# Helicobacter pylori Infection and Insulin Resistance in Diabetic and Nondiabetic Population

Authors: Jamshid Vafaeimanesh; Mahmoud Parham; Mohammadreza Seyyedmajidi; Mohammad Bagherzadeh
Journal: The Scientific World Journal
 (2014)

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## Abstract

Helicobacter pylori (HP) is a common worldwide infection with known gastrointestinal and nongastrointestinal complications. One of the gastrointestinal side effects posed for this organism is its role in diabetes and increased insulin resistance. The aim of this study was to evaluate the association between HP and insulin resistance in type 2 diabetic patients and nondiabetics. This cross-sectional study was carried out from May to December 2013 on 211 diabetic patients referred to diabetes clinic of Shahid Beheshti Hospital of Qom and 218 patients without diabetes. HP was evaluated using serology method and insulin resistance was calculated using HOMA-IR. The prevalence of H. pylori infection was 55.8% and 44.2% in diabetics and nondiabetics (P=0.001). The study population was divided into two HP positive and negative groups. Among nondiabetics, insulin resistance degree was 3.01±2.12 and 2.74±2.18 in HP+ and HP− patients, respectively P=0.704. Oppositely, insulin resistance was significantly higher in diabetic HP+ patients rather than seronegative ones (4.484±2.781 versus 3.160±2.327, P=0.013). In diabetic patients, in addition to higher prevalence of HP, it causes a higher degree of insulin resistance.


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## Body

## 1. Introduction

The most common infection in the world, especially in developing countries, isHelicobacter pylori (HP) infection which is an etiological factor for developing peptic ulcer, gastric cancer, and acute polymorphonuclear infiltration in the gastric mucosa [1, 2]. The mononuclear infiltration is characterized by the local production and systemic diffusion of proinflammatory cytokines affecting remote tissues and organic systems [3, 4]. This systemic inflammation causes some extragastrointestinal side effects ofHP including ischemic heart disease [1], sideropenic anemia [5], idiopathic thrombocytopenic purpura [6], neurologic diseases [7], and hepatobiliary diseases [8].It has been shown thatHP infection plays a role in some endocrine disorders, such as autoimmune thyroid diseases, diabetes, and primary hyperparathyroidism and may have a high prevalence among patients with diabetes [9, 10]. The association betweenHP and diabetes was first explored in Simon et al.’s study [11]. Recently, a meta-analysis [12] showedHP infection was increased to 1.33 among patients with diabetes. In addition, some studies have shown an increased incidence of diabetes among people withHP infection so that the first report thatHP infection increased incidence of diabetes was in a study by Jeon et al. [13] using a prospective cohort of 782 Latino individuals >60 years of age.Etiopathogenesis ofHP infection in diabetic patients has not been defined clearly. However, this hypothesis is now proposed thatHP infection is more prevalent among people with diabetes but it is not clear whether diabetics have more susceptibility to this infection orHP infection increases the susceptibility to diabetes. One of the hypotheses aboutHP infection as a risk factor for diabetes is increased insulin resistance in these patients.As insulin resistance can develop in the presence of inflammation or as a result of alterations in counter regulatory hormones that affect insulin,HP may thus promote insulin resistance by inducing chronic inflammation and affecting insulin-regulating gastrointestinal hormones [14, 15]. The first direct evidence for an association between chronicHP infection and insulin resistance rose from Aydemir et al.’s study [15] showing higher homeostatic model assessment-estimated insulin resistance (HOMA-IR) scores inHP positive (HP+) individuals. In contrast, some studies have not shown this association [16].Regarding these conflicting findings and the fact that proving a causal role betweenHP infection and insulin resistance increase has important role in controlling the important and common diseases such as diabetes and nonalcoholic fatty liver, we aimed to evaluate the association betweenHP infection and insulin resistance in type 2 diabetic patients and nondiabetics.


## 2. Materials and Methods

### 2.1. Patients

This cross-sectional study was carried out from May to December 2013 on 211 type 2 diabetic patients referred to diabetes clinic of Shahid Beheshti Hospital of Qom and 218 nondiabetic patients. Type 2 diabetic patients with diabetes duration of >5 years and receiving oral hypoglycemic drugs participated in this study as case group and the control group was selected from attendants with the patient referring to the endocrinology clinic. Diabetes diagnosis was based on American Diabetes Association’s criteria (fasting plasma glucose diagnostic of ≥126 mg/dL, 2-hour plasma glucose value of ≥200 mg/dL, and HbA1c of ≥6.5%) [17].In case of receiving insulin, pregnancy, smoking, history ofHP treatment (proton-pump inhibitor, H2 blocker, and bismuth) or receiving antibiotics in the previous 6 months, surgery on upper GI tract, gastric cancer, and using nonsteroidal anti-inflammatory drugs, patients were excluded from the study. Then, the presence ofHP infection patients was evaluated. After 8-hour fasting overnight, blood samples were taken at 4°C and, right after sampling, the serum was centrifuged at 2000 rpm for 15 minutes. Anti-HP IgG antibody was measured by ELISA kit, made by Padtan Elm Co, Iran. In case of serum titer above 30 AU/mL, it was considered positive. Serum insulin was measured using ELISA kit, DiaMetra Co, Italy. We calculated and compared homeostasis model assessment of insulin resistance (HOMA-IR) in this study multiplying the fasting glucose value (mg/dL) by serum insulin value in each person and then dividing it by 405.


### 2.2. Statistical Analysis

Data analysis was performed by SPSS version 16.0 using descriptive statistics, mean, standard deviation, percentage, and frequency. The analysis was performed byt-test, Chi-square test, and Fisher’s exact test.


### 2.3. Ethics

All individuals signed informed consent prior to their enrolment in the study. Also, the study was planned according to the ethical guidelines following the Declaration of Helsinki and Ethics Committee of Qom University of Medical Sciences approved it.


## 2.1. Patients

This cross-sectional study was carried out from May to December 2013 on 211 type 2 diabetic patients referred to diabetes clinic of Shahid Beheshti Hospital of Qom and 218 nondiabetic patients. Type 2 diabetic patients with diabetes duration of >5 years and receiving oral hypoglycemic drugs participated in this study as case group and the control group was selected from attendants with the patient referring to the endocrinology clinic. Diabetes diagnosis was based on American Diabetes Association’s criteria (fasting plasma glucose diagnostic of ≥126 mg/dL, 2-hour plasma glucose value of ≥200 mg/dL, and HbA1c of ≥6.5%) [17].In case of receiving insulin, pregnancy, smoking, history ofHP treatment (proton-pump inhibitor, H2 blocker, and bismuth) or receiving antibiotics in the previous 6 months, surgery on upper GI tract, gastric cancer, and using nonsteroidal anti-inflammatory drugs, patients were excluded from the study. Then, the presence ofHP infection patients was evaluated. After 8-hour fasting overnight, blood samples were taken at 4°C and, right after sampling, the serum was centrifuged at 2000 rpm for 15 minutes. Anti-HP IgG antibody was measured by ELISA kit, made by Padtan Elm Co, Iran. In case of serum titer above 30 AU/mL, it was considered positive. Serum insulin was measured using ELISA kit, DiaMetra Co, Italy. We calculated and compared homeostasis model assessment of insulin resistance (HOMA-IR) in this study multiplying the fasting glucose value (mg/dL) by serum insulin value in each person and then dividing it by 405.


## 2.2. Statistical Analysis

Data analysis was performed by SPSS version 16.0 using descriptive statistics, mean, standard deviation, percentage, and frequency. The analysis was performed byt-test, Chi-square test, and Fisher’s exact test.


## 2.3. Ethics

All individuals signed informed consent prior to their enrolment in the study. Also, the study was planned according to the ethical guidelines following the Declaration of Helsinki and Ethics Committee of Qom University of Medical Sciences approved it.


## 3. Results

In this study, 211 diabetic and 218 nondiabetic subjects were studied. Female/male ratio in patients with diabetes and nondiabetic patients was 135/76 and 109/109, respectively. In patients with diabetes, the prevalence ofHP infection was 55.8% while it was 44.2% in nondiabetics. The study population was divided into twoHP positive and negative groups. As it is shown in Table 1, patients with diabetes and nondiabetic subjects were not significantly different in terms of gender, age, body mass index, and physical activity level.Table 1
The characteristics of the patients with respect to seropositivity forHP.
Parameter
HP– N (%)
HP+ N (%)
P value
Gender (female/male)
Nondiabetic
57 (52.3%)/51 (46.8%)
52 (47.7%)/58 (53.2%)
0.489
Diabetic
47 (65.3%)/25 (34.7%)
88 (63.3%)/51 (36.7%)
0.778
Insulin resistance risk factors
Age (year)
Nondiabetic
39.18 ± 12.44
39.88 ± 12.50
0.669
Diabetic
51.5 ± 8.3
53.5 ± 9.0
0.128
BMI
Nondiabetic
26.25 ± 5.04
26.24 ± 4.33
0.871
Diabetic
29.4 ± 4.9
28.8 ± 4.8
0.427
Exercise degree
>150 min per week
Nondiabetic
4 (3.7)
2 (1.8)
0.299
Diabetic
2 (2.9%)
11 (7.9%)
0.478
30–150 min per week
Nondiabetic
14 (13.0)
7 (6.4)
Diabetic
4 (5.7%)
10 (7.2%)
<30 min per week
Nondiabetic
27 (25.0)
37 (33.6)
Diabetic
15 (21.4%)
26 (18.7%)
No
Nondiabetic
63 (58.3)
64 (58.2)
Diabetic
51 (72.9%)
92 (66.2%)Among nondiabetic subjects, HOMA-IR score was3.01±2.12 and 2.74±2.18 inHP+ andHP− patients, respectively. Although insulin resistance was higher inHP+ individuals, this difference was not statistically significant (P=0.704). Oppositely, insulin resistance was significantly higher inHP+ diabetic patients rather than seronegative ones (4.48±2.78 versus 3.16±2.32, P=0.013).As shown in Table2, although the blood sugar level inHP+ diabetic patients was higher thanHP− subjects, the difference was not statistically significant (P=0.468). Evaluation of lipid profile showed that the only significant difference between both groups was lower HDL amongHP+ diabetic patients (60.7±26.7 versus 69.2±29.2, P=0.037) (Table 2).Table 2
Insulin resistance, glycemic control, and medication type in patients with respect to seropositivity forHP.
Parameter
HP−
HP+
P value
Serum insulin (μIU/mL)
Nondiabetic
11.65 ± 4.88
12.71 ± 4.64
0.708
Diabetic
6.97 ± 2.64
10.12 ± 4.72
0.002
HOMA-IR score
Nondiabetic
2.74 ± 2.18
3.01 ± 2.12
0.704
Diabetic
3.16 ± 2.32
4.48 ± 2.78
0.013
FBS (mg/dL)
Nondiabetic
92.75 ± 11.70
92.58 ± 14.92
0.915
Diabetic
173.43 ± 61.32
180.12 ± 64.27
0.468
Lipid profile
HDL (mg/dL)
Nondiabetic
54.23 ± 19.79
56.55 ± 20.05
0.390
Diabetic
69.2 ± 29.2
60.7 ± 26.7
0.037
LDL (mg/dL)
Nondiabetic
83.26 ± 29.75
85.96 ± 32.67
0.525
Diabetic
107.1 ± 43.2
116.0 ± 51.7
0.212
TG (mg/dL)
Nondiabetic
142.63 ± 112.27
140.81 ± 95.20
0.897
Diabetic
224.2 ± 100.2
229.3 ± 114.6
0.747
Cholesterol (mg/dL)
Nondiabetic
161.16 ± 42.68
157.50 ± 38.86
0.509
Diabetic
205.1 ± 63.2
207.3 ± 67.4
0.8


## 4. Discussion

In this study the rate ofHP seropositivity among diabetic and nondiabetic patients was patients and nondiabetics and the difference between the groups was statistically significant (P=0.001) [10]. Another seroprevalence study in United Arab Emirates showed that positive antibody titer forHP infection (IgA > 250) in diabetics was 63.3% compared to nondiabetics 48.1%; similarly, according to IgG antibody titer (IgG > 300),HP infection was determined in diabetic patients at a rate of 76.7% compared to an infection rate of 64.8% in nondiabetics [18]. Candelli and colleagues found that the prevalence ofHP infection was higher in diabetics (24%) than in controls of similar age, gender, and socioeconomical status after three years of follow-up and the reinfection rate was higher in diabetic patients [19].In contrast to these studies, other researchers did not report this association [20–22]. It is not clear whether diabetics have more susceptibility to this infection orHP infection increases the susceptibility to diabetes. One of the hypotheses aboutHP infection as a risk factor for diabetes is increased insulin resistance in these patients. In some studies, people with diabetes are considered at risk ofHP infection and it is suggested that autonomic neuropathy and poor glycemic control might have a significant role in this field [10].An association betweenHP infection and changes in gastric motility, acid secretion, and diabetes-induced impairment of cellular and humoral immunity has been reported in several studies [11–13, 23]. Also, altered glucose metabolism may produce chemical changes in the gastric mucosa due to altered glucose metabolism [24] and individuals with diabetes are more frequently exposed to pathogens than their healthy counterparts as they regularly attend hospital settings [25].In contrast, some investigators believe thatHP infection is a more favorable condition for developing diabetes. For example, it is commonly believed that the chronic inflammation induced byHP infection is strongly associated to the pathogenesis of diabetes, which is linked to a general activation of the innate immune system, and a chronic, cytokine-mediated state of low-grade inflammation. Proinflammatory cytokines affect many tissues which cause recognizable features of diabetes [26].Inflammation of the adipose tissue is considered a key factor in the pathogenesis of insulin resistance andβ-cell potential autoinflammation impairs insulin secretion in diabetes.HP-induced gastritis can affect the secretion of gastric-related hormones such as leptin and ghrelin, as well as gastrin and somatostatin, which may influence a predisposition to diabetes [27, 28].One of the hypotheses aboutHP infection as a risk factor for diabetes is increased insulin resistance in these patients. One of the first studies in this field was in Aydemir et al.’s study in 2005 on 63HP+ and 27HP− patients. Age, gender, and BMI were not different between both groups. HOMA-IR level was 1.73±1.1 inHP− group, whereas it was 2.56±1.54 inHP+ group. This study addressed the association betweenHP and insulin resistance, although the sample size was small [15].In 2009 Gunji and colleagues [29] have studied 1107 nondiabetic Japanese patients and found that among those with higher insulin resistance score (HOMA-IR ≥ 2.5), the prevalence of theHP was higher (39.4 versus 28.7%, P=0.027). Although people with higher insulin resistance were fewer (99 cases versus 1008), a recent systematic review for the association betweenHP infection and quantitative indexes of insulin resistance showed a positive association betweenHP infection and insulin resistance, independent of several confounders [30].On the contrary, opposite studies exist too. For example, Gillum stated that there is no consistent association betweenHP infection and diabetic prevalence or variables of the insulin resistance syndrome in American men 40–74 years of age [31]. Also, Malamug and colleagues’ study in 2014 was in accordance with that study [16].In our study insulin resistance was significantly higher in diabetic patients withHP infection (4.484±2.781 versus 3.160±2.327, P=0.013). In contrast, although inHP+ nondiabetic patients insulin resistance was higher than seronegative individuals (3.01±2.12 versus 2.74±2.18), it was not statistically significant (P=0.704). These findings suggest the hypothesis thatHP infection does not increase the risk of diabetes in nondiabetic population. But in diabetics,HP is more prevalent and alsoHP+ diabetics have a greater HOMA-IR score and need higher levels of insulin for glycemic control.This study warrants further studies aimed at clarifying whichHP strain is involved in insulin resistance, whether or not inflammation is involved, and whether inflammatory cytokines are present (or genetics for proinflammatory haplotypes). Also will cure of the pathogen alter the insulin resistance?However, further studies are needed to investigate the association betweenHP and insulin resistance because understanding the causal role of this organism in insulin resistance is important for controlling the important and common diseases such as diabetes and nonalcoholic fatty liver.


## 5. Conclusion

HP infection does not significantly increase insulin resistance in nondiabetic individuals but in diabetic patients; in addition to higher prevalence ofHP, it causes a higher degree of insulin resistance and needs higher levels of insulin for the same control similar to seropositive subjects.



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*Source: 391250-2014-10-23.xml*