Introduction

Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped pathogenic bacterium which can establish a persistent infection within human gastric mucosa, and affects approximately up to half of the world population [1]. This problem is particularly notable in developing countries, and the prevalence rate in China may be as high as 54.7% [2]. The effects of this organism may not only be confined to the gastrointestinal tract but also be associated with extra-intestinal ailments such as its role in diabetes and increased insulin resistance [3].

Diabetes mellitus is a group of metabolic diseases characterized by high levels of blood sugar (glucose). Type 2 diabetes mellitus (T2DM) is increasingly common and is responsible for the death of an estimated 3.8 million adults across the world [4]. Although major risk factors (e.g., lifestyle, genetic background, socioeconomic factors) for T2DM have been identified, they provide only partial explanations.

The relationship of H. pylori and DM was first explored in 1989 by Simon et al. [5]. But previous studies provided inconsistent conclusions concerning the association between various clinical manifestation of diabetes and H. pylori infection [6,7,8,9]. Recent study suggests the role of inflammation in the pathogenesis of T2DM, which is an important process induced by H. pylori infection [10]. It has been shown that H. pylori infection may increase insulin resistance through inducing chronic inflammation and affecting the levels of some insulin-regulating gastrointestinal hormones. This research sought to investigate the possible relationship between H. pylori infection and T2DM patients as well as the potential mediators concerning this correlation.

Patients and methods

The study was a hospital-based, analytic observational study and performed through a cross-sectional method. T2DM patients aged 18–65 and recruited from the Second Affiliated Hospital of Bengbu Medical College were included into the study. Our research protocol was approved by ethical committee of Bengbu Medical College, and a written informed consent was signed by each participants according to national and institutional guidelines. Exclusion criteria were as follows: (1) patients over 65 years; (2) women patients who were currently pregnant or breastfeeding; (3) patients with a history of gastrointestinal tract surgery; (4) patients who were currently using antisecretory drugs (proton-pump inhibitor or H2 receptor blockers); (5) patients who had undergone or were currently undergoing H. pylori eradication therapy; (6) patients who were obliged to continuous use of antibiotics for various reasons.

We compiled a brief checklist covering demographic data and clinical parameters, including age, gender, duration of diabetics, and anti-diabetic treatment. The body mass index (BMI) is a statistical measure based on a person’s weight and height (weight/height2 = kg/m2). We also checked the laboratory parameters. GLU (glucose oxidase method); TC (CHOD-PAP substrate method); TG (GPO-PAP enzymatic method); HDL-C (selective inhibition method); LPa (latex-enhanced immunoturbidimetry); Apo A, Apo B, and HsCRP (turbidimetric immunoassay); and HCY (enzyme method) were measured on Beckman Coulter UniCel DxC 800 Synchron. LDL-C was calculated by the Friedewald formula. HbA1c was determined by ion-exchange HPLC method (HLC-723G8 automatic glycosylated hemoglobin analyzer). Commercially available human enzyme-linked immunosorbent assay (ELISA) for the determination of plasma ghrelin and leptin (eBioscience Inc., USA) was performed according to manufacturers’ instructions. The leukocyte and platelet counts were determined by flow cytometry, and Mindray BC-5800 automatic blood cell analyzer was used for the detection.

In all patients, the diagnosis of H. pylori infection was determined by ELISA for anti-H. pylori IgG, with a reported sensitivity and specificity of 96% [11]. Measurement of specific anti-H. pylori IgG reveals an immune response that represents either a current infection or a previous exposure, since IgG disappears only several months after eradication of the microorganism. Then, we divided the subjects into two groups according to H. pylori infection as H. pylori–positive patients and H. pylori–negative patients. The association between H. pylori infection and demographic factors, and biochemical and anthropometric indicators was investigated in all patients.

Statistical analysis

Statistical Package for the Social Sciences (SPSS) 20.0 Package program was used for the analysis of data. The data were presented as mean ± SD. Adjustment to normality was checked through the Kolmogorov-Smirnov test. Quantitative variables with normal distribution were compared by H. pylori status using independent sample t test or the Mann-Whitney U test as appropriate. Qualitative parameters were analyzed with the chi-square test. Two-tailed p values of below 0.05 were considered significant.

Results

A total of 72 T2DM patients with a mean age of 54 (± 7) were enrolled in this study, including 44 males and 28 females. The presence of H. pylori infection was diagnosed in 47 (65.28%) of 72 diabetic patients. In male patients, the prevalence of H. pylori infection was 68.18% while it was 60.71% in females. The demographic and laboratory characteristics of the study population, divided into H. pylori–positive and H. pylori–negative groups, are displayed in Tables 1 and 2.

Table 1 Characteristics of study subjects with respect to the H. pylori infection
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Table 2 The relationship between HbA1c in diabetic patients and H. pylori positivity
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Patients infected with H. pylori and non-infected with H. pylori were not significantly different in terms of gender, age, BMI, duration of diabetics, and anti-diabetic treatment. The level of GLU, TC, TG, HDL-C, Apo A, Apo B, HsCRP, HCY, leukocyte, and platelet counts were not significantly different between H. pylori–positive and H. pylori–negative groups (p > 0.05), although CRP levels determined by high-sensitivity assay showed mild and variable increases in H. pylori infection. Diabetic patients infected by H. pylori showed significantly increased serum Lpa (297.83 ± 299.51 vs 154.24 ± 83.63, p < 0.05) and decreased leptin (4.59 ± 7.55 vs 9.82 ± 10.76, p < 0.05) than non-infected patients (Table 1). HbA1c, the major fraction of glycated hemoglobin, is most valuable glucose monitoring index for patients with diabetes [12]. A significant relationship between glycemic control and the presence of H. pylori was detected. Patients with H. pylori infection had higher HbA1c level (9.21 ± 2.15 vs 8.00 ± 1.77, p < 0.05). Additionally, 55.6% of the patients with HbA1c ≤ 7% were H. pylori negative and 72.2% of the patients with HbA1c > 7% were found to be H. pylori positive (Table 2), indicating that H. pylori–infected group had worse glycemic control.

Discussion

It is well known that diabetic patients have an increased risk of suffering chronic infections because of cellular and humoral immune deficiency. It has been reported that the prevalence of H. pylori infection varies between 30 and 80% in diabetic patients [13,14,15,16]. In this recent study of our institute, the prevalence of H. pylori infection in diabetics was found to be 65.28% and this rate was concordant with results observed in different related studies.

H. pylori plays a major pathogenic role in a wide array of gastric disorders, including simple gastritis, peptic ulcers, and gastric malignancies. During the last two decades, the associations among H. pylori and several extragastric manifestations, such as iron deficiency anemia, cardiovascular disease, as well as diabetes mellitus (DM), and other metabolic syndromes [17,18,19,20], strongly emerged in literature. The relationship between H. pylori and DM was first explored in 1989. From then on, it has been suggested that infection with H. pylori is potentially linked to DM in many aspects [21,22,23,24]. However, the question of whether H. pylori infection is associated with poorer glycemic control in patients with DM remains controversial.

This study showed a positive association between H. pylori status and HbA1c levels, a valid and sensitive biomarker for long-term glycemic control among a group of middle-aged to elderly Chinese subjects with T2DM. Patients with H. pylori infection had significantly elevated HbA1c level. Additionally, compared with low HbA1c (≤ 7%), the patients with HbA1c > 7% showed a significantly higher H. pylori–infection rate (72.2% vs 44.4%), indicating that H. pylori–infected group had worse glycemic control.

The mechanisms linking H. pylori to glycemic control in T2DM are complicated. It is well known that insulin resistance and abnormal insulin secretion are the main pathogenic factors in T2DM. H. pylori might affect pathophysiological process of insulin resistance through subclinical chronic inflammation, by which the bacterium influences glycemic control in diabetics [25]. An alternative hypothesis is that gastrointestinal conditions resulting from H. pylori infection could delay gastric emptying and consequently causes poor glucose control. Furthermore, H. pylori–induced gastritis can potentially affect the secretion of gastric-related hormones, which are secreted from gastric mucosa and are involved in energy homeostasis, modulating insulin sensitivity and glucose homeostasis. Leptin, a multifunctional polypeptide primarily produced by adipocytes, favors energy expenditure increase and food intake reduction [26]. In recent years, increased evidence indicates that high levels of leptin may impair glucose-stimulated insulin secretion and induce apoptosis of β cells. Our study showed that H. pylori infection elevated the production of leptin among patients with T2DM, and thus might promote the development of diabetes.

DM is always a multifactorial metabolic disorder characterized by changes in the metabolism of carbohydrates, fats, and protein. A growing body of evidence has demonstrated a significant relationship between lipid profiles and thrombotic activation–related anti-thrombin (AT)-III and H. pylori infection [27]. In the present study, lipid profile was not significantly different between H. pylori–positive and H. pylori–negative groups, but LPa levels were found to be significantly increased in infected diabetic patients. LPa is a new novel marker of cardiac events, and serum elevated level of LPa is an independent risk factor for coronary heart disease (CHD) [28], so H. pylori infection has been hypothesized to predispose diabetics to cardiovascular and cerebral diseases.

In conclusion, our results demonstrated a significant association between H. pylori infection and impaired glycemic control in type 2 diabetic patients. Leptin appeared to mediate this effect. The relationship between H. pylori and LPa level remains speculative, but a greater understanding may give important insights into the cardiac events in diabetic patients. A few limitations warrant consideration: first, this was a single-center study, and the small sample size used in this study remains as a limitation. Further investigations are recommended, with a larger subject population, to validate the findings reported here. Second, we did not investigate the patients with H. pylori infection after treatment. More investigations will be required to evaluate the effects of H. pylori eradication on the metabolic status in diabetic patients.