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Association of Helicobacter pylori infection with complications of diabetes: a single-center retrospective study

BMC Endocrine Disorders volume 24, Article number: 152 (2024) Cite this article

Abstract

Background

Previous studies examined the association of Helicobacter pylori infection (H. pylori) with complications of diabetes, but the results have been inconsistent. The aim of this study of patients with type-2 diabetes (T2D) was to determine the association of H. pylori infection with the major complications of diabetes.

Methods

This single-center retrospective study examined patients with T2D who received H. pylori testing between January 2016 and December 2021. Logistic regression analyses were used to evaluate the association of H. pylori infection with four major complications of diabetes.

Results

We examined 960 patients with T2D, and 481 of them (50.1%) were positive for H. pylori. H. pylori infection was significantly associated with diabetic nephropathy (odds ratio [OR] = 1.462; 95% confidence interval [CI]: 1.006,2.126; P = 0.046). In addition, the co-occurrence of H. pylori positivity with hypertension (OR = 4.451; 95% CI: 2.351,8.427; P < 0.001), with glycated hemoglobin A1c (HbA1c) of at least 8% (OR = 2.925; 95% CI: 1.544,5.541; P = 0.001), and with diabetes duration of at least 9 years (OR = 3.305; 95% CI:1.823,5.993; P < 0.001) further increased the risk of diabetic nephropathy. There was no evidence of an association of H. pylori infection with retinopathy, neuropathy, or peripheral vascular disease.

Conclusions

Our study of T2D patients indicated that those with H. pylori infections had an increased risk of nephropathy, and this risk was greater in patients who also had hypertension, an HbA1c level of 8% or more, and diabetes duration of 9 years or more.

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Introduction

Helicobacter pylori is a Gram-negative bacterium that infects the gastric mucosa of the upper gastrointestinal tract, and is present in approximately half of all people worldwide. Although most infected individuals are asymptomatic, infection can lead to chronic gastritis, peptic ulcers, gastric adenocarcinomas, and mucosa-associated lymphoid tissue lymphoma [1]. A recent literature review concluded there were positive correlations of H. pylori infection with extra-gastroduodenal manifestations, such as diabetes, neurological diseases, hematological diseases, cardiovascular diseases, and autoimmune diseases [2].

Type-2 diabetes (T2D) is a major public health problem worldwide. In 2017, an estimated 451 million people between the ages of 18 and 99 years had diabetes, and this number is expected to increase to 693 million by 2045 [3]. The uncontrolled hyperglycemia in patients with diabetes can lead to serious microvascular and macrovascular complications, and these complications adversely affect the duration and quality of life [4, 5] and are a significant economic burden for healthcare systems. Strict glycemic control can prevent or delay these complications, and thereby improve long-term health and reduce treatment-associated costs. A meta-analysis of 13 studies concluded that diabetes was significantly associated with H. pylori infection [6]. Another meta-analysis of 41 case-control studies identified H. pylori as a risk factor for diabetes, particularly T2D [7]. H. pylori infection is also associated with higher levels of fasting plasma glucose (FPG) and glycated hemoglobin A1c (HbA1c) in patients with diabetes [8, 9]. The importance of these two indicators was emphasized in a longitudinal observational cohort study of Korean patients with newly diagnosed T2D, which found that early achievement of the target level of HbA1c was associated with long-term durable glycemic control and a decreased risk of complications [10]. A systematic review and meta-analysis from 2021 concluded that H. pylori eradication improved glycemic control in patients with T2D [11]. Other studies demonstrated that H. pylori eradication led to decreased levels of HbA1c and improved glycemic control [12, 13]. Therefore, many studies support the presence of an association of H. pylori infection with diabetes and hyperglycemia.

Although several studies have examined the relationship of H. pylori infection with diabetes complications (nephropathy, retinopathy, neuropathy, and peripheral vascular disease [PVD]), their conclusions have been inconsistent [14,15,16,17,18,19,20,21,22,23]. Demir et al. showed that diabetes patients with H. pylori infection had a higher incidence of neuropathy, but there was no association between retinopathy, nephropathy, and H. pylori infection [14]. A study in Turkey showed that H. pylori positivity was significantly associated with the presence of nephropathy and neuropathy [15]. Although some studies reported that the prevalences of nephropathy, neuropathy, retinopathy and PVD complications were significantly higher in diabetes patients who were H. pylori-positive [16,17,18,19,20], other studies reported contrary results [21,22,23]. These discordant results may be due to differences in study design, patient populations, sample size, or other factors. Therefore, clinical investigations with large samples are needed to investigate this topic. The aim of the present study was to investigate the association of H. pylori infection with complications of diabetes, especially diabetic nephropathy, retinopathy, neuropathy, PVD.

Patients and methods

Study population

The electronic medical records of patients with T2D at Changzhou No. 2 People’s Hospital, Affiliated with Nanjing Medical University between January 2016 and December 2021 were retrospectively examined. Diabetes was defined according to the 1999 criteria of the World Health Organization [24] as the presence of diabetic symptoms (such as polydipsia, polyuria, polyphagia, and unexplained weight loss) and a random plasma glucose of at least 11.1 mmol/L, or a FPG of at least 7.0 mmol/L, or a plasma glucose of at least 11.1 mmol/L at 2 h after a 75 g dose of oral glucose. H. pylori infection was diagnosed by a positive result from the 13C-urea breath test (13C-UBT), or the rapid urease test (RUT), or serological testing.

The inclusion criteria were diagnosis of T2D, age of at least 18 years, receipt of an H. pylori infection test, receipt of screening for diabetes complications (diabetic nephropathy, retinopathy, neuropathy, PVD), and complete data on demographics and serum biochemical indexes.

The exclusion criteria were type 1 diabetes, a history of H. pylori eradication therapy, any malignancy, chronic renal failure requiring dialysis treatment, treatment with a PPI, bismuth, or an antibiotic in the preceding 1 month, absence of an H. pylori infection test, and missing information regarding complications of diabetes (diabetic nephropathy, retinopathy, neuropathy, PVD).

Data collection

The baseline demographic data and serum biochemical indexes included age, gender, body mass index (BMI), smoking and alcohol habits, history of hypertension, known duration of T2D, HbA1c, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), calcium, endoscopic findings and comorbidities. BMI (kg/m2) was calculated from body weight and height.

Assessment of diabetic complications

According to the American Diabetes Association [25], the diagnosis of diabetic nephropathy is based on the presence of a low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) and/or increased level of urinary albumin (≥ 30 mg/g creatinine) that persisted more than 3 months. Diabetic retinopathy is a common microvascular complication that leads to vision loss, and was determined by an ophthalmologist using a standard fundus examination [26]. Diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations, and diagnosis is based on the exclusion of similar disorders [26]. The diagnosis of neuropathy was based on the results of electromyography and nerve fiber conduction examinations, as previously described [27]. PVD was diagnosed from clinical findings of a history of intermittent claudication pain, absence of pulse in a physical examinations, or both of these, with confirmation from a color-Doppler ultrasound examination [28].

Statistical analysis

Descriptive data are presented as mean ± standard deviation (SD), median (interquartile range [IQR]), or number (percentage). The independent samples t-test was used to compare continuous data that had normal distributions, the Mann-Whitney U test was used to compare continuous data that had non-normal distributions, and the χ2 test was used to compare categorical data. Receiver operating characteristic (ROC) curves were constructed, and the Youden index was used to identify the optimal cutoff values for HbA1c, age, and known duration of diabetes for prediction of diabetic nephropathy and PVD. To assess the effect of different individual risk factors on T2D complications and the joint effects of H. pylori infection and other risk factors on these complications, binary logistic regression analysis was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). A P value below 0.05 was considered to be significant, and all statistical analyses were performed using SPSS Statistics version 26.0 (IBM Corporation, Armonk, NY, USA).

Results

We examined the records of 960 T2D patients who met all the eligibility criteria (Table 1). There were 481 H. pylori-positive patients and 479 H. pylori-negative patients. For the H. pylori-negative patients, the prevalence of atrophic gastritis was 13.6% and the prevalence of peptic ulcer was 5.8%. The other endoscopic findings of H. pylori-negative patients included nodular gastritis, gastric erosion, and gastric polyp. The H. pylori-positive group had a higher prevalence of diabetic nephropathy (P = 0.042), but the two groups had no statistically significant differences in retinopathy, neuropathy, or PVD.

Table 1 Clinical characteristics of diabetes patients who tested positive or negative for H. pylori infection*
Full size table

We performed univariate and multivariate logistic regression to identify the risk factors for diabetic nephropathy (Table 2). The multivariate analysis showed that the significant and independent risk factors for diabetic nephropathy were H. pylori infection (aOR = 1.462, 95% CI: 1.006–2.126, P = 0.046), hypertension (aOR = 2.802, 95% CI: 1.829–4.293, P < 0.001), long duration of diabetes (aOR = 1.057, 95% CI: 1.031–1.084, P < 0.001), high level of HbA1c (aOR = 1.161, 95% CI: 1.065–1.267, P < 0.001), and high level of TG (aOR = 1.114, 95% CI, 1.044–1.188, P = 0.001).

Table 2 Logistic regression analysis of factors associated with diabetic nephropathy*
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ROC analysis of the continuous variables from the multivariable analysis for the prediction of diabetic nephropathy indicated that the area under the curve (AUC) was 0.595 for HbA1c and 0.613 for diabetes duration (Fig. 1). Based on the Youden index, the cutoff value was 8% for HbA1c and 9 years for diabetes duration. The other 3 significant factors from the multivariable analysis were binary variables, including the TG level (< 1.7 mmol/L vs. ≥1.7 mmol/L), which was classified according to the American Association of Clinical Endocrinology Clinical Practice Guideline [29].

Fig. 1
figure 1

Receiver operating characteristic curves for prediction of diabetic nephropathy

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We evaluated the joint effects of H. pylori infection with other factors on the risk of diabetic nephropathy (Table 3). The results demonstrated that the co-occurrence of H. pylori positivity with hypertension (aOR = 4.451, 95% CI: 2.351–8.427, P < 0.001), with an HbA1c level of at least 8% (aOR = 2.925, 95% CI: 1.544–5.541, P = 0.001), and with diabetes duration of at least 9 years (aOR = 3.305, 95% CI:1.823–5.993, P < 0.001) were significantly associated with diabetic nephropathy.

Table 3 Joint effects of H. Pylori infection and traditional risk factors on diabetic nephropathy*
Full size table

We then performed univariate and multivariate logistic regression analyses of the risk factors for PVD (Table 4). The results of the multivariate analysis showed that H. pylori infection was not a significant risk factor for PVD (aOR = 0.955, 95% CI: 0.718–1.270, P = 0.752). However, greater age (aOR = 1.063, 95% CI: 1.046–1.080, P < 0.001), smoking (aOR = 2.278, 95% CI: 1.584–3.277, P < 0.001), hypertension (aOR = 1.833, 95% CI: 1.372–2.449, P < 0.001), and long duration of diabetes (OR = 1.034, 95% CI: 1.011–1.057, P = 0.003) were significantly and independently associated with PVD.

Table 4 Logistic regression analysis of factors associated with peripheral vascular disease*
Full size table

ROC analysis of significant continuous variables from the multivariable analysis indicated that the AUC value was 0.679 for age and 0.606 for diabetes duration for prediction of PVD (Fig. 2). Based on the Youden index, the cutoff values were 56-years-old for age and 8 years for diabetes duration.

Fig. 2
figure 2

Receiver operating characteristic curves for prediction of peripheral vascular disease

Full size image

As above, we also evaluated the joint effects of H. pylori infection with other factors on the risk of PVD (Table 5). The results showed that the co-occurrence of H. pylori positivity with age of at least 56 years (aOR = 2.771, 95% CI: 1.807–4.250, P < 0.001), history of smoking (aOR = 2.344, 95% CI: 1.464–3.752, P < 0.001) were significantly associated with PVD.

Table 5 Joint effects of H. Pylori infection and traditional risk factors on peripheral vascular disease
Full size table

Discussion

The major result of this retrospective study is that infection by H. pylori was an independent risk factor for diabetic nephropathy. We also demonstrated that the co-occurrence of H. pylori infection with traditional risk factors (hypertension, long duration of diabetes duration, high level of HbA1c) further increased the risk of diabetic nephropathy. Although our results showed that H. pylori infection was not associated with retinopathy, neuropathy, or PVD, we found that the co-occurrence of H. pylori infection with several traditional risk factors (age, smoking) increased the risk of PVD. In addition, although our control diabetic group was H. pylori-negative, these individuals had many gastric alterations, such as atrophic gastritis and peptic ulcer, suggesting that T2D patients are more vulnerable to gastric mucosal injuries.

It is uncertain how H. pylori infection in the gut affects the pathogenic processes that are responsible for diabetic nephropathy, although there are several possible mechanisms. First, several studies suggested that inflammatory responses that are secondary to infection could lead to systemic inflammation, and systemic inflammation is an established risk factor for diabetic nephropathy [30]. In support of this interpretation, patients with diabetes are more vulnerable to H. pylori infections, and several studies reported that T2D patients with H. pylori infections were more likely to have elevated levels of multiple inflammatory cytokines, including C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8) [15, 16, 21]. There is also a close relationship of T2D with dysfunctional endothelial cells, increased insulin resistance, disrupted lipid metabolism, and proteinuria [31,32,33,34].

Second, chronic H. pylori infection can lead to atrophic gastritis, which reduces the absorption of folate and vitamin-B12. The conversion of homocysteine (HCY) into methionine requires these two co-factors, and their depletion leads to an increased level of HCY. An elevated level of HCY can contribute to vascular endothelial damage, in that it increases atherosclerosis and thrombogenesis and it inhibits the secretion of nitric oxide (NO) by endothelial cells. These responses can cause platelet aggregation and vasoconstriction, and increase the risk for arteriosclerosis and hypertension [35, 36], which can lead to diabetic nephropathy.

Our results also demonstrated that H. pylori infection, hypertension, diabetes duration, HbA1c level, and TG level were independent risk factors for diabetic nephropathy. Moreover, we showed that the co-occurrence of H. pylori positivity with hypertension, with an HbA1c level of 8% or more, and with diabetes duration of 9 or more years further increased the risk of diabetic nephropathy. These additive or synergistic effects are biologically plausible. In particular, nuclear factor-kappa B (NF-κB) is a transcription factor that regulates the level of many chemokines, cell adhesion proteins, inflammatory cytokines, and other molecules that function in the pathogenesis of diabetic nephropathy [30]. In addition, the NF-κB-mediated stimulation of the expression of pro-inflammatory genes and their signaling pathways has a major effect in promoting the progression of hypertension to diabetic nephropathy [37], and H. pylori infection can activate NF-κB signaling [38]. Taken together with our results, we suggest that the NF-κB-mediated secretion of inflammatory cytokines may be responsible for kidney damage in patients who have concomitant H. pylori infection and hypertension. This alternative interpretation can also explain why T2D patients with hypertension and H. pylori infection have a greater risk of diabetic nephropathy.

HbA1c is the best single biomarker of long-term glycemic control, and higher levels reflect long-term hyperglycemia [39]. Hyperglycemia is a well-established risk factor for diabetic nephropathy [40], and several studies reported that H. pylori infection was associated with increased levels of plasma glucose and HbA1c in patients with T2D [8, 9, 41]. These previous studies suggest that the combination of an elevated level of HbA1c and H. pylori infection is a biologically plausible explanation for the increased risk of diabetic nephropathy.

A prolonged duration of diabetes is another significant risk factor for diabetic nephropathy [40], and there is evidence that diabetes duration is positively associated with H. pylori infection [42]. This is consistent with our finding that the co-occurrence of a longer duration of diabetes and H. pylori infection further increased the risk of diabetic nephropathy. However, we found no elevated risk of diabetic nephropathy in patients who had H. pylori infection with an elevated TG level (≥ 1.7 mmol/L). This may be because of our small sample size, in that only 41 of our patients (4.3%) had both H. pylori infection and an elevated TG level. We therefore suggest that future studies with larger samples examine this relationship.

A recent systematic review and meta-analysis concluded that infection by H. pylori was associated with atherosclerosis [43]. An earlier study by Hamed et al. demonstrated that the prevalence of PVD was significantly greater in H. pylori-positive patients who had diabetes, and that this effect may be mediated by the increased levels of inflammatory cytokines [16]. Even though we found no evidence that H. pylori infection affected the risk for PVD, we did find that T2D patients who had H. pylori infection combined with an age of 56 years or more or with a history of smoking had a much higher risk of PVD. Therefore, we suggest that physicians should consider the use of H. pylori eradication therapy to reduce the risk of PVD in diabetes patients who are elderly or have a history of smoking. If these patients are positive for H. pylori, then eradication therapy should be implemented.

This study had two major strengths. First, to our best knowledge, this is the first study to demonstrate that the combination of H. pylori infection with traditional risk factors increased the risk for complications of T2D. This finding may be helpful for improving the treatments and outcomes of patients with T2D complications in clinical settings. Second, we had a relatively large sample of T2D patients, all of whom were tested for H. pylori infection, and we adjusted for the major traditional risk factors in our statistical analyses, and this increased the reliability of the results.

Nevertheless, there were also some limitations in our study. First, because this was a retrospective observational study, we could only evaluate the significance of associations, and could not identify causal relationships. Second, all patients were from a single medical center, and therefore might not be representative of the general population of China. Therefore, large, multicenter, prospective studies of this topic are warranted. Third, there were differences in the sensitivity and specificity of the three different tests used to diagnose H. pylori infection, and these differences could have affected the reported associations. Fourth, vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related diseases. Due to the lack of VacA/CagA data, we are unable to determine the association of these virulence factors with the major complications of diabetes. Fifth, although our control diabetic group was H. pylori-negative, these individuals had many gastric alterations, such as atrophic gastritis and peptic ulcer. Comparison with a diabetic control group that had no gastric alterations would likely lead to more significant findings. Finally, we did not assess the effect of H. pylori eradication and medication on diabetic nephropathy because we did not have access to follow-up data.

Conclusions

In conclusion, our results suggest that H. pylori infection of patients with T2D is an independent risk factor for diabetic nephropathy. We also found that the co-occurrence of H. pylori infection with hypertension, with diabetes duration of 9 years or more, and with an HbA1c level of 8% or more further increased the risk for diabetic nephropathy. We suggest that clinicians should pay more attention to T2D patients with H. pylori infections to better prevent the progression to diabetic nephropathy, and should also consider H. pylori eradication therapy to prevent or slow the development of diabetic nephropathy.

Data availability

It is possible to access the data after coordination with the corresponding author by email.

Abbreviations

H. Pylori :

Helicobacter pylori

T2D:

Type-2 diabetes

OR:

Odds ratio

CI:

Confidence interval

HbA1c:

Glycated hemoglobin A1c

PVD:

Peripheral vascular disease

13C-UBT:

13C-urea breath test

RUT:

Rapid urease test

BMI:

Body mass index

TC:

Total cholesterol

HDL-C:

High-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol,

TG:

Triglycerides

SD:

Standard deviation

IQR:

Interquartile range

ROC:

Receiver operating characteristic curves

TNF-α:

Tumor necrosis factor-α

IL-1:

Interleukin-1

IL-6:

Interleukin-6

IL-8:

Interleukin-8

HCY:

Homocysteine

NO:

Nitric oxide

NF-κB:

Nuclear factor-kappa B

VacA:

Vacuolating cytotoxin A

CagA:

Cytotoxin-associated gene-A

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Acknowledgements

Not applicable.

Funding

The Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project, NO. 2022CZBJ051; Clinical Research Project of Changzhou Medical Center of Nanjing Medical University (CMCC202309); Changzhou commission of health Science and Technology Project (ZD202336).

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Author notes

  1. Zhuoya Li and Jie Zhang should be considered joint first author.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, 29 Xinglong Lane, Tianning District, Changzhou, China

    Zhuoya Li, Yizhou Jiang, Kai Ma, Cheng Cui & Xiaoyong Wang

  2. Department of Endocrinology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu Province, 213000, China

    Jie Zhang

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Contributions

Z. L. and J. Z. : acquisition of data, analysis and interpretation of data, drafting the article. Y.J. and K. M. : acquisition of data, analysis and interpretation of data. C. C. : interpretation of data, revising the article. X. W. : conception and design of the study, critical revision, analysis and interpretation of data, final approval.All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaoyong Wang.

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Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. This study was approved by the Institutional Review Board of Changzhou No. 2 People’s Hospital, Affiliated with Nanjing Medical University, Changzhou, China ([2022] KY010-01). Since the present study is a retrospective analysis of patient data, the need for informed consent was waived by the Institutional Review Board of Changzhou No. 2 People’s Hospital, Affiliated with Nanjing Medical University.

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The authors declare no competing interests.

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Li, Z., Zhang, J., Jiang, Y. et al. Association of Helicobacter pylori infection with complications of diabetes: a single-center retrospective study. BMC Endocr Disord 24, 152 (2024). https://doi.org/10.1186/s12902-024-01678-2

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Keywords

BMC Endocrine Disorders

ISSN: 1472-6823

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