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diabetes research and clinical practice 99 (2013) 200208

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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

Association between Helicobacter pylori infection and diabetes


mellitus: A meta-analysis of observational studies
Xiaoying Zhou a,b,1, Cuiling Zhang a,b,1, Junbei Wu a,b,1, Guoxin Zhang a,*
a
b

Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China

article info

abstract

Article history:

Aims: Some studies have shown Helicobacter pylori (H. pylori) infection to be associated with

Received 11 September 2012

diabetes mellitus, but the relationship remains controversial. This meta-analysis was

Received in revised form

designed to quantify the association between H. pylori infection and diabetes.

27 October 2012

Methods: A computerized search of PubMed and Embase was carried out. Studies that

Accepted 15 November 2012

provided data on H. pylori infection in both diabetes and control groups were selected.

Published on line 8 February 2013

An unconditional logistic regression model was used to analyze potential parameters


related to H. pylori prevalence. Subgroup analyses were conducted for types of diabetes,

Keywords:

methods of detection, geographical distribution, hemoglobin A1c (HbA1c) levels and evi-

Helicobacter pylori

dence grade.

Diabetes mellitus

Result: Forty-one studies were identified, involving 14,080 patients, with a total H. pylori

Meta-analysis

infection rate of 42.29%. The OR for H. pylori infection was increased to 1.33 (95% CI: 1.081.64;
P = 0.008) among the patients with diabetes. Subgroup analysis revealed a significantly
higher infection rate of H. pylori in the type 2 diabetes group versus the control group:
OR = 1.76, 95% CI: 1.402.21, P < 0.00001.
Conclusions: The pooled data suggests a trend toward more frequent H. pylori infections in
diabetes patients, especially in type 2 diabetes patients. As this is a meta-analysis of
observational studies, more randomized controlled trials should be done in the future.
# 2012 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Diabetes mellitus is a systemic metabolic disease that may


affect many organ systems, including the gastrointestinal
tract. Helicobacter pylori is regarded as a major gastroduodenal
pathogen and is etiologically linked with duodenal and gastric
disease [1]. Some studies have reported a higher prevalence of
H. pylori infection in people with diabetes [15]. The reasons for
this phenomenon may be that chemical changes in the gastric
mucosa, due to alterations in glucose metabolism, may
promote H. pylori colonization; in addition, the immune status

of diabetic patients is compromised, which may lead to an


increased susceptibility to H. pylori infection [2]. However,
other studies have indicated neutral or even negative results
[630]. Thus, the significance of diabetes mellitus as a risk
factor for H. pylori gastric colonization remains unknown [8].
This meta-analysis was conducted to gain a better
understanding of whether people with diabetes are more
prone to H. pylori infection than those without the disease. The
existence of a correlation between H. pylori and diabetes
mellitus may be of great use in clinic to treat people with
diabetes for gastrointestinal diseases.

* Corresponding author. Tel.: +86 25 83718836x6973; fax: +86 25 83674636.


E-mail address: guoxinz@njmu.edu.cn (G. Zhang).
1
These authors contributed equally to this work.
0168-8227/$ see front matter # 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.diabres.2012.11.012

diabetes research and clinical practice 99 (2013) 200208

2.

Materials and methods

2.1.

Inclusion criteria

Study design: published case-control and cross-sectional


1. studies.
2. Studies providing data dealing with H. pylori infection in
both diabetes group and control group.
3. Studies in which H. pylori infection was confirmed by 13Curea breath test, mucosal biopsy, enzyme-linked immunoassay (ELISA) and/or polymerase chain reaction (PCR). At
least one positive test was regarded as confirmation of
infection.

2.2.

Exclusion criteria

1. Case report and observational studies without control


groups.
2. Studies in which the data of H. pylori infection rate were not
available for either diabetes group or control group.
3. Subset of a published article by the same authors.
4. Studies limited to animals.
5. Studies in which research subjects had history of drug use
for antibiotics, H2 blockers, or proton pump inhibitors
within 4 weeks.

2.3.

Literature search

The PRISMA guidelines for conducting meta-analysis were


followed [31]. Two investigators (XYZ and CLZ) performed a
systematic literature search of PubMed and Embase, from
inception to April 2012, using the MeSH terms (Helicobacter
pylori or H. pylori) AND (diabetes mellitus OR diabetes). The
two investigators worked independently, at different times
and at different medical science information centers affiliated to Nanjing Medical University. The searches were repeated
several times. The last search was conducted on April 13,
2012. The relevant articles texts and reference lists were
manually search to broaden the scope of our findings. We
evaluated the full-texts of papers published in English, and
the English abstracts of papers published in other languages.
When further information was required from a potentially
relevant manuscript, the corresponding authors were contacted by the reviewers.

2.4.

Data extraction and appraisal of study quality

The two investigators who performed the literature search also


performed the data extraction, working independently. The
first authors, year and country of publication, study type,
method of detection, diagnosis, type of specimen, sample size
and type of organism identified were recorded for each included
study. The numbers of Helicobacter-positive and -negative
patients in the diabetes group and the control group were
collected. When data from one study was reported in more than
one manuscript, only one was selected for the meta-analysis,
according to the following criteria (applied consecutively): (1)
availability of adjusted odds ratio (OR) estimates for diabetics
and non-diabetics; (2) longer follow-up period (applicable to

201

nested case-control and cross-sectional analyses); and (3) larger


sample size. When the relationship between H. pylori infection
and diabetes was reported in different articles referring to the
same study, both were considered eligible, but only one was
included in the meta-analysis.

2.5.

Statistical analysis

In this study, the random effect model or fixed effect model


was used for meta-analysis, according to the heterogeneity
between studies. Heterogeneity was tested by the Q test
(P < 0.10 was considered indicative of statistically significant
heterogeneity) and the I2 statistic (values of 25%, 50% and 75%
were considered to represent low, medium and high heterogeneity, respectively). The fixed effect model was used when
there was no significant heterogeneity (I2 < 50%); otherwise
the random effect model was used [32]. P values were
calculated by I2 tests. All the reported P values were twosided, and P values < 0.05 were regarded as statistically
significant for all included studies.
Calculation of dichotomous variables was carried out using
the OR with the 95% confidence interval (CI) as the summary
statistic. The MantelHaenszel method was used to combine
ORs for the outcome parameters. Yates correction was
performed for studies containing a zero value in one cell
for the number of positive cases in one of the two groups [33].
Meta-regression analysis (random effects model) with REML
method was used to examine the impact of variables on
heterogeneity between studies. Beggs test and Harbords
weighted linear regression test were used to evaluate the
publication bias [34]. Analyses were performed using STATA
statistical software, Version 12.0.

3.

Results

3.1.

Description of studies

Both of the two investigators agreed on the results of data


extraction. The strategy used for study selection is displayed
in Fig. S1. Forty-one studies published between 1996 and 2011
were eligible for meta-analysis (Table 1). Only 13 studies in this
meta-analysis reached the significance level for difference in
H. pylori infection when considered independently of one
another, 28 of the studies lacked evidence of any difference in
prevalence between the diabetic and control populations, and
some even showed a lower rate of infection in patients with
diabetes. These studies involved 14,080 patients, with a total
H. pylori infection rate of 42.29% (5955/14,080). The cumulative
sample size of the diabetes group was 4595, of which 2263 were
H. pylori-positive (49.25%). Of the total 9485 controls, only 3692
(38.92%) were H. pylori-positive. An influence analysis indicated that no single study dominated the combined results.
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.diabres.2012.11. 012.

3.2.
Subgroup analysis of H. pylori infection prevalence in
people with diabetes
The results of the meta-analysis showed that the prevalence
of H. pylori infection in patients with diabetes was higher than

202

diabetes research and clinical practice 99 (2013) 200208

Table 1 Characteristics of studies on H. pylori in diabetics and non-diabetic control.


Year

Reference

Country

Method of
detection
Biopsy
ELISA
13
C-urea breath test
ELISA
Biopsy
ELISA
Biopsy
ELISA
ELISA
ELISA
Biopsy
ELISA
Biopsy
Biopsy
Biopsy
ELISA
Biopsy
13
C urea breath test
ELISA
Biopsy
ELISA
13
C urea breath test
ELISA
13
C urea breath test
13
C urea breath test
ELISA
Biopsy
ELISA
ELISA
Biopsy
ELISA
Biopsy, ELISA
ELISA
ELISA, Biopsy,
13
C-urea breath test
ELISA
Biopsy
Biopsy
H. pylori stool antigen
13
C urea breath test
Biopsy
ELISA

1996
1997
1998
1998
1998
1998
1999
1999
2000
2000
2001
2001
2001
2001
2001
2001
2001
2001
2002
2002
2002
2002
2002
2002
2003
2004
2005
2006
2007
2008
2008
2008
2008
2009

Malecki M
Pocecco M
Gasbarrini A
de Luis DA
Gentile S
Vaira D
Guvener N
Salardi S
Dore MP
Arslan D
Gary T.C.Ko
Xia HH
M. Ravera
Marrollo M
Senturk O
Vazeou A
Ivandic A
Quatrini M
Zelenkova J
Anastasios R
Colombo C
Cenerelli S
De Block CE
Maule S
Candelli M
Gillum RF
Gulcelik NE
Jaber SM
Bener A
Demir M
Hamed SA
Ariizumi K
Nicholas C.
Ciortescu I

Poland
Italy
Italy
Spain
Italy
Italy
Turkey
Italy
Italy USA
Turkey
China
Australia
Uganda
Italy
Turkey
UK
Croatia
Italy
Czech
Greece
Italy
Italy
Belgium
Italy
Italy
Maryland
Ankara, Turkey
Saudi Arabia
United Arab Emirates
Turkey
Egypt
Japan
Nigerian
Romanian

2009
2009
2009
2010
2010
2010
2011

Krause I
Cabral VL
Lazaraki G
Devrajani BR
Sfarti C
Ibrahim A
El-Eshmawy MM

Colombia
Brazil
Greece
Pakistan
Romania
Egypt
Egypt

that in the control group (49.25% versus 38.92%, OR = 1.33, 95%


CI: 1.081.64, P = 0.008) (Fig. 1), and the heterogeneity was high
(I2 statistic = 80.8%). Subgroup analyses of different types of
diabetes, various detection methods, geographic distribution
and evidence grade were performed to investigate the
influencing factors that may have impacted the overall results.
Analysis of the 15 studies of type 2 diabetes confirmed a
significantly higher infection rate of H. pylori (63.81% versus
control group: 42.16%, OR = 1.76, 95% CI: 1.402.21,
P < 0.00001). Analysis of the 15 studies of type 1 diabetes
showed no difference in infection rate between the diabetes
group and control group (38.26% versus 30.04%, OR = 1.26, 95%
CI: 0.841.87, P = 0.26) (Fig. 2).
Four techniques, including ELISA, mucosal biopsy, 13Curea breath test and stool antigen assay, were utilized for
identifying the presence of H. pylori in all tests evaluated in
this meta-analysis. ELISA was performed in 18 of the
studies to detect the H. pylori-specific IgG or IgA in serum
samples. The pooled data indicated that the positive rate of

Specimen
Tissue
Serum
Breathe
Serum
Tissue
Serum
Tissue
Serum
Serum
Serum
Tissue
Serum
Tissue
Tissue
Tissue
Serum
Tissue
Serum
Tissue
Serum
Serum

Serum
Tissue
Serum
Serum
Tissue
Serum
Tissue,Serum
Serum
Serum
Serum
Tissue
Tissue
Stool
Tissue
Serum

Disease

Grade of
reference

HP (+)
in DM

HP (+) in
controls

I + II
I
I
I
II
DM
II
I
I + II
I
II
I + II
I + II
I + II
II
I
I + II
DM
I + II
DM
I
II
I
II
I
II
II
I
II
II
I + II
DM
II
I + II

Low
Moderate
Low
Moderate
Moderate
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Moderate
Low
Moderate
Low
Low
Low
High
Moderate
Moderate
Low
Low
Low

12/39
18/69
43/116
38/80
122/164
40/112
41/51
18/103
195/385
49/88
32/63
142/429
2/22
48/74
59/67
8/118
31/46
49/71
53/195
25/67
41/138
13/30
72/229
22/31
34/121
193/366
59/78
21/61
161/210
87/141
68/80
36/67
21/60
70/100

68/100
17/310
17/50
34/100
82/164
104/400
14/25
25/236
223/506
13/42
31/55
54/170
43/110
56/117
58/72
8/171
8/40
33/71
110/216
37/105
45/138
18/43
42/100
15/31
43/147
1628/4218
33/71
128/543
136/210
83/142
46/60
46/67
17/60
73/100

I
I
II
II
I
II
I

Low
Low
Moderate
Moderate
Moderate
High
Moderate

31/57
5/15
20/49
54/74
49/69
53/98
128/162

113/140
17/30
12/29
38/74
25/40
58/102
41/80

these antibodies was similar between the diabetes group


and the control group (44.09% versus 37.85%, OR = 1.14, 95%
CI: 0.831.57, P = 0.41). Mucosal biopsy also showed a
positive rate that was similar between the two groups
(61.19% versus 54.46%, OR = 1.27, 95% CI: 0.792.04, P = 0.32)
in 14 studies, as did the 13C-urea breath test (38.42% versus
36.84%, OR = 1.22, 95% CI: 0.891.68, P = 0.21). However,
when these four techniques were compared, the positive
rate of H. pylori detection was significantly different among
each (ELISA: 39.61%, mucosal biopsy: 55.90%, 13C-urea
breath test: 37.71%, Hp stool antigen: 62.16%; P < 0.05 for
all) (supplementary Fig. 1).
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.diabres.2012.
11.012.
Stratification analysis by geographic region indicated that
the levels of H. pylori among people with diabetes were higher
in Asia, but not statistically significant in other districts. The
ORs were 1.66 (95% CI: 1.162.37) for the 10 studies conducted

diabetes research and clinical practice 99 (2013) 200208

203

Fig. 1 Meta-analysis of studies on the prevalence of H. pylori in the diabetes group compared with the control group.

in Asia (P = 0.005), 1.34 (95% CI: 0.991.83) for the 22 studies


from Europe (P = 0.06), 1.21 (95% CI: 0.552.66) for the five
studies from Africa (P = 0.64), 1.06 (95% CI: 0.731.55) for the
one study from Oceania (P = 0.75), 1.77 (95% CI: 1.432.20) for
the one study from North America (P < 0.00001), and 0.30 (95%
CI: 0.170.55) for the two studies from South America
(P < 0.001) (supplementary Fig. 2).
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.diabres.2012.11.012.
Subgroup analysis assessing the quality of evidence for
each included study was performed and each study was
classified into low, moderate or high quality. The moderate
group included 11 studies, and the pooled data indicated that
the positive rate of H. pylori was higher in the diabetes group
than that in the control group (OR = 1.75, 95% CI: 1.162.24). In
the low group, the positive rate was similar between the two

groups (OR = 1.19, 95% CI: 0.951.55) in 28 studies, as in the high


group (OR = 1.29, 95% CI: 0.662.55) (supplementary Fig. 3).
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.diabres.2012.
11.012.
However, for the four factors, meta-regression did not
identify one that significantly influenced the result (supplementary material).
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.diabres.2012.
11.012.

3.3.

Publication bias

Funnel plot analysis did not show any evidence of publication


bias (Beggs test z = 0.35, P = 0.734, continuity corrected).

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diabetes research and clinical practice 99 (2013) 200208

Fig. 2 Forest graph of H. pylori infection stratified by diabetes type.

Harbords weighted linear regression (B) also indicated a nonsignificant publication bias (P = 0.921) (Fig. 3).

4.

Discussion

A meta-analysis of 41 studies from across the globe indicated


that, H. pylori infection was higher in patients with diabetes
than that in those without the disease (P = 0.008). Five reasons
may explain this finding. Firstly, diabetes-induced impairment of cellular and humoral immunity may enhance
sensitivity to H. pylori infection [48]. Secondly, diabetesinduced reduction of gastrointestinal motility and acid
secretion may promote pathogen colonization and infection
rate in the gut [20]. Thirdly, H. pylori gastric infection itself may
increase secretion of pro-inflammatory cytokines, and elevated levels of inflammatory cytokines may lead to changes in the

structure of insulin receptor substrate interfering with its


interaction with its receptors and inhibiting the action of
insulin [2,49]. Fourthly, altered glucose metabolism may
produce chemical changes in the gastric mucosa that promote
H. pylori colonization [6]. Finally, people with diabetes are more
frequently exposed to pathogens than their healthy counterparts as they regularly attend hospital settings [5].

4.1.

Type of diabetes

Based on our results, the type 2 diabetes group had a higher


infection rate compared with the type 1 group, and their
respective control groups. In type 2 diabetes, cells become
resistant to the action of insulin, and the pancreas is unable to
produce enough insulin to overcome this resistance. Instead of
moving into cells for metabolic processing, sugar accumulates
in the bloodstream [45]. Both genetic and environmental

diabetes research and clinical practice 99 (2013) 200208

205

Fig. 3 Estimating publication bias by Beggs test (A) and Harbords weighted linear regression test (B). Beggs test (A) was
adopted for measuring publication bias and showed a non-significant publication bias (P = 0.917). Harbords weighted
linear regression (B) also indicated a nonsignificant publication bias (P = 0.921).

factors have been implicated in the development of type 2


diabetes. However, the exact etiology remains uncertain and
further investigations are needed. One of the most well
accepted risk factors for type 2 diabetes is obesity [46,47].
When a person is overweight, the cells in the body become less
sensitive to the insulin that is released from the pancreas, and
there is some evidence that fat cells are more resistant to
insulin than muscle cells. Perdichizzi et al. reported a higher
prevalence of H. pylori infection in both obese patients and
patients with diabetes compared with normal weight and nondiabetic control groups [35]. In addition, the mean age of type 2
diabetes patients is older than that of type 1 diabetes patients
[11]. Gasbarrini et al. showed that infection rate increases with
age and duration [9]. In the present meta-analysis, no
difference of H. pylori infection rate was found between type
1 diabetes patients and the non-diabetic control group. A
hypothesis explaining the distinct results between type I and II
diabetes might simply be that factors contributing to the
pathogenesis of type I are rather distinct from those
contributing to the pathogenesis of type II diabetes. Type 1
diabetes occurs as the result of autoimmune destruction of the
pancreatic islet insulin-producing beta cells, which leaves the
patient with little or no insulin. It has been reported that H.

pylori infection may also be associated with some autoimmune


diseases [9]. However, our results do not agree with such a
relationship.

4.2.

Method of detection

ELISA is an inexpensive and technically simple test of serum


samples to determine the presence of antibodies against H.
pylori. Our data showed that the positive rate of antibodies to
H. pylori was similar between the diabetic and control groups.
However, it is important to note that ELISA does not confirm a
current active infection. As antibodies may persist after an
infection has cleared, it is possible that some of the patients
who tested positive by ELISA did not represent active infection.
Also, the fact that some patients became IgG negative after
successful eradication treatment should be considered as
false-negative results.
The 13C-urea breath test is preferred as it is non-invasive
and convenient [36]. However, due to different 13C-based UBT
protocols (using various doses of 13C-urea), different times and
intervals of the breath sample collection, and different test
meals with various effects on delaying gastric emptying,
makes direct comparison of UBT results difficult [50].

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diabetes research and clinical practice 99 (2013) 200208

Mucosal biopsy, including methods of histology, rapid


urease test and bacterial culture are considered the gold
standard for diagnosing H. pylori infection status. However,
biopsy-based methods may suffer from sampling error,
because of the patchy nature of the infection and low
concentration of bacteria in some regions [37]. In the 41
studies included in the present meta-analysis, only one used
the H. pylori stool antigen test (HpSA). This test is a rapid, noninvasive method with high sensitivity (94%) and specificity
(94%), and is potentially very helpful in diagnosing active H.
pylori infection [1]. However, stool samples require patient
compliance, and are inconvenient to handle.
In addition, since the publication year of our 41 studies
ranged from 1996 to 2011, it is possible that testing using a
single detection method may have produced different positive
rates of H. pylori infection due to advances in each of the
technologies. Therefore, the active and extensive research
ongoing in the H. pylori field promises the development of new,
more accurate and more convenient detection methods [38].

4.3.

Geographical distribution

The reported prevalence of H. pylori infection has ranged


widely between nations. In developing countries, such as Latin
America and Africa, the infection rate is significantly higher
than that in developed countries. The lower prevalence of H.
pylori infection in industrialized nations is attributed to the
higher standards of hygiene and socioeconomics [3941]. In
addition, it has been suggested that ethnicity and place of birth
may also play a role in susceptibility to H. pylori infection
[42,43].
The relationship between HbA1C value and H. pylori
infection is unclear [44]. It has been reported that HbA1c
levels were significantly greater in H. pylori-positive patients
with type 1 diabetes than in H. pylori-negative type 1 diabetes
patients [4,6]. However, other studies have reported contradicting results [17,19]. H. pylori seropositivity was significantly
associated with the duration of diabetes [4], but this result was
not confirmed by other studies [7,22].

presence of a drug may have confounded our metaanalysis results [3]. Finally, the fact that data were derived
from the abstracts of papers not written in English might
contribute to the selection bias.

5.

Conclusions

In conclusion, this meta-analysis revealed a trend toward a


higher presence of H. pylori in diabetes patients than in the
non-diabetes control group. Moreover, this trend was
significant in geographic regions with a higher prevalence
of this infectious agent. Because sensitivity and specificity
differ greatly among various detection techniques, a gold
standard for the identification of Helicobacter species has yet
to be established. Due to the limited number of studies and
their small sample sizes, further research should be conducted to investigate the possible relationship between
diabetes and H. pylori infection. Considering the obvious
heterogeneity in our study, large-scale and multicenter
studies are still needed to clarify the association of Helicobacter species and diabetes.

Grant support
National Natural Science Foundation of China (No. 81072032).

Author contributions
Xiaoying Zhou, Cuiling Zhang and Junbei Wu contributed to
collect and analyze the data, and wrote the first draft of the
paper. Guoxin Zhang contributed to design the study and
proofread the manuscript.

Conflict of interest
The authors declare that they have no conflict of interest.

4.4.

Study limitations

Firstly, the selection of the controls varied between


studies. Secondly, H. pylori infection was diagnosed by
different methods and strategies among the studies, with
some relying on a single detection method and others
using more than one method. This may have produced
different positive rates of H. pylori infection due to
advances in each of the technologies and could have
influenced the cumulative positive rates. Thirdly, as the
papers included in the present meta-analysis were limited
to those published and listed on PubMed until April 2012, it
is possible that some relevant published or unpublished
studies, which may have met the inclusion criteria, were
missed. These overlooked studies may have corrected
some inherent biases due to study design. Fourthly, the
type of drug therapy used by patients with diabetes was
not considered in the present meta-analysis. Some drugs
used to treat diabetes, such as thiazolidinediones, may
suppress inflammatory markers and it is possible that the

Acknowledgement
We would like to thank Prof. Rongbin Yu for his kind help in
reviewing our statistical process and advising on study design.

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