The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis
The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis
Yong-chao Qiao 0 1 2
Yin-ling Chen 0 1 2
Yan-hong Pan 0 1 2
Fang Tian 0 1
Yan Xu 0 1
Xiao- xi Zhang 0 1 2
Hai-lu Zhao 0 1 2
0 Funding: This study was supported by the National Natural Science Foundation of China (81471054) and the Innovation Project of Guangxi Graduate Education (JGY2015128). (
1 Editor: Hiroyoshi Ariga , Hokkaido Daigaku , JAPAN
2 Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University , Guilin , China , 2 Department of Immunology, Xiangya School of Medicine, Central South University , Changsha, Hunan , China , 3 Department of Immunology, Faculty of Basic Medicine, Guilin Medical University , Guilin , China
A total of 23 articles (1631 T1DM cases, 1429 healthy controls) were included for this
metaanalysis. Compared with the controls, the patients had significantly increased serum TNF-α
level (P < 0.001). Similar results were also found among all subgroup analysis of different
age, disease duration and ethnicity (with the exception of Asian) (all P < 0.05). Regression
analysis indicated that age (P = 0.680), disease duration (P = 0.957), and ethnicity (P =
0.526) of patients were not significant impact factors for the high heterogeneity. The results
were stable according to the sensitivity analysis and no publication bias existed in this
Serum TNF-α level in T1DM patients has significantly elevated among all age, disease dura
tion and ethnicity groups.
The aim of this study was used meta-analysis to investigate changes of serum tumor necro
sis factor-alpha (TNF-α) in patients with type 1 diabetes mellitus (T1DM).
Relevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and
Chinese-Cqvip databases (published from January 1, 1999 to September 30, 2016). Eligible
reports were included for pooled analysis of serum TNF-α level and subgroup analysis was
performed in relation with age, disease duration and ethnicity.
Competing interests: The authors have declared
that no competing interests exist.
Type 1 diabetes mellitus (T1DM) is a systemic disease leading to abnormal fat, carbohydrate,
and protein metabolism due to insulin deficiency [
]. Metabolic proinflammatory disorder,
such as chronic hyperglycemia and increased levels of circulating cytokines, suggests
immunological disturbances [2±5], which seriously affects the quality of life of the patients and imposes
a large economic burden on the national health care system [
]. The reasons responsible for
this disease are almost summarized as genetic and environmental factors.
The role of inflammation in diabetes mellitus (DM) has recently been implicated [
that inflammatory reaction, mediated by acute phase proteins and cytokines, could lead to
the prevention or promotion of diabetes [
]. Inflammatory cytokines such as
interleukine-6 (IL-6) [
], IL-17 [
], transforming growth factor-beta (TGF-β)  and
C-reactive protein (CRP) [
] have been shown to be elevated in DM patients, and the
elevated cytokines play an important role in the development and progression of
Tumor necrosis factor-alpha (TNF-α) produced by activated macrophages, CD4+
lymphocytes, natural killer cells, neutrophils, mast cells, eosinophils and neurons, is a cytokine involved
in systemic inflammation and always results in acute phase reaction [
]. TNF-α may induce
insulin resistance through direct effects on the insulin signaling pathway, and thus participates
in the pathogenesis of type 2 DM and obesity [17±20]. As an endogenous factor, TNF-α not
only influences energy balance, but also is associated with weight loss, hypermetabolism and
resting energy expenditure in malignant diseases [
]. Many researchers focus on the change of
serum TNF-α level [21±26] in DM patients, yet findings are inconsistent. In the present study,
we performed a pooled analysis of data to define the change of serum TNF-α in T1DM patients.
This study was performed based on the Preferred Reporting Items for Systematic Reviews and
Meta-analysis (PRISMA) criteria [
]. The work described here was performed in accordance
with the Declaration of Helsinki. This study was approved by the Ethical Committee of Guilin
Medical University. We systematically searched five databases (PubMed, Cochrane Library,
CNKI, WanFang and Chinese-Cqvip) about the studies published from January 1, 1999 to
September 30, 2016. The search strategy using medical terms as following: (ªtumor necrosis factor
alphaº or ªTNF-αº) and (ªtype 1 diabetesº or ªdiabetic patientsº or ªdiabetes mellitusº or
ªDMº or ªT1DMº). Otherwise, we identified the additional reports through references cited in
Inclusion criteria and exclusion criteria
All related articles were reviewed using the criteria as follows: (1) Studies focusing on the
change of serum TNF-α level in T1DM patients; (2) Case-control research; (3) Patients used
insulin alone; (4) Data expressed as Mean ± SD; and (5) Definitions of T1DM met the criteria
recommended by the World Health Organization [
Exclusion criteria: (1) For duplicated studies and reports, we only included the latest paper
into our final analysis; (2) Animal studies, reviews, editorials, case reports, and personal
experience summaries; (3) No healthy controls in the study; (4) Original data displayed as figures
or no original data reported; and (5) Inconsistent with the inclusion criteria as described
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Quality assessment and data extraction
The Newcastle-Ottawa Scale (NOS) was used to assess the quality of all eligible studies [
and the following information from each eligible study was extracted independently by two
reviewers: (1) first author's surname; (2) date of publication; (3) country of the studied
population; (4) mean age of patients; (5) sample size of case-control; (6) mean disease duration of
patients; (7) Mean ± SD displayed the level of serum TNF-α. Considering disagreement, we
invited the third investigator to assess such articles through discussion.
We extracted the data (sample size, Mean ± SD) to clarify the change of TNF-α in T1DM
patients versus controls, followed by Chi-squared Q test and I2 statistics to estimate the
]. When P < 0.1 or I2 > 50%, we selected a random-effect model to account for
possible heterogeneity between studies; otherwise a fixed-effect model was used in the absence
of heterogeneity [
]. In order to evaluate the age and disease duration impact on serum
TNF-α, all the patients in the included studies were stratified into three groups by age (<12,
12±24, >24 years old) and by disease duration (<5, 5±10, >10 years) respectively. And the
impact of different ethnicity of patients was explored by subgroup analysis of five ethnicity
groups (Asia, Europe, America, Africa and Oceania). Regression analysis was used to
investigate sources of heterogeneity. In addition, we conducted sensitivity analysis by excluding
individual studies or selecting articles with high NOS score ( ) or changing the Cochran's Q
statistic methods to check the stability of the results. Publication bias was judged by an Egger's
test (P < 0.05 was considered representative of statistically significant publication bias) [
Stata 12.0 software was used in this pooled analysis.
The process and results of selection
The study selection process was displayed in Fig 1. With our search criteria, we collected 3397
potential studies and excluded 1074 due to duplication. After reading the titles and abstracts,
2226 articles were excluded for no controls, not DM relevant, review and editorial articles or
animal studies. Then, we excluded 76 articles due to original data expressed with figures, duplicated
data, or no original data. Finally, 20 articles (23 case-control studies) met the criteria and were
included in this meta-analysis [1, 7, 21±25, 35±47] (S1 Appendix), involving 1631 T1DM patients
and 1429 healthy controls. The specific characteristics of the 23 studies are shown in Table 1.
Results of meta-analysis and subgroup analysis
The T1DM patients had significantly increased serum TNF-α level compared with the controls
(SMD, 1.23; 95% CI, 0.77 to 1.68; P < 0.001) (Fig 2) and significant heterogeneity (P < 0.001)
existed in this meta-analysis.
In the subgroup analysis by age, disease duration, and ethnicity, T1DM patients
consistently had significantly increased levels of TNF-α among the three age groups (all P < 0.01)
(Fig 3), and three disease duration groups (all P < 0.05) (Fig 4), and four ethnicity subgroups
(all P < 0.05) except Asia group (SMD, 0.67; 95%CI, -1.03 to 2.36; P = 0.439) (Fig 5).
Regression analysis was used to explore the source of high heterogeneity of age, disease
duration, and ethnicity for the serum level of TNF-α, and the results displayed as follows: age (t =
-0.42; 95% CI, -1.035 to 0.689; P = 0.680), disease duration (t = -0.06; 95% CI, -1.091 to 1.036;
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Fig 1. The flow chart of the articles search and inclusion process.
P = 0.957), and ethnicity of patients (t = 0.64; 95% CI, -0.298 to 0.567; P = 0.526), which
indicated that age, disease duration, and ethnicity of patients were not significant impact factors
for the high heterogeneity in this meta-analysis.
We first performed sensitivity analysis by excluding individual studies and found the results
remaining consistent (Fig 6A). Next, sensitivity analysis was conducted by selecting studies
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FCM, ¯ow cytometry method; ELISA, enzyme-linked immunosorbent assay; ECMA, enzyme chemiluminescence immunometric assay; SZ, sample size; M/
F, male/female; SD, standard deviation; NR, not report.
aData converted from median (range).
bSD data converted from SE.
cData converted from median (interquartile range).
with high NOS score ( ) or excluding studies with high risk of bias and we found that all the
outcomes still had no significant changes. Otherwise, fixed effects model was chosen to pool
the data, all the results were similar to those generated by random effects model.
Egger's test showed that no publication bias existed in this meta-analysis (t = 2.04; P = 0.054;
95% CI, -0.074 to 7.370) (Fig 6B).
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Fig 2. Forest plots for the level of serum TNF-α between T1DM patients and healthy controls with random effects model (SMD, 1.23, 95% CI, 0.77
to 1.68, P < 0.001).
TNF-α is highly involved with macrophage activation and increased serum TNF-α level have
been observed in insulin resistance stages and diabetes mellitus development [
inconsistency still existed and no meta-analysis was conducted about the change of serum
TNF-α level in T1DM patients. The results of this study clearly demonstrate that T1DM
patients had significantly elevated serum level of TNF-α and significant correlation existed
between TNF-α level and patients' age, disease duration and ethnicity.
TNF-α level may play an important role and many factors may contribute to the serum
TNF-α level in diabetes. TNF-α, as the major physiological and pathophysiological regulators
of vascular adhesion molecules, is a key proinflammatory cytokine with widespread metabolic
effects, and directly regulate the production of several cardiovascular risk factors [
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Fig 3. Forest plots about subgroup analysis for the level of TNF-α between T1DM patients and controls with random effects model among
different age groups. Age, 0±12 years old, SMD, 1.18, 95% CI, 0.40 to 1.96, P = 0.003; Age, 12±24 years old, SMD, 2.14, 95% CI, 0.79 to 3.49, P = 0.002;
Age, > 24 years old: SMD, 0.79, 95% CI, 0.19 to 1.39, P = 0.010; Overall, SMD, 1.26, 95% CI, 0.79 to 1.73, P < 0.001.
TNF-α via effects on soluble intercellular adhesion molecule-1, may promote vascular
adhesion, otherwise plasma levels of TNF-α are associated with dyslipidaemia and increase blood
pressure, adding to vascular disease risk, besides, the actions of TNF-α is probably modified by
altered production of soluble receptors in type 1 diabetic patients [
]. Increased TNF-α and
interleukine-6 (IL-6) levels through metabolic control exist in types 1 and 2 diabetic patients,
which suggest that the control of diabetes improves the capacity of activation and maintenance
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Fig 4. Forest plots about subgroup analysis for the level of TNF-α between T1DM patients and controls with random effects model among
different disease duration groups. Duration, 0±5 years, SMD, 1.43, 95% CI, 0.58 to 2.27, P = 0.001; Duration, 5±10 years, SMD, 1.87, 95% CI, 0.31 to
3.43, P = 0.019; Duration, > 10 years, SMD, 1.25, 95% CI, 0.31 to 2.20, P = 0.009; Overall, SMD, 1.48, 95% CI, 0.93 to 2.02, P < 0.001.
of these pro-inflammatory cytokines [52±54]. Other study [
] demonstrated TNF-α levels
were elevated in T1DM which was correlated positively with HbA1c and inversely with HDL
cholesterol levels. In addition, a significant relationship between TNF-α levels and both BMI
and WHR also was observed in analysis of the combined groups [
Owning the various biological effects, TNF-α has been proved to have certain catabolic
effects on fat cells, and neutralization of TNF-α in obese rats causes a significant increase in
the peripheral uptake of glucose in response to insulin, which indicates an important role in
the insulin resistance and diabetes that often accompany obesity [
]. TNF-α, through
increasing the activities of the NF-κB transcriptional factor [
], protein kinase C , amino
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Fig 5. Forest plots about subgroup analysis for the level of TNF-α between T1DM patients and controls with random effects model among
different ethnicity groups. Asia, SMD, 0.67, 95% CI, -1.03 to 2.36, P = 0.439; Europe, SMD, 1.30, 95% CI, 0.59 to 2.01, P < 0.001; America, SMD, 0.67,
95% CI, 0.15 to 1.19, P = 0.012; Africa, SMD, 2.07, 95% CI, 0.86 to 3.29, P = 0.001; Oceania, SMD, 1.24, 95% CI, 0.78 to 1.69, P < 0.001; Overall, SMD,
1.23, 95% CI, 0.77 to 1.68, P < 0.001.
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Fig 6. Sensitivity analysis and publication bias about the serum TNF-α level in T1DM. A: sensitivity analysis; B: publication bias, t = 2.04; P = 0.054;
95% CI, -0.074 to 7.370.
terminal kinase and inhibitor kinase, could cause serine/threonine phosphorylation of the
insulin receptor substrate, interfere with normal phosphorylation of tyrosine, and weaken
signal transduction of insulin, resulting in insulin resistance [
], otherwise, TNF-α may be result
in the destruction of pancreatic beta cells and lead to the development of T1DM [
Age, disease duration and ethnicity of T1DM patients were focused on in this study. In a
previous study [
], serum TNF-α level was not associated with the presence and severity of
microalbuminuria, otherwise, the level of urinary TNF-α was only significantly influenced by
albumin-creatinine ratio (ACR), although other factors had been included in the multivariate
analysis: age, duration of diabetes, BMI, history of cardiovascular disease, presence of
retinopathy, hypertension, and HbA1c levels. Lo, H. C., et al. [
] found that serum concentrations of
TNF-α had no significant change in type 1 diabetic children compared with healthy siblings
between different age groups (1±6 years old group, 6±12 years old group and 12±18 years old
group), which was inconsistent with our findings. Small sample size and different statistical
approach maybe illuminate the phenomenon. Ethnicity maybe another impact factor for the
level of TNF-α and no significant change existed in Asia populations. In this multifactorial
disease, Asia populations with varied geographic distribution, linked to climate, diet, lifestyle and
economic status may contribute to the discrepancy.
Significant heterogeneity still existed after subgroups analysis and regression analysis
indicated that these factors were not potential sources for the high heterogeneity, and we assume
that sources of heterogeneity may be attributed to the diversity in design, sample sizes,
measurement errors and so on. Otherwise, sensitivity analysis indicated the results were stable and
no publication bias existed in this meta-analysis.
Several limitations should be considered when cautiously interpreting the results. Firstly,
we could not conduct further subgroup analyses such as by gender, body weight and other
factors because of insufficient original data. Secondly, only reports in English and reports in
Chinese were chosen and eligible studies might have not been unpublished or published in other
languages. Small sample size, limited statistical power and high heterogeneity of the included
studies could also influence the results. Furthermore, some reports included in this
meta-analysis failed to disclose the status of diabetic complications, which may have impact on the
results. All these limitations should be kept in mind when interpreting the findings.
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In summary, the present meta-analysis indicates that compared with the healthy controls,
the T1DM patients have significantly increased serum level of TNF-α. The role of TNF-α in
the development of diabetes and diabetic complications warrant future investigation.
S1 Appendix. The references of the data source with DOI and access no.
S1 Table. PRISMA 2009 checklist.
Data curation: YCQ YLC.
Formal analysis: YCQ YLC YHP FT YX.
Funding acquisition: HLZ.
Investigation: YCQ YLC YHP FT YX XXZ.
Methodology: YCQ HLZ.
Project administration: YCQ.
Writing ± original draft: YCQ HLZ.
Writing ± review & editing: YCQ HLZ.
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