Meta-Analysis Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2015; 21(17): 5407-5416
Published online May 7, 2015. doi: 10.3748/wjg.v21.i17.5407
Is Helicobacter pylori infection associated with glycemic control in diabetics?
Yi-Ning Dai, Wei-Lai Yu, Hua-Tuo Zhu, Jie-Xia Ding, Chao-Hui Yu, You-Ming Li
Yi-Ning Dai, Wei-Lai Yu, Hua-Tuo Zhu, Jie-Xia Ding, Chao-Hui Yu, You-Ming Li, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Author contributions: Dai YN, Yu WL and Li YM proposed the study; Dai YN, Yu WL, Zhu HT and Ding JX collected the data; Dai YN, Yu WL, Zhu HT, Ding JX and Yu CH analyzed and interpreted the data; Dai YN and Yu WL drafted the manuscript; Yu CH and Li YM revised the manuscript; All the authors contributed to the design of the study and interpretation of its findings, and read and approved the final version to be published.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: You-Ming Li, MD, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. li_youming1956@163.com
Telephone: +86-571-87236532 Fax: +86-571-87236532
Received: July 24, 2014
Peer-review started: August 14, 2014
First decision: October 14, 2014
Revised: October 31, 2014
Accepted: December 8, 2014
Article in press: December 8, 2014
Published online: May 7, 2015

Abstract

AIM: To investigate whether Helicobacter pylori (H. pylori) infection is associated with glycemic control and whether hyperglycemia is modified by eradication therapy.

METHODS: The databases of PubMed, Cochrane Library, Chinese BioMedicine Web Base and Chinese Science and Technology Journals were searched from inception to June 2014. Studies examining the association between H. pylori infection and glycemic control and⁄or the effect of eradication treatment on glycemic control in diabetic humans were eligible for inclusion. Meta-analyses were conducted using the Review Manager software version 5.2. The outcome measures are presented as weighed mean differences (WMDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed by the Cochran Q test and the I2 statistic.

RESULTS: A total of 21 relevant publications were identified. A meta-analysis of 11 studies with 513 patients with diabetes mellitus (DM) showed significantly lower glycosylated hemoglobin (HbA1c) levels in the H. pylori-negative than H. pylori-positive DM participants (WMD = 0.43, 95%CI: 0.07-0.79; P = 0.02). In children and adolescents with type 1 DM (T1DM), there was a positive association between H. pylori infection and HbA1c level (WMD = 0.35, 95%CI: 0.05-0.64; P = 0.02), but there was no difference in those with type 2 DM (T2DM, WMD = 0.51, 95%CI: -0.63-1.65; P = 0.38). A meta-analysis of six studies with 325 T2DM participants showed a significant difference in the fasting plasma glucose levels between H. pylori-positive and H. pylori-negative participants (WMD = 1.20, 95%CI: 0.17-2.23; P = 0.02). Eradication of H. pylori did not improve glycemic control in the T2DM participants in a three-month follow-up period (HbA1c decrease: WMD = -0.03, 95%CI = -0.14-0.08; P = 0.57; fasting plasma glucose decrease: WMD = -0.06, 95%CI: -0.36-0.23; P = 0.68). Glycemic control was significantly better in T1DM participants who were not reinfected than in those who were reinfected (HbA1c: WMD = 0.72, 95%CI: 0.32-1.13: P = 0.00).

CONCLUSION: H. pylori infection is associated with poorer glycemic control in T1DM patients, but eradication may not improve glycemic control in DM in a short-term follow-up period.

Key Words: Diabetes mellitus, Eradication, Glycemic control, Helicobacter pylori, Meta-analysis, Reinfection

Core tip: Infection with Helicobacter pylori (H. pylori) has been suggested to play a pathogenic role in diabetes mellitus. The association between H. pylori and glycemic control in diabetics remains controversial. Our systematic review suggests a positive association between H. pylori and glycemic control in diabetics, especially in patients with type 1. While a short-term follow-up analysis demonstrated that H. pylori eradication does not improve glycemic control in diabetics, the long-term effects of eradication treatment remain unknown. Thus, the question remains as to whether the indication for H. pylori eradication in diabetic patients should be extended.



INTRODUCTION

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped, microaerophilic bacterium that plays a major pathogenic role in gastric diseases, including, but not limited to, chronic gastritis, peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue-associated lymphoma[1-3]. Studies published in the literature over the past two decades have suggested potential associations for H. pylori and several extragastric manifestations, such as idiopathic thrombocytopenic purpura, iron deficiency anemia, and atherosclerotic disease[4,5], as well as cardiovascular disease, diabetes mellitus (DM), nonalcoholic fatty liver disease, and other metabolic syndromes[6-9].

It has been suggested that infection with H. pylori is potentially linked to DM in many aspects. Various studies have reported a higher prevalence of H. pylori infection[10-13], a lower eradication rate[12-16] and a more frequent reinfection prevalence[12,13,17-19] in diabetic patients vs controls. Moreover, H. pylori infection is considered to be associated with metabolic control in diabetics[6,7,20]. Chen et al[20] found that H. pylori seropositivity was positively associated with glycosylated hemoglobin (HbA1c) levels through a large-scale cross-sectional analysis, which indicated a role of H. pylori in impaired glucose tolerance in adults. However, the questions of whether H. pylori infection is associated with poorer glycemic control in diabetic patients and whether eradication of H. pylori can improve their glycemic control remain controversial. Thus, we performed a systematic review with the aim of assessing whether H. pylori infection is associated with glycemic control in patients with DM and whether hyperglycemia in diabetics is modified by eradication of H. pylori.

MATERIALS AND METHODS
Search strategy

The PubMed, Cochrane Library, Chinese BioMedicine Web Base and Chinese Science and Technology Journals databases were systematically searched from inception to June 2014 for relevant studies. No language restriction was used. The search terms included: “Helicobacter pylori”[Mesh] or “Helicobacter pylori” or “H. pylori” and “Diabetes mellitus”[Mesh] or “diabetes mellitus” or “diabetes” or “diabetic” or “hyperglycemia” and “glucose” or “sugar” or “glucose control” or “glycemic control” or “glycaemic control” or “insulin” or “insulin sensitivity.” We also performed manual searches and screenings of the reference lists of each article identified by the electronic search.

Selection criteria

Cross-sectional studies, case-control studies, cohort studies and randomized controlled trials (RCTs) examining the association between H. pylori infection and glycemic control and/or the effect of eradication treatment on glycemic control in diabetic humans were considered eligible for study inclusion. Letters were also selected for use in our systematic review and meta-analysis. Two reviewers independently judged the eligibility of each study identified by the electronic and manual searches, and disagreements were resolved by consulting a third reviewer.

To be accepted for study inclusion, articles had to meet the following criteria: (1) study of subjects that had received previous diagnosis of DM [either type 1 (T1) or type 2 (T2)]; (2) measurement of fasting plasma glucose (FPG), HbA1c, insulin or C-peptide, and/or other parameters reflecting glycemic control in H. pylori-positive vs H. pylori-negative patients, in patients with H. pylori reinfection vs those who were not reinfected after successful eradication, in patients with successful H. pylori eradication treatment vs patients with H. pylori infection that was not eradicated, or in patients before and after an H. pylori eradication treatment; (3) H. pylori infection was confirmed by methods that were either invasive (histology, culture, or rapid urease test) or noninvasive (serologic test, 13C-urea breath test, stool antigen test). Age and gastrointestinal symptoms of the subjects at the time of enrollment were not considered as inclusive/exclusive criteria for study inclusion.

Articles were excluded if they provided no sufficient information of H. pylori infection or parameters reflecting glycemic control. Case series were also excluded.

Data extraction and quality assessment

A data extraction sheet was developed and pilot-tested using randomly selected studies, the results of which were used to refine the sheet accordingly. Data were extracted by two reviewers working independently. The following information was extracted from each included paper: (1) study characteristics, including author and year of publication, location of the study, sample size, study design, and type of intervention; (2) population information, including age, sex, type of DM, H. pylori status, duration of DM, presence or absence of dyspeptic symptoms, type of therapy for DM; (3) outcome data, including mean change and standard deviation in FPG, HbA1c, insulin or C-peptide, and other parameters reflecting glycemic control; (4) diagnosis of H. pylori infection; and (5) eradication treatment schedules and follow-up time. Disagreements were resolved by discussion.

The quality of included studies was also assessed by two reviewers working independently. Observational studies were assessed using standards by reference to Quality Assessment Forms[21] that ranged from 0 to 11 points, concerning the selection and representativeness of subjects, the diagnosis of DM and H. pylori infection, the comparability of the experimental group and the control group, the measurement of parameters, the loss of follow-up, and many other factors. RCTs were assessed by the Jadad scale[22], which ranged from 0 to 5 points, with higher scores indicating better quality.

Statistical analysis

The outcome measures were continuous and are presented as weighed mean differences (WMD) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed by the Cochran Q test and the I2 statistic. Heterogeneity was considered significant by the Cochran Q test for P < 0.05 or I2 > 50%[23,24]. A fixed or random effects model was adopted, depending on the absence or presence of heterogeneity. Funnel plots[25] were generated to initially assess publication bias, after which publication bias was confirmed using Egger’s[26] and Begg’s[27] tests. The meta-analyses were conducted using Review Manager software, version 5.2, while the Egger’s and Begg’s tests were carried out using Stata software, version 12.0.

In cases when the study design and population characteristics varied markedly, we decided not to combine studies but instead to show outcome data of each study in a table form or to describe the conclusion of each study.

RESULTS
Study selection, quality, and characteristics

The electronic searches yielded 193 publications with potential relevancy. After each publication was reviewed, only 21 met our inclusion criteria and were selected for study[17-19,28-45], including 14 studies that investigated the association between H. pylori and glycemic control in diabetics (11 examined HbA1c level[17,28-37], 6 examined FPG[29,32,35,37-39], and 2 examined the levels of insulin and C-peptide[36,40] in H. pylori-positive and H. pylori-negative diabetic patients), 6 studies of the effect of eradication treatment (2 trials that compared glycemic control in H. pylori-eradicated and noneradicated diabetic patients[41,42], and 4 trials that compared glycemic control before and after H. pylori eradication treatment in diabetics[33,43-45]), and two studies of the association between H. pylori reinfection and glycemic control[18,19].

The principal characteristics of the selected trials, as well as the quality score of each study, are shown in Table 1. All observational studies scored ≥ 7, and the Jadad scores of the two RCTs were both 3, which represented moderate to high quality. The basic information of the population is shown in Table 2. There were no significant differences in diabetes duration or gastrointestinal symptoms between the subjects in the experimental and control groups of each study, except for those denoted in the table, or those studies with data that were unavailable.

Table 1 Characteristics of the selected studies in our systematic review.
Ref.LocationStudy design and type of interventionDM patients,n (HP+/HP-)1Diagnosis ofH. pyloriParameter(s) measuredGlycemic control(HP+ vs HP-)Quality score2
de Luis et al[43], 2000
Spain
Observational;
13 (13/13)
UBT and serologic test
HbA1c
ND
9
before and after eradication (6-mo-follow-up)
Arslan et al[28], 2000
Turkey
Observational;
88 (49/39)
Serologic test
HbA1c
ND
8
HP+ vs HP-
Ko et al[29], 2001
Hong Kong, China
Observational;
63 (32/31)
RUT
HbA1c and FPG
ND
9
HP+ vs HP-
Jones et al[30], 2002
Australia
Observational;
63 (15/48)
Serologic test
HbA1c
ND
9
HP+ vs HP-
Ojetti et al[18], 2002
Italy
Observational;
34 (13/21)
UBT and histology
HbA1c
Worse
7
reinfected vs not reinfected (1-yr-follow-up)
Candelli et al[31], 2003
Italy
Observational;
121 (34/87)
UBT and serologic test
HbA1c
ND
8
HP+ vs HP-
Wang et al[32], 2003
China
Observational;
94 (75/19)
Serologic test
HbA1c and FPG
ND
8
HP+ vs HP-
Candelli et al[33], 2004
Italy
Observational;
58 (29/29)
UBT
HbA1c
ND
8
HP+ vs HP-
before and after eradication (6-mo-follow-up)
Agrawal et al[38], 2005
India
Observational;
80 (50/30)
RUT
FPG
Worse
8
HP+ vs HP-
Moghimi et al[41], 2007
Iran
RCT
41 (22/19)
UBT
HbA1c decrease and FPG decrease
ND
3 (Jadad score)
eradication vs non-eradication (3-mo-follow-up)
Ojetti et al[19], 2007
Italy
Observational;
40 (11/29)
UBT and histology
HbA1c
Worse
7
reinfected vs not reinfected (5-yr-follow-up)
Toporowska-Kowalska et al[34], 2007
Poland
Observational;
198 (48/150)
UBT
HbA1c
Worse
7
HP+ vs HP-
Khalil et al[44], 2007
Belgium
Observational;
100 (49/51)
UBT
HbA1C
ND
7
before and after eradication (12-mo-follow-up)
Demir et al[35], 2008
Turkey
Observational;
141 (87/54)
RUT and histology
HbA1c and FPG
ND
9
HP+ vs HP-
Lu et al[40], 2010
China
Observational;
80 (49/31)
UBT and histology
Insulin and C-peptide
Worse
8
HP+ vs HP-
Candelli et al[17], 2012
Italy
Observational;
69 (17/52)
UBT
HbA1c
ND
8
HP+ vs HP-
Wei[39], 2012
China
Observational;
68 (38/30)
RUT
FPG
Worse
7
HP+ vs HP-
Zhou et al[36], 2012
China
Observational;
180 (84/96)
Serologic test
HbA1c, insulin and C-peptide
ND
8
HP+ vs HP-
Vafaeimanesh et al[42], 2013
Iran
RCT;
93 (46/47)
UBT
HbA1c decrease and FPG decrease
ND
3 (Jadad score)
eradication vs noneradication (6-mo-follow-up)
Peng et al[37], 2013
China
Observational;
85 (43/42)
RUT and histology
HbA1c and FPG
Worse
7
HP+ vs HP-
Wada et al[45], 2013JapanObservational;
72 (72/72)UBT and histologyHbA1cND7
before and after eradication (6-mo-follow-up)
Table 2 Population information of the selected studies.
Ref.DM typeAge (yr)Sex (M/F, n)DM duration (yr)Type of therapy for DMGI symptoms, n
de Luis et al[43], 2000T1DM44.9 ± 15.54/913.49 ± 7.0Insulin10 with dyspepsia
(1-33)
Arslan et al[28], 2000T1DM12.6 ± 4.236/52HP+: 3.85 ± 3.62;Insulin5 had upper GI symptoms
HP-: 2.30 ± 2.12 (P = 0.02)1
(0-13)
Ko et al[29], 2001T2DM49.9 ± 12.029/34HP+: 5.2 ± 5.7;Irrespective29 had upper GI symptoms
HP-: 7.3 ± 6.6 (NS)
(1-26; median: 3)
Jones et al[30], 2002T1DM and T2DM44.7 ± 2.9925/3816.6 ± 1.4Insulin; oral drugsGI symptoms occurred frequently
Ojetti et al[18], 2002T1DM42 ± 918/16NAInsulinNone had GI symptoms
Candelli et al[31], 2003T1DM15 ± 665/566.6 ± 4.6InsulinA proportion had GI symptoms
Wang et al[32], 2003T2DM(28-83)44/50HP+: 5.8 ± 2.2;Insulin and oral drugsA proportion had GI symptoms2
HP-: 9.3 ± 6.5 (P < 0.05)1
Candelli et al[33], 2004T1DM13.35 ± 3.6228/30NAInsulin35 had GI symptoms
Agrawal et al[38], 2005T2DM52.8 ± 11.162/18NANA36 had GI symptoms
Moghimi et al[41], 2007T2DMNANANo difference in two groupsInsulin and oral drugsNA
Ojetti et al[19], 2007T1DM48 ± 923/1727.5 ± 12.5InsulinNA
Toporowska-Kowalska et al[34], 2007T1DM14.38 ± 3.75NA(0.5-16)InsulinNA
Khalil et al[44], 2007T1DM14.2 ± 2.856/446.2 ± 2.3Insulin45 had vague abdominal pain
Demir et al[35], 2008T2DM52.0 ± 8.244/976.1 ± 5.9Insulin, oral drugs or diet aloneAll had GI symptoms
HP+: 5.9 ± 6.1;
HP-: 6.28 ± 5.9 (NS)
Lu et al[40], 2010T1DM18.6 ± 10.645/35No difference in two groupsInsulinNA
Candelli et al[17], 2012T1DM16.8 ± NA (9-21)41/28NAInsulinA proportion had GI symptoms
Wei[39], 2012T2DM50.0 ± 11.236/32NANANA
Zhou et al[36], 2012T2DM59.22 ± 2.5787/93NANANA
Vafaeimanesh et al[42], 2013T2DM55.3 ± 10.450/43NANon-insulin usersA proportion had GI symptoms
Peng et al[37], 2013T2DM50.1 ± 10.351/34No difference in two groupsNANA
Wada et al[45], 2013T2DM63.7 ± 1.155/17NANANA
H. pylori infection and glycemic control

Eleven of the included publications[17,28-37] measured plasma HbA1c level in H. pylori-positive and H. pylori-negative patients with DM, including five studies[17,28,31,33,34] involving children and adolescents with T1DM, five studies[29,32,35-37] involving T2DM patients, and one study[30] in which the T1DM and T2DM patients were not distinguished. Overall, the pooled mean difference in HbA1c level showed a positive association with H. pylori infection (WMD = 0.43, 95%CI: 0.07-0.79; P = 0.02). Through the subgroup analysis, we found that the HbA1c level was significantly higher in the H. pylori-positive children and adolescents with T1DM than in their H. pylori-negative counterparts (WMD = 0.35, 95%CI: 0.05-0.64; P = 0.02). However, there was no significant difference in the HbA1c levels between H. pylori-positive and H. pylori-negative patients with T2DM (WMD = 0.51, 95%CI: -0.63-1.65; P = 0.38). Overall, the studies included were heterogeneous (I² = 72%: P < 0.01). But significant homogeneity was observed among the studies on children and adolescents with T1DM (I² = 25%; P = 0.26), whereas the studies on T2DM patients were heterogeneous (I² = 83%; P < 0.01; Figure 1).

Figure 1
Figure 1 Helicobacter pylori infection and glycosylated hemoglobin levels in diabetic patients. The forest plot demonstrates the positive association between Helicobacter pylori infection and HbA1c levels in children and adolescents with type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM). IV: Inverse variance.

Six observational studies[29,32,35,37-39] assessed FPG in H. pylori-positive and H. pylori-negative T2DM patients, the meta-analysis of which showed a positive association between H. pylori infection and FPG (WMD = 1.20, 95%CI: 0.17-2.23; P = 0.02). The included studies did not show homogeneity ( = 70%; P < 0.01; Figure 2).

Figure 2
Figure 2 Helicobacter pylori infection and fasting plasma glucose levels in type 2 diabetes mellitus patients. The forest plot demonstrates the positive association between Helicobacter pylori infection and fasting plasma glucose levels in type 2 diabetes mellitus patients. The studies included were not homogeneous. IV: Inverse variance.

Two observational studies[36,40] assessed the association of H. pylori infection and plasma insulin and C-peptide levels in patients with DM. We did not perform a meta-analysis for these parameters due to insufficient data and varied population characteristics. The study by Lu et al[40] found that fasting and 1-h and 2-h postprandial insulin was significantly lower in the T1DM patients with H. pylori positivity than in those with H. pylori negativity (P < 0.05). The study by Zhou et al[36] found no significant difference in the fasting C-peptide levels of T2DM patients with H. pylori positivity and H. pylori negativity (P > 0.05).

Effect of eradication

Two RCTs[41,42] assessed the effect of H. pylori eradication on HbA1c and FPG decreases in T2DM patients, after 3 or 6 mo of follow-up. Moghimi et al[41] compared H. pylori-positive patients with or without eradication [achieved by omeprazole (40 mg), azithromycin (500 mg), bismuth subcitrate (480 mg), and metronidazole (1000 mg) for 10 d]. Vafaeimanesh et al[42] compared H. pylori-positive patients with successful eradication to those who failed to achieve eradication treatment [by omeprazole (40 mg), metronidazole (1000 mg), amoxicillin (2000 mg) and bismuth subcitrate (480 mg), or by omeprazole (40 mg), clarithromycin (1000 mg), and amoxicillin (2000 mg) for 14 d]. Meta-analysis of these studies indicated no significant difference of glycemic control in the eradication group vs the noneradication group at 3 mo after treatment (HbA1c decrease: WMD = -0.03, 95%CI: -0.14-0.08, P = 0.57; FPG decrease: WMD = -0.06, 95%CI: -0.36-0.23; P = 0.68). The included studies were homogeneous (HbA1c decrease: = 0%; P = 0.76; FPG decrease: = 0%; P = 0.52; Figure 3).

Figure 3
Figure 3 Effect of Helicobacter pylori eradication on glycemic control in type 2 diabetes mellitus patients. A: Glycosylated hemoglobin decrease (%); B: Fasting plasma glucose decrease (mmol/L). The forest plot demonstrates that eradication of Helicobacter pylori did not improve glycemic control in type 2 diabetes mellitus patients in a 3-mo follow-up period. IV: Inverse variance.

Four observational studies[33,43-45] compared plasma HbA1c levels in H. pylori-positive diabetic patients before and after eradication treatment. Because the populations were heterogeneous in age, type of DM, gastrointestinal symptoms and so on, we did not perform meta-analysis and instead listed the results of each study in Table 3. All four studies suggested that eradication therapy for H. pylori does not affect glycemic control according to short-term follow-up (3-12 mo) in diabetic subjects.

Table 3 Glycosylated hemoglobin levels in Helicobacter pylori-positive diabetics before and after eradication treatment.
Ref.Eradication regimenBefore treatmentAfter treatment
P value
3 mo6 mo12 mo
de Luis et al[43], 2000A: 2000 mg, C: 1000 mg, O: 40 mg; 10 d7.7 ± 1.4NA7.3 ± 1.0NA> 0.05
Candelli et al[33], 2004< 14 yr: A: 50 mg/kg, C: 30 mg/kg, R: 2 mg/kg; 7 d8.2 ± 1.0NA8.3 ± 1.0NA> 0.05
> 14 yr: A: 2000 mg, C: 750 mg, R: 20 mg; 7 d
Khalil et al[44], 2007Two antibiotics among A, C or M; O; 7 d7.4 ± 1.3NANA7.9 ± 1.1> 0.05
Wada et al[45], 2013A: 1500 mg, C: 800 mg, L: 60 mg or O: 40 mg or R: 40 mg; 7 d6.9 ± 0.17.0 ± 0.17.0 ± 0.1NA> 0.05
Reinfection with H. pylori and glycemic control

Two cohort studies[18,19] assessed plasma HbA1c levels in H. pylori reinfected T1DM patients after H. pylori eradication compared to those who were not reinfected. Glycemic control was significantly better in those who were not reinfected (WMD = 0.72, 95%CI: 0.32-1.13; P < 0.01). Significant homogeneity was observed among the studies ( = 15%; P = 0.28; Figure 4).

Figure 4
Figure 4 Helicobacter pylori reinfection and glycosylated hemoglobin levels in type 1 diabetes mellitus patients. The forest plot demonstrates the positive association between Helicobacter pylori re-infection and glycosylated hemoglobin levels in type 1 diabetes mellitus patients. IV: Inverse variance.
Publication bias

Examination of the funnel plots (Figure 5) suggested some publication bias, but the results of Egger’s and Begg’s tests showed no evidence of significant bias in the studies considered. For studies on HbA1c level in H. pylori-positive and H. pylori-negative patients, the P-values of Egger’s and Begg’s tests were 0.365 and 0.350, respectively. For studies on FPG in H. pylori-positive vs H. pylori-negative patients, the P-values of Egger’s and Begg’s tests were 0.631 and 0.452, respectively.

Figure 5
Figure 5 Funnel plots for publication bias. Each dot represents the mean difference for glycosylated hemoglobin level (A) or fasting plasma glucose level (B) in Helicobacter pylori-positive and Helicobacter pylori-negative diabetics.
DISCUSSION

The results of the systematic review and meta-analyses suggest that H. pylori infection is associated with higher HbA1c levels in T1DM children and adolescents, which indicates poorer glycemic control. However, further studies are needed to prove whether H. pylori infection is associated with glycemic control in patients with T2DM because significant heterogeneity exists among the studies that have assessed HbA1c level and the studies that have assessed FPG level in H. pylori-positive and H. pylori-negative T2DM patients. We found that the subjects with T2DM in our selected studies may differ in several ways that affect glycemic control, including type of therapy for diabetes, diabetes duration, dyspeptic symptoms, and the compliance for glycemic control. These inconsistencies result in heterogeneity among the studies assessing glycemic control in T2DM patients. In contrast, the subjects with T1DM in our selected studies were all dependent upon insulin therapy, and as a result, no significant heterogeneity was seen in these studies.

Lu et al[40] reported that fasting and postprandial insulin secretions were significantly higher in H. pylori-negative T1DM patients than in their H. pylori-positive counterparts. Although there was a limitation of small sample size in that study, the previous finding is consistent with our current finding of better glycemic control occurring in H. pylori-negative T1DM patients compared to the H. pylori-positive patients with T1DM.

The results from the current systematic review also support the conclusion that eradication of H. pylori may not improve glycemic control in diabetic patients in a short-term follow-up period. Because the number of studies was limited and the follow-up time of the studies was short, further studies are needed to confirm the effect of H. pylori eradication on glycemic control in both T1DM and T2DM patients. Furthermore, results from our meta-analysis showed that H. pylori reinfection is associated with poorer glycemic control in T1DM patients.

A recent meta-analysis performed by another group that assessed the association of H. pylori and glycemic control in diabetics showed that H. pylori carriers did not have higher HbA1C levels than the noncarriers[46]. The authors concluded that H. pylori infection did not worsen glycemic control in patients with DM. Nevertheless, their meta-analysis did not estimate the quality of each included study. Moreover, the authors only examined a single parameter (HbA1C level) to estimate glycemic control of the subjects. The different search strategy used in our current meta-analysis, as well as the different databases that were searched and the different inclusion criteria that were applied, may have led to different conclusions. However, considering the relatively limited population in the current meta-analysis, we appeal for further large-scale observational studies to verify this association. On the other hand, our systematic review further assessed the effects of H. pylori eradication treatment and reinfection with H. pylori on glycemic control in diabetic humans, which may have some value for clinical practice.

The overall quality of the selected articles is moderate to high. Many of the studies evaluated confounding factors that may affect glycemic control, such as age, sex, duration of DM and gastrointestinal symptoms; in those studies, however, the cases and controls were comparable based upon the consistent measures of the potential confounders. Nevertheless, a few studies observed differences among the confounders in their comparative analyses, without any adjustments. The sample sizes of the selected studies were also small, which represents a major limitation. Furthermore, most of the selected articles were descriptive studies, which precluded their ability to determine the causal relationship between H. pylori and glycemic control.

The mechanisms linking H. pylori and glycemic control in diabetics are complicated. It is well known that T1DM occurs because of the autoimmune destruction of pancreatic islets (the micro-organ in which insulin production and secretion occur), whereas insulin resistance is a central pathogenic factor in T2DM. H. pylori might condition the pathophysiology of autoimmune response and insulin resistance syndrome by pathologic consequences through chronic inflammation outside the stomach, by which the bacterium affects glycemic control in diabetic patients[9,13,47,48]. In another aspect, gastrointestinal conditions related to H. pylori infection could delay gastric emptying, consequently favoring poor glucose control[13,43]. Furthermore, Ibrahim et al[49] demonstrated that infection with cytotoxin-associated gene A antigen-positive strains of H. pylori is strongly associated with poor glycemic control in T2DM patients. This finding suggests that the more pathogenic type of H. pylori, which expresses the cytotoxin-associated gene A antigen and the vacuolating cytotoxin-associated gene antigen, may play a major pathogenic role in DM through its interactions with factors related to the host inflammatory response.

Although H. pylori seems to be a pathogenic factor for DM, eradication of H. pylori does not benefit all diabetic patients. Khamaisi et al[50] reported a case of an 80-year-old man with end-stage renal disease and well-controlled T2DM, who developed severe hypoglycemia after administration of clarithromycin due to a clarithromycin-repaglinide drug interaction. Otsuka[51] reported the case of an 82-year-old man with insulin-controlled T2DM who experienced severe hypoglycemia during triple drug therapy. These collective findings remind us that clinicians should be aware of possible drug interactions that may occur in diabetics while undergoing H. pylori eradication therapy, so as to be careful to avoid adverse events.

Nowadays, the indications for treatment of H. pylori include peptic ulcer, mucosa-associated lymphoid tissue, functional dyspepsia, long-term nonsteroidal anti-inflammatory drug use, gastric cancer, iron-deficiency anemia and idiopathic thrombocytopenic purpura[4]. Since our study has suggested a positive association between H. pylori and glycemic control in diabetics, there should be a debate about whether we need to extend the H. pylori eradication indications for patients with DM. Since this systematic review does not allow for a conclusion about the long-term effect of H. pylori eradication on glycemic control in diabetics, further studies with large populations are needed to observe glycemic control in diabetics after eradication therapy in a longer follow-up period.

COMMENTS
Background

Helicobacter pylori (H. pylori) is potentially related to a series of extragastric diseases, including diabetes mellitus (DM). DM is a major health burden worldwide, and glycemic control in DM is an issue of great public concern. The findings regarding the association between H. pylori and glycemic control in diabetics have been largely inconsistent. Therefore, the authors conducted a systematic review to explore the relationship between H. pylori and glycemic control in DM.

Research frontiers

H. pylori is known to play a role in autoimmune disease and insulin resistance through complex processes. A large-scale survey has suggested an association between H. pylori and impaired glucose tolerance in adults. Consequently, a current hotspot in DM research is the association between H. pylori infection and glycemic control, as well as the effect of eradication treatment on glycemic control.

Innovations and breakthroughs

Previous studies have indicated that DM is linked to a higher prevalence of H. pylori, a lower eradication rate, and a higher incidence of reinfection. In addition, it is believed that H. pylori is associated with metabolic control in DM. However, the association between H. pylori and glycemic control in diabetics remains controversial. This systematic review has evaluated this potential association from a comprehensive perspective, including infection, eradication, reinfection with H. pylori and glycemic control. Meta-analyses were performed to examine the overall effect.

Applications

The results of this study indicate that H. pylori infection is associated with poorer glycemic control in type 1 DM patients and that eradication of H. pylori may not improve glycemic control in the short-term (3-12 mo). These findings may provide insights into clinical therapy and promote discussions as to whether the H. pylori eradication indications should be extended for DM patients.

Terminology

H. pylori is a gram-negative, spiral-shaped, microaerophilic bacterium that is related to gastric diseases in humans. Infection with H. pylori remains a worldwide threat to human health. DM is a common metabolic disease, which is characterized by high plasma glucose levels for a prolonged period. Type 1 DM results from the insufficient secretion of insulin, while type 2 DM is due to insulin resistance.

Peer-review

This is an interesting meta-analysis about the relation between H. pylori and glycemic control in diabetics. The title clearly states the purpose of the study. The study selection criteria were broad and included letters. The results section is clearly presented. The authors concluded that H. pylori infection is associated with poorer glycemic control in type 1 DM patients and that eradication of H. pylori may not improve glycemic control in diabetic patients over a short-term period. The fact that the authors found no improvement in HbA1c before and after eradication confirms the uncertainty of the relationship.

Footnotes

P- Reviewer: Dorchy H, Peedikayil MC, Shibata T, Tomkin GH S- Editor: Yu J L- Editor: Wang TQ E- Editor: Wang CH

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