. [12] declared that vaspin levels in T2DM patients were significantly higher than levels in healthy
controls. A similar result was observed by Zhang et al. [13], but not all [8,14–16]. Therefore, meta-analysis is needed to evaluate the associations between levels of vaspin and obesity and T2DM.
2.
Methods
2.1.
Study selection
We searched several databases (Medline, PubMed and EMBase) to obtain published articles that are relevant to our study through January, 2014. We used ‘vaspin’ or ‘visceral adipose tissue-derived serpin’ as keywords to search for articles relevant to obesity and T2DM. In addition, we also examined references of received articles. Studies that meet all the following criteria will be included in meta-analysis: (1) the study investigated the association between vaspin and obesity or T2DM and (2) cross-sectional study or case control study of the diseases; (3) at least two groups (obese or diabetic group vs. control group) involved in a single study and (4) the controls in both groups were checked for their eligibility [normal BMI (<30 kg/m2) for analysis of obesity; normal glucose tolerance as fasting blood glucose < 6.1 mmol/l and 2 h-postload blood glucose < 7.8 mmol/l for analysis of T2DM]. Exclusion criteria were: (1) review articles, letters and meeting abstracts and (2) studies regarding children, adolescents or pregnant women. A flow chart of the searching
Potentially relevant articles identified and screened for retrieval (n=172)
142 articles excluded based on the title and abstracts
Studies of diabetes retrieved for more detailed evaluation (n=16)
Studies of obesity retrieved for more detailed evaluation (n=14)
Studies excluded, with no control group (n=4), FDRs of diabetic patients (n=1)
Studies excluded, with no control group (n=4), obese children or morbidly obesity (n=4)
11 studies on T2DM
89
6 studies on obesity
Fig. 1 – Flow chart of current study.
90
diabetes research and clinical practice 106 (2014) 88–94
Table 1 – Included studies on the serum vaspin in obesity and T2DM. The first Author
Year
Country
Case N
Obesity studies Jin-Kyung Cho Eunheui Jeong Hala O. EI-Mesallamy Sung Hee Choi
2010 2010 2011 2011
Korea Korea Egypt Korea
Giuseppe Derosa Jung Min Kim
2013 2013
Italy Korea
T2DM studies Byung-Soo Youn
2008
Germany
Jeannette Seeger YE Yin
2008 2009
Germany China
Nese Ersoz Gulcelik Anke Tonjes Ke Li Lili Zhang Hala O. El-Mesallamy Ren-Nan Feng
2009 2010 2011 2011 2011 2011
Turkey Germany China China Egypt China
Sanae Teshigawara Z Li
2012 2012
Japan China
Vaspin level (ng/ml)
Healthy control N
Vaspin level (ng/ml)
107 5 19 47 34 363 33 14
1.6 1.7 0.69 0.22 3.09 0.48 0.60 (0.40–0.99) M 0.51 (0.30–0.97) F 0.9 0.08 0.46 0.42 M 1.34 0.90 F
383 5 19 136 97 365 64 142
0.8 0.8 0.43 0.08 0.29 0.35 0.40 (0.26–0.66) M 0.53 (0.27–0.99) F 0.5 0.09 1.00 1.74 M 1.34 1.95 F
53 80 30 22 17 37 56 30 31 19 60 60 275 61
0.7 0.1 M 0.8 0.1 F 0.8 0.9 0.476 (0.320–0.771) M 0.592 (0.438–0.695) F 0.15 0.009 2.07 1.45 1.83 0.55 1.19 0.74 3.09 0.48 0.62 0.28* 0.51 0.29 0.99 0.04 0.59 0.24
36 18 30 40 44 37 43 30 37 19 60 60 259 26
0.4 0.1 M 1.2 0.4 F 1.1 1.3 0.362 (0.258–0.580) M 0.380 (0.294–0.517) F 0.18 0.10 1.55 1.31 0.53 0.24 0.54 0.28 0.29 0.35 0.69 0.31* 0.69 0.31 0.86 0.02 0.46 0.12
M:male; F:female. Newly diagnosed.
*
results is presented in Fig. 1 and the information of each study is provided in Table 1. Our study was strictly conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines [17].
2.2.
Data extraction
Two authors (R-N. F. and Y-C. L.) extracted data independently and reached on all items, including first author’s last name, year of publication, country of origin, selection and characteristics of cases and controls, ethnicity of the study population, diagnostic criteria of obesity and diabetes, serum vaspin levels and numbers of cases and controls. The articles with overlapping data sets or the same study subjects were excluded and the results of each included study were evaluated according to the checklist proposed by Metaanalysis of Observational Studies in Epidemiology.
2.3.
Statistical analysis
The heterogeneity of the pooled mean differences was estimated using I2 statistic. We used a random-effect model if heterogeneity was observed; otherwise the fixedeffect model was applied in the absence of heterogeneity. Relative influence of each study on the pooled estimate was assessed by omitting one study at a time for sensitivity analysis. Publication bias was observed using a funnel plot. All analyses were performed using Review manager 5.0 and a P value of <0.05 was considered statistically significant.
3.
Results
3.1.
Study selection and the characteristics
A total of 172 articles were identified from the primary literature search. After we screened the titles and abstracts and filtered review articles, letters and meeting abstracts, 14 and 16 relevant articles remained for serum vaspin in obesity and T2DM studies, respectively. Eight and 5 articles were excluded due to lack of control or child subjects with obesity and T2DM. At last, 6 studies of obesity [9–11,18–20] and 11 studies of T2DM [8,12,13,14,15,16,18,21,22,23,24] were included in our study (Fig. 1). The characteristics were shown in Table 1.
3.2. Meta-analysis of the association of vaspin with obesity In total, 1833 participants were included. As there was a significant heterogeneity across 6 studies (I2 = 98%, P < 0.00001), we selected random effect model for the analyses. Significantly increased levels of serum vaspin were observed in obesity group compared with the levels in nonobese group with a mean difference of 0.51 ng/ml [95% confidence interval (CI): 0.10–0.93, P = 0.02] (Fig. 2A).
3.3. Meta-analysis of the association of vaspin with T2DM A total of 1500 participants were included. As there was a significant heterogeneity across the 11 studies (I2 = 98%,
diabetes research and clinical practice 106 (2014) 88–94
91
Fig. 2 – Meta-analysis of the differences of serum vaspin between obese patients and lean healthy controls (A) and between T2DM patients and healthy controls (B).
P < 0.00001), the random effect model was used. The serum vaspin levels of obesity group were 0.36 ng/ml [95% confidence interval (CI): 0.23–0.9, P < 0.00001] significantly higher than those of T2DM group (Fig. 2B).
3.4.
Sensitive analysis
To test the influence of single study on results, we evaluated the stability of the results through a one-leave-out strategy. This is a method that excludes each study to see whether there is a significant alteration of the combined values. In the meta-analysis of the association with vaspin and obesity, after excluding each of the studies, the differences between obese and non-obese groups varied from 0.22 ng/ml (95% CI: 0.04–0.41) to 0.66 ng/ml (95% CI: 0.21–1.10). Two studies (Choi et al. and Derosa et al.) had great impacts on the final result (Table 2). In the meta-analysis of the association of serum vaspin with T2DM, after excluding any 1 study, the differences between T2DM and healthy control groups varied from 0.16 ng/ml (95% CI: 0.06–0.25) to 42 ng/ml (95% CI: 0.29–0.56). No single study influenced the results remarkably, which strengthened our findings.
3.5.
Publication bias
The shape of the funnel plots was prone to be symmetrical, suggesting that there was no evidence of publication bias (Fig. 3). The results of this meta-analysis led to our conclusion that serum vaspin was significantly elevated in obese subjects and T2DM patients.
4.
Discussion
To the best of our knowledge, we firstly used a meta-analysis to investigate the serum vaspin levels in patients with obesity and T2DM and confirmed that obese and T2DM patients are more likely to have higher levels of serum vaspin.
4.1.
Vaspin and insulin resistance
Increased visceral adipose tissue mass is associated with higher prevalence of insulin resistance and risks of T2DM and cardiovascular diseases [25–27]. A higher level of serum vaspin in obese subjects suggested a close link between vaspin and insulin resistance and obesity related diseases. In OLETF rats,
92
diabetes research and clinical practice 106 (2014) 88–94
Fig. 3 – Funnel plots analysis to detect publication bias. Each point represents an independent study for the indicated association. (A) Obesity vs. lean healthy controls and (B) T2DM vs. healthy controls.
vaspin serum levels were significantly decreased in parallel of aging and the development of diabetes. Tissue expression of vaspin and its serum levels increased in the prediabetic status and decreased with worsening of diabetes and body weight loss. Additionally, administration of recombinant vaspin was shown to improve glucose tolerance and insulin sensitivity in obese mice and reverse the altered expression of genes relevant to insulin resistance [6]. Youn et al. [8] reported that vaspin level was increased after physical training. Another study reported that vaspin level was reduced by short-term continuous subcutaneous insulin infusion treatment [22]. All these evidence suggested that vaspin may have beneficial effect on insulin resistance and T2DM. The higher level of vaspin in obese, IGT and T2DM patients could be a result of compensatory reaction for poor insulin sensitivity. The administration of recombinant human vaspin can improve
insulin sensitivity and glucose tolerance, and reverse the expression of genes in diet induced obese mice. Of note, as a compensatory molecule to metabolic disorder, the treatment targeted on vaspin or recombinant human vaspin might be interesting to clinicians.
4.2.
Genotype polymorphisms of vaspin
Genotype polymorphism may play a role in the development of diabetes and metabolic syndrome. In one study, Kempf et al. [28] reported a significant association of vaspin SNP rs2236242 with T2DM, with the AA genotype bearing an higher risk than AT genotype (adjusted OR = 2.35, 95% CI = 1.59–3.46), however, no association between this SNP and obesity was reported in this study. By contrast, Mohammad Hashemi et al. [29] reported that rs2236242 AA genotype may be protective to
diabetes research and clinical practice 106 (2014) 88–94
Table 2 – Sensitivity analysis with each study omitted in random-effects model. Study omitted
Mean difference
95% CI
P
Obesity studies None Cho 2010 Choi 2011 F Choi 2011 M Derosa 2013 EI-Mesallamy 2011 Jeong 2010 Kim 2013 F Kim 2013 M
0.52 0.48 0.59 0.54 0.52 0.22 0.55 0.58 0.66
0.10–0.93 0.02–0.93 0.11–1.08 0.03–1.11 0.19–1.23 0.04–0.41 0.06–1.04 0.13–1.03 0.21–1.10
0.02 0.04 0.02 0.06 0.15 0.02 0.03 0.01 0.004
T2DM studies None EI-Mesallamy 2011 Feng 2011 Feng 2011* Gulcelik 2009 Li 2011 Li 2012 Seeger 2008 Teshigawara 2012 Tonjes 2010 Yin 2009 F Yin 2009 M Youn 2008 F Youn 2008 M Zhang 2011
0.36 0.16 0.41 0.36 0.42 0.29 0.39 0.38 0.41 0.35 0.38 0.38 0.42 0.37 0.34
0.23–0.49 0.06–0.25 0.28–0.55 0.23–0.49 0.25–0.59 0.14–0.42 0.24–0.53 0.25–0.52 0.20–0.63 0.22–0.49 0.24–0.52 0.24–0.52 0.29–0.56 0.22–0.53 0.20–0.47
<0.00001 0.001 <0.00001 <0.00001 <0.00001 <0.0001 <0.00001 <0.00001 0.0002 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001
M:male; F:female. * Newly diagnosed diabetes.
susceptibility of metabolic syndrome. However, the association between vaspin levels and rs2236242 has not been reported yet. Interestingly, Sanae Teshigawara et al. [12] reported that in 7% of the Japanese population, higher levels of serum vaspin are closely linked to minor allele sequence A of rs77060950. Therefore, we hypothesize that common genetic variants may influence the vaspin levels then attributed to the development of obesity or/and T2DM.
4.3.
Explanations for the negative associations
First, lifestyle modification or medicine therapy of obese or T2DM patients might confound our results. Mi Kyung Lee et al. [30] found lifestyle modification including physical activity, dietary modification, and behavioral modification education could reduce serum vaspin levels in children. Ke Li et al. [22] reported that fasting plasma vaspin concentrations were significantly decreased after CSII treatment in T2DM patients. Furthermore, lower serum vaspin has also been reported in T2DM patients with microvascular complications [14] and in previously diagnosed Chinese T2DM patients [23]. Thus, we hypothesize that the course of diabetes and its complications might influence vaspin secretion in T2DM patients. However, no study has been adjusted for above factors yet. Thus, the duration of T2DM and some lifestyle factors should be considered when investigating the associations. Second, as polymorphisms of rs2236242 and rs77060950 might influence the serum vaspin levels, genetic factors of both SNPs could impact the true associations between vaspin, obesity and T2DM. Further study on vaspin levels and these SNPs
93
should be conducted. Third, due to the small number of current studies on obesity included in our analysis (n = 6), we cannot perform stratified analysis for the association between r serum vaspin and obesity by ethnicity. More investigations are needed. In conclusion, we firstly confirmed that obese subjects and T2DM patients are more likely to have higher levels of serum vaspin. However, further researches are warranted to unravel the underlying biological mechanisms.
Funding The study was supported by Heilongjiang Province Science and Technology Research Project of Education Office (No. 12531265)
Conflicts of interest The authors declare that they have no conflicts of interest.
references
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[13] Zhang L, Li L, Yang M, Liu H, Yang G. Elevated circulating vaspin levels were decreased by rosiglitazone therapy in T2DM patients with poor glycemic control on metformin alone. Cytokine 2011;56:399–402. [14] Gulcelik NE, Karakaya J, Gedik A, Usman A, Gurlek A. Serum vaspin levels in type 2 diabetic women in relation to microvascular complications. Eur J Endocrinol 2009;160: 65–70. [15] Ye Y, Hou XH, Pan XP, Lu JX, Jia WP. Serum vaspin level in relation to postprandial plasma glucose concentration in subjects with diabetes. Chin Med J (Engl) 2009;122:2530–3. [16] Seeger J, Ziegelmeier M, Bachmann A, Lossner U, Kratzsch J, et al. Serum levels of the adipokine vaspin in relation to metabolic and renal parameters. J Clin Endocrinol Metab 2008;93:247–51. [17] Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. J Am Med Assoc 2000;283:2008–12. [18] El-Mesallamy HO, Kassem DH, El-Demerdash E, Amin AI. Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus. Metabolism 2011;60:63–70. [19] Choi SH, Kwak SH, Lee Y, Moon MK, Lim S, et al. Plasma vaspin concentrations are elevated in metabolic syndrome in men and are correlated with coronary atherosclerosis in women. Clin Endocrinol (Oxf) 2011;75:628–35. [20] Kim JM, Kim TN, Won JC. Association between serum vaspin level and metabolic syndrome in healthy korean subjects. Metab Syndr Relat Disord 2013;11:385–91. [21] Maedler K, To¨njes A, Fasshauer M, Kratzsch J, Stumvoll M, et al. Adipokine pattern in subjects with impaired fasting
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glucose and impaired glucose tolerance in comparison to normal glucose tolerance and diabetes. PLOS ONE 2010;5:e13911. Li K, Li L, Yang M, Liu H, Liu D, et al. Short-term continuous subcutaneous insulin infusion decreases the plasma vaspin levels in patients with type 2 diabetes mellitus concomitant with improvement in insulin sensitivity. Eur J Endocrinol 2011;164:905–10. Feng R-N. Vaspin in newly and previously diagnosed Chinese type 2 diabetic females: a case-control study. Asian Biomed 2011;5:525–9. Li Z, Ma C, Li L, Pan X, Chen L. Vaspin serum concentration in patients with type 2 diabetes and carotid plaque. J Int Med Res 2012;40:1670–6. Bjorntorp P. Metabolic implications of body fat distribution. Diab Care 1991;14:1132–43. Frayn KN. Visceral fat and insulin resistance – causative or correlative? Br J Nutr 2000;83(Suppl. 1):S71–7. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738. Kempf K, Rose B, Illig T, Rathmann W, Strassburger K, et al. Vaspin (SERPINA12) genotypes and risk of type 2 diabetes: Results from the MONICA/KORA studies. Exp Clin Endocrinol Diab 2010;118:184–9. Hashemi M, Rezaei H, Eskandari-Nasab E, Kaykhaei MA, Zakeri Z, et al. Association between chemerin rs17173608 and vaspin rs2236242 gene polymorphisms and the metabolic syndrome, a preliminary report. Gene 2012;510:113–7. Lee MK, Jekal Y, Im JA, Kim E, Lee SH. Reduced serum vaspin concentrations in obese children following shortterm intensive lifestyle modification. Clin Chim Acta 2010;411:381–5.
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Higher vaspin levels in subjects with obesity and type 2 diabetes mellitus: A meta-analysis Rennan Feng a,b, Yanchuan Li a,b, Cheng Wang c, Chao Luo e, Liyan Liu a,b, Fuchuan Chuo a,b, Qiang Li d,*, Changhao Sun a,b,** a
Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China c Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, China d Department of Endocrine and metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin, China e STD & AIDS Center, Harbin Center for Disease Control and Prevention, Harbin, China b
article info
abstract
Article history:
Aims: Visceral adipose tissue-derived serpin (vaspin) was identified as a new adipocytokine.
Received 26 February 2014
Many studies reported vaspin concentrations in obese subjects and type 2 diabetes mellitus
Received in revised form
(T2DM) patients. However, large variation in levels of vaspin seen in different studies may be
14 May 2014
attributable to differences of sample size. The aim of this study is to establish an accurate
Accepted 20 July 2014
confidence interval of vaspin levels in obese subjects and T2DM patients using a large-scale
Available online 27 July 2014
meta-analysis. Methods: Publications of the association between vaspin and obesity and T2DM in the
Keywords:
databases of Medline, PubMed and EMBase were collected. The keywords included ‘‘vaspin’’
Vaspin
and ‘‘visceral adipose tissue-derived serpin’’. Review manager 5.0 was used to process the
Obesity
data.
Diabetes
Results: For the analysis of obesity, 6 studies with 1826 participants were included in our
Meta-analysis
meta-analysis; the level of vaspin was 0.52 ng/ml [95% confidence interval (CI)](0.10–0.93, P = 0.02) higher in obese subjects than that in non-obese healthy controls. Eleven studies with 1570 patients were included for the analysis of T2DM; the level of vaspin was 0.36 ng/ml [95%CI] (0.23–0.49, P < 0.00001) higher compared with that in healthy controls. Conclusions: Significantly higher levels of serum vaspin were observed in obese subjects and T2DM patients. # 2014 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Adipose tissue is a highly active endocrine organ that plays critical roles in energy homeostasis through secreting bioactive molecules (adipocytokines) [1]. It interacts with
central and peripheral organs such as brain, liver and skeletal muscles to function in many physical processes [2]. Several adipose tissue-derived hormones, for example leptin [3], were found to be able to improve insulin resistance, metabolic disturbance and reduce the risk of cardiovascular disease [1,4,5].
* Corresponding author. Tel.: +86 0451 87502801; fax: +86 0451 87502885. ** Corresponding author at: Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China. Tel.: +86 0451 87502801; fax: +86 0451 87502885. E-mail addresses: [email protected] (Q. Li), [email protected] (C. Sun). http://dx.doi.org/10.1016/j.diabres.2014.07.026 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice 106 (2014) 88–94
Previously, Hida et al. [6] demonstrated that visceral adipose tissue-derived serpin (vaspin), known as a new adipocytokine, was secreted from visceral adipose tissue. In an animal model of abdominal obesity with T2DM, it was shown to sensitize insulin that targeted on white adipose tissues in obese rats. They also found the expression of vaspin was tissue-specific that the highest level was observed in white adipose tissues. Noticeably, its tissue serum levels showed an increase trend with prediabetic stage, but decreased in diabetes upgrade development along with a sharp body weight loss. In addition, the study showed that further administration of vaspin could help to improve glucose tolerance and insulin sensitivity of obese mice [6]. Convincing evidence indicated that vaspin may also ameliorate atherosclerosis by protecting against the damage of vascular endothelial cells through the mediation of PI-3 kinase/Akt pathway [7]. Recently, Youn et al. [8] investigated the relationship between circulating vaspin and obesity related factors (i.e., BMI and insulin sensitivity). Strong correlations were found for circulating vaspin and BMI and insulin sensitivity. Moreover, the study showed that vaspin levels were increased dramatically after 4 weeks’ physical training. Derosa et al. [9] and Cho et al. [10] reported higher serum vaspin levels in obese subjects compared with those were lean or having normal weight. However, the result could not be replicated by Jeong et al. [11]. The association was inconclusive for T2DM patients as well. Teshigawara et al. [12] declared that vaspin levels in T2DM patients were significantly higher than levels in healthy
controls. A similar result was observed by Zhang et al. [13], but not all [8,14–16]. Therefore, meta-analysis is needed to evaluate the associations between levels of vaspin and obesity and T2DM.
2.
Methods
2.1.
Study selection
We searched several databases (Medline, PubMed and EMBase) to obtain published articles that are relevant to our study through January, 2014. We used ‘vaspin’ or ‘visceral adipose tissue-derived serpin’ as keywords to search for articles relevant to obesity and T2DM. In addition, we also examined references of received articles. Studies that meet all the following criteria will be included in meta-analysis: (1) the study investigated the association between vaspin and obesity or T2DM and (2) cross-sectional study or case control study of the diseases; (3) at least two groups (obese or diabetic group vs. control group) involved in a single study and (4) the controls in both groups were checked for their eligibility [normal BMI (<30 kg/m2) for analysis of obesity; normal glucose tolerance as fasting blood glucose < 6.1 mmol/l and 2 h-postload blood glucose < 7.8 mmol/l for analysis of T2DM]. Exclusion criteria were: (1) review articles, letters and meeting abstracts and (2) studies regarding children, adolescents or pregnant women. A flow chart of the searching
Potentially relevant articles identified and screened for retrieval (n=172)
142 articles excluded based on the title and abstracts
Studies of diabetes retrieved for more detailed evaluation (n=16)
Studies of obesity retrieved for more detailed evaluation (n=14)
Studies excluded, with no control group (n=4), FDRs of diabetic patients (n=1)
Studies excluded, with no control group (n=4), obese children or morbidly obesity (n=4)
11 studies on T2DM
89
6 studies on obesity
Fig. 1 – Flow chart of current study.
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Table 1 – Included studies on the serum vaspin in obesity and T2DM. The first Author
Year
Country
Case N
Obesity studies Jin-Kyung Cho Eunheui Jeong Hala O. EI-Mesallamy Sung Hee Choi
2010 2010 2011 2011
Korea Korea Egypt Korea
Giuseppe Derosa Jung Min Kim
2013 2013
Italy Korea
T2DM studies Byung-Soo Youn
2008
Germany
Jeannette Seeger YE Yin
2008 2009
Germany China
Nese Ersoz Gulcelik Anke Tonjes Ke Li Lili Zhang Hala O. El-Mesallamy Ren-Nan Feng
2009 2010 2011 2011 2011 2011
Turkey Germany China China Egypt China
Sanae Teshigawara Z Li
2012 2012
Japan China
Vaspin level (ng/ml)
Healthy control N
Vaspin level (ng/ml)
107 5 19 47 34 363 33 14
1.6 1.7 0.69 0.22 3.09 0.48 0.60 (0.40–0.99) M 0.51 (0.30–0.97) F 0.9 0.08 0.46 0.42 M 1.34 0.90 F
383 5 19 136 97 365 64 142
0.8 0.8 0.43 0.08 0.29 0.35 0.40 (0.26–0.66) M 0.53 (0.27–0.99) F 0.5 0.09 1.00 1.74 M 1.34 1.95 F
53 80 30 22 17 37 56 30 31 19 60 60 275 61
0.7 0.1 M 0.8 0.1 F 0.8 0.9 0.476 (0.320–0.771) M 0.592 (0.438–0.695) F 0.15 0.009 2.07 1.45 1.83 0.55 1.19 0.74 3.09 0.48 0.62 0.28* 0.51 0.29 0.99 0.04 0.59 0.24
36 18 30 40 44 37 43 30 37 19 60 60 259 26
0.4 0.1 M 1.2 0.4 F 1.1 1.3 0.362 (0.258–0.580) M 0.380 (0.294–0.517) F 0.18 0.10 1.55 1.31 0.53 0.24 0.54 0.28 0.29 0.35 0.69 0.31* 0.69 0.31 0.86 0.02 0.46 0.12
M:male; F:female. Newly diagnosed.
*
results is presented in Fig. 1 and the information of each study is provided in Table 1. Our study was strictly conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines [17].
2.2.
Data extraction
Two authors (R-N. F. and Y-C. L.) extracted data independently and reached on all items, including first author’s last name, year of publication, country of origin, selection and characteristics of cases and controls, ethnicity of the study population, diagnostic criteria of obesity and diabetes, serum vaspin levels and numbers of cases and controls. The articles with overlapping data sets or the same study subjects were excluded and the results of each included study were evaluated according to the checklist proposed by Metaanalysis of Observational Studies in Epidemiology.
2.3.
Statistical analysis
The heterogeneity of the pooled mean differences was estimated using I2 statistic. We used a random-effect model if heterogeneity was observed; otherwise the fixedeffect model was applied in the absence of heterogeneity. Relative influence of each study on the pooled estimate was assessed by omitting one study at a time for sensitivity analysis. Publication bias was observed using a funnel plot. All analyses were performed using Review manager 5.0 and a P value of <0.05 was considered statistically significant.
3.
Results
3.1.
Study selection and the characteristics
A total of 172 articles were identified from the primary literature search. After we screened the titles and abstracts and filtered review articles, letters and meeting abstracts, 14 and 16 relevant articles remained for serum vaspin in obesity and T2DM studies, respectively. Eight and 5 articles were excluded due to lack of control or child subjects with obesity and T2DM. At last, 6 studies of obesity [9–11,18–20] and 11 studies of T2DM [8,12,13,14,15,16,18,21,22,23,24] were included in our study (Fig. 1). The characteristics were shown in Table 1.
3.2. Meta-analysis of the association of vaspin with obesity In total, 1833 participants were included. As there was a significant heterogeneity across 6 studies (I2 = 98%, P < 0.00001), we selected random effect model for the analyses. Significantly increased levels of serum vaspin were observed in obesity group compared with the levels in nonobese group with a mean difference of 0.51 ng/ml [95% confidence interval (CI): 0.10–0.93, P = 0.02] (Fig. 2A).
3.3. Meta-analysis of the association of vaspin with T2DM A total of 1500 participants were included. As there was a significant heterogeneity across the 11 studies (I2 = 98%,
diabetes research and clinical practice 106 (2014) 88–94
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Fig. 2 – Meta-analysis of the differences of serum vaspin between obese patients and lean healthy controls (A) and between T2DM patients and healthy controls (B).
P < 0.00001), the random effect model was used. The serum vaspin levels of obesity group were 0.36 ng/ml [95% confidence interval (CI): 0.23–0.9, P < 0.00001] significantly higher than those of T2DM group (Fig. 2B).
3.4.
Sensitive analysis
To test the influence of single study on results, we evaluated the stability of the results through a one-leave-out strategy. This is a method that excludes each study to see whether there is a significant alteration of the combined values. In the meta-analysis of the association with vaspin and obesity, after excluding each of the studies, the differences between obese and non-obese groups varied from 0.22 ng/ml (95% CI: 0.04–0.41) to 0.66 ng/ml (95% CI: 0.21–1.10). Two studies (Choi et al. and Derosa et al.) had great impacts on the final result (Table 2). In the meta-analysis of the association of serum vaspin with T2DM, after excluding any 1 study, the differences between T2DM and healthy control groups varied from 0.16 ng/ml (95% CI: 0.06–0.25) to 42 ng/ml (95% CI: 0.29–0.56). No single study influenced the results remarkably, which strengthened our findings.
3.5.
Publication bias
The shape of the funnel plots was prone to be symmetrical, suggesting that there was no evidence of publication bias (Fig. 3). The results of this meta-analysis led to our conclusion that serum vaspin was significantly elevated in obese subjects and T2DM patients.
4.
Discussion
To the best of our knowledge, we firstly used a meta-analysis to investigate the serum vaspin levels in patients with obesity and T2DM and confirmed that obese and T2DM patients are more likely to have higher levels of serum vaspin.
4.1.
Vaspin and insulin resistance
Increased visceral adipose tissue mass is associated with higher prevalence of insulin resistance and risks of T2DM and cardiovascular diseases [25–27]. A higher level of serum vaspin in obese subjects suggested a close link between vaspin and insulin resistance and obesity related diseases. In OLETF rats,
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Fig. 3 – Funnel plots analysis to detect publication bias. Each point represents an independent study for the indicated association. (A) Obesity vs. lean healthy controls and (B) T2DM vs. healthy controls.
vaspin serum levels were significantly decreased in parallel of aging and the development of diabetes. Tissue expression of vaspin and its serum levels increased in the prediabetic status and decreased with worsening of diabetes and body weight loss. Additionally, administration of recombinant vaspin was shown to improve glucose tolerance and insulin sensitivity in obese mice and reverse the altered expression of genes relevant to insulin resistance [6]. Youn et al. [8] reported that vaspin level was increased after physical training. Another study reported that vaspin level was reduced by short-term continuous subcutaneous insulin infusion treatment [22]. All these evidence suggested that vaspin may have beneficial effect on insulin resistance and T2DM. The higher level of vaspin in obese, IGT and T2DM patients could be a result of compensatory reaction for poor insulin sensitivity. The administration of recombinant human vaspin can improve
insulin sensitivity and glucose tolerance, and reverse the expression of genes in diet induced obese mice. Of note, as a compensatory molecule to metabolic disorder, the treatment targeted on vaspin or recombinant human vaspin might be interesting to clinicians.
4.2.
Genotype polymorphisms of vaspin
Genotype polymorphism may play a role in the development of diabetes and metabolic syndrome. In one study, Kempf et al. [28] reported a significant association of vaspin SNP rs2236242 with T2DM, with the AA genotype bearing an higher risk than AT genotype (adjusted OR = 2.35, 95% CI = 1.59–3.46), however, no association between this SNP and obesity was reported in this study. By contrast, Mohammad Hashemi et al. [29] reported that rs2236242 AA genotype may be protective to
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Table 2 – Sensitivity analysis with each study omitted in random-effects model. Study omitted
Mean difference
95% CI
P
Obesity studies None Cho 2010 Choi 2011 F Choi 2011 M Derosa 2013 EI-Mesallamy 2011 Jeong 2010 Kim 2013 F Kim 2013 M
0.52 0.48 0.59 0.54 0.52 0.22 0.55 0.58 0.66
0.10–0.93 0.02–0.93 0.11–1.08 0.03–1.11 0.19–1.23 0.04–0.41 0.06–1.04 0.13–1.03 0.21–1.10
0.02 0.04 0.02 0.06 0.15 0.02 0.03 0.01 0.004
T2DM studies None EI-Mesallamy 2011 Feng 2011 Feng 2011* Gulcelik 2009 Li 2011 Li 2012 Seeger 2008 Teshigawara 2012 Tonjes 2010 Yin 2009 F Yin 2009 M Youn 2008 F Youn 2008 M Zhang 2011
0.36 0.16 0.41 0.36 0.42 0.29 0.39 0.38 0.41 0.35 0.38 0.38 0.42 0.37 0.34
0.23–0.49 0.06–0.25 0.28–0.55 0.23–0.49 0.25–0.59 0.14–0.42 0.24–0.53 0.25–0.52 0.20–0.63 0.22–0.49 0.24–0.52 0.24–0.52 0.29–0.56 0.22–0.53 0.20–0.47
<0.00001 0.001 <0.00001 <0.00001 <0.00001 <0.0001 <0.00001 <0.00001 0.0002 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001
M:male; F:female. * Newly diagnosed diabetes.
susceptibility of metabolic syndrome. However, the association between vaspin levels and rs2236242 has not been reported yet. Interestingly, Sanae Teshigawara et al. [12] reported that in 7% of the Japanese population, higher levels of serum vaspin are closely linked to minor allele sequence A of rs77060950. Therefore, we hypothesize that common genetic variants may influence the vaspin levels then attributed to the development of obesity or/and T2DM.
4.3.
Explanations for the negative associations
First, lifestyle modification or medicine therapy of obese or T2DM patients might confound our results. Mi Kyung Lee et al. [30] found lifestyle modification including physical activity, dietary modification, and behavioral modification education could reduce serum vaspin levels in children. Ke Li et al. [22] reported that fasting plasma vaspin concentrations were significantly decreased after CSII treatment in T2DM patients. Furthermore, lower serum vaspin has also been reported in T2DM patients with microvascular complications [14] and in previously diagnosed Chinese T2DM patients [23]. Thus, we hypothesize that the course of diabetes and its complications might influence vaspin secretion in T2DM patients. However, no study has been adjusted for above factors yet. Thus, the duration of T2DM and some lifestyle factors should be considered when investigating the associations. Second, as polymorphisms of rs2236242 and rs77060950 might influence the serum vaspin levels, genetic factors of both SNPs could impact the true associations between vaspin, obesity and T2DM. Further study on vaspin levels and these SNPs
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should be conducted. Third, due to the small number of current studies on obesity included in our analysis (n = 6), we cannot perform stratified analysis for the association between r serum vaspin and obesity by ethnicity. More investigations are needed. In conclusion, we firstly confirmed that obese subjects and T2DM patients are more likely to have higher levels of serum vaspin. However, further researches are warranted to unravel the underlying biological mechanisms.
Funding The study was supported by Heilongjiang Province Science and Technology Research Project of Education Office (No. 12531265)
Conflicts of interest The authors declare that they have no conflicts of interest.
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