Helicobacter pylori infection and diabetes: Is it a myth or fact?

Abstract

Helicobacter pylori (H. pylori) is one of the most common human bacterial pathogens, and infection causes a wide array of gastric disorders, including simple gastritis, peptic ulcers and gastric malignancies. Gastrointestinal inflammation caused by H. pylori can influence the absorption of glucose and lipids, which are also abnormal in diabetes mellitus. Type 2 diabetes mellitus (T2DM), formerly known as non-insulin-dependent diabetes mellitus or adult-onset diabetes, is a metabolic disorder that is characterized by high levels of blood glucose resulting from insulin resistance and relative insulin deficiency. It is an emerging pandemic and is rapidly becoming a serious threat to public health. Emerging data now indicate a strong relationship between H. pylori infection and the incidence of T2DM. The mechanisms underlying the pathogenesis of diabetes are complex, involving insulin resistance, chronic inflammation, insulin secretion deficiency as a result of pancreas β-cell dysfunction, glucotoxicity, and lipotoxicity. H. pylori infection is known to be involved in the pathogenesis of insulin resistance, and the growing awareness of its role in diabetes is important for the early detection of glucose dysregulation and prevention of T2DM in high-risk communities. This review probes the possible relationship between H. pylori and diabetes according to epidemiological surveys and discusses putative mechanisms underlying this correlation.

Key Words: Helicobacter pylori; Type 2 diabetes; Insulin resistance; Inflammation; Cytokines

Core tip: A growing body of evidence suggests that Helicobacter pylori (H. pylori) infection is associated with diabetes, and may cause insulin resistance and chronic inflammation that contribute to the disease. H. pylori-induced gastritis can also potentially affect the secretion of gastric-related hormones and inflammatory cytokines. However, the relationship between H. pylori infection and diabetes is still under debate and further studies are warranted to define their association in more detail, and to characterize the corresponding mechanisms and mediators.

INTRODUCTION

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped pathogenic bacterium that specifically colonizes the gastric epithelium causing chronic gastritis, peptic ulcer disease, and/or gastric malignancy[1,2]. H. pylori is mainly acquired in childhood by the fecal-oral, oral-oral or gastro-oral route[3], and has been recognized as a worldwide public health problem that is more prevalent in developing countries. The infection induces an acute polymorphonuclear infiltration in the gastric mucosa, which is gradually replaced by an immunologically-mediated, chronic, predominantly mononuclear cellular infiltration[4]. The mononuclear infiltration is characterized by the local production and systemic diffusion of pro-inflammatory cytokines[5] that can affect remote tissues and organic systems[6]. As a result, an increased prevalence of extra-digestive diseases has been reported in those with evidence of H. pylori infection in recent years, including ischemic heart disease[7], autoimmune thyroid diseases[8], sideropenic anemia[9], idiopathic thrombocytopenic purpura[10], neurologic diseases[11-13], and hepatobiliary diseases[14-17]. Indeed, this bacterium produces a low-grade inflammatory state, induces molecular mimicry mechanisms, and interferes with the absorbance of nutrients and drugs, possibly influencing the occurrence and/or evolution of many diseases[18].

Type 2 diabetes mellitus (T2DM) is an emerging pandemic, responsible for an estimated 3.8 million adult deaths worldwide[19]. The pathogenesis of T2DM is complex, with risk factors associated with lifestyle (e.g., diet, obesity, physical activity), genetic background, and socioeconomic factors[20,21]. In T2DM, the pancreas can no longer produce enough insulin to overcome the cellular loss of sensitivity, resulting in the accumulation of sugar in the bloodstream[22]. Identification of treatable causes of this disease will aid in the development of strategies to delay or prevent its onset or slow its progression. Recent evidence implicates the pathological involvement of inflammation in T2DM, which is an important process induced by H. pylori infection[23]. This review focuses on the possible relationship between H. pylori and diabetes as well as the potential mechanisms and mediators concerning this correlation.

EPIDEMIOLOGICAL SURVEYS LINKING H. PYLORI WITH DIABETES

The link between H. pylori infection and diabetes remains controversial, as some studies indicate a higher prevalence of infection in diabetic patients[24-26], while others report no difference[27-29]. The relationship between H. pylori and diabetes mellitus was first explored in 1989 by Simon et al[30] who found that the prevalence of H. pylori infection in patients with diabetes mellitus was significantly higher than in asymptomatic controls (62% vs 21%). However, the test used for detecting H. pylori was only a rapid urease test, and their comparison did not adjust for age, which is a major confounding factor. Additional supportive data have come from groups in the Netherlands[31], Italy[32], Turkey[26], and Africa[33]. Recently, a meta-analysis conducted by Zhou et al[34] involved 14080 patients from 41 studies with a total H. pylori infection rate of 42.29%. The odds ratio (OR) for H. pylori infection was increased to 1.33 among patients with diabetes, especially in patients with T2DM (OR = 1.76). The first demonstration that H. pylori infection leads to an increased incidence of diabetes was in a study by Jeon et al[35] using a prospective cohort of 782 Latino individuals > 60 years of age. Participants, whose diabetic status was not known at the initiation of the study, had serum assayed twice yearly for a decade for antibodies to H. pylori, herpes simplex virus 1, varicella zoster virus, cytomegalovirus, and Toxoplasma gondii. During the course of the study, 144 individuals developed diabetes (presumably type 2), and individuals who were initially seropositive for H. pylori were found to be more than two times more likely to develop diabetes than those who were seronegative, even after adjusting for age, sex, education, and covariates such as smoking, body mass index (BMI), blood pressure, and lipids. In contrast, antibodies to the other infectious agents were not associated with an increased risk for the development of diabetes.

Levels of glycated hemoglobin (HbA1c), which result from the non-enzymatic glycosylation of hemoglobin and reflect the integrated blood glucose levels during the preceding 3-4 mo, can be used to diagnose prediabetes and diabetes and to predict diabetes prevalence and incidence[36-38]. A study performed by Chen and Blaser has provided new insight into the association between the seroprevalence of H. pylori infection and the mean levels of HbA1c in two large national surveys: the National Health and Nutrition Examination Survey (NHANES) III and the NHANES 1999-2000[39]. Their report showed that H. pylori seropositivity, and H. pylori cagA positivity in particular, was associated with higher mean HbA1c levels, an association that persisted after excluding individuals with a history of diabetes mellitus and controlling for potential confounders. The association was evident mainly in adults over 18 years of age. They also showed a synergistic effect of H. pylori and BMI on increased levels of HbA1c, indicating a role of H. pylori in impaired glucose tolerance in adults that may be potentiated by a higher BMI level. Similar results were reported in a recent study by Hsieh et al[40] showing long-term H. pylori infection was significantly associated with high levels of HbA1c, decreased insulin secretion, and a higher prevalence of T2DM in Taiwanese patients. Taken together, these results suggest that proper screening of H. pylori infection combined with regular monitoring of blood glucose and HbA1c levels may be effective for early detection of glucose dysregulation and prevention of T2DM.

In contrast, other studies have found no association between H. pylori infection and diabetes[27-29,41,42]. In a large, well-designed study by Xia et al[42], the seroprevalence of H. pylori infection was not significantly different in patients with diabetes mellitus compared to nondiabetic controls. In another study conducted in Nigeria, Oluyemi et al[43] found no significant difference in H. pylori prevalence between T2DM patients and controls, which is consistent with the results from various other regions of the world, including Italy[44], China[28], Turkey[45] and Romania[29]. The discrepancies reported concerning the association of H. pylori and diabetes are likely due to inconsistencies in the methods used to define H. pylori positivity and diabetic status, the limited sample sizes, and adjustments for potential confounders such as age and socioeconomic status[42]. In addition, the accuracy of self-reported data on medical history depends on the subjects’ knowledge and understanding of the relevant information, their ability to recall, and their willingness to report[46], which also may change over time.

PATHOGENETIC MECHANISMS IN H. PYLORI AND DIABETES

Although there is no concrete evidence demonstrating that H. pylori plays a role in diabetes, the possibility for a causal relationship is an intriguing issue deserving discussion. There are several lines of evidence to implicate increased susceptibility to infection in diabetic patients. Firstly, a diabetes-induced impairment of cellular and humoral immunity may enhance an individual’s sensitivity to H. pylori infection[47]. Secondly, diabetes-induced reduction of gastrointestinal motility and acid secretion may promote pathogen colonization and infection rate in the gut[35]. Thirdly, altered glucose metabolism may produce chemical changes in the gastric mucosa that promote H. pylori colonization[48]. Finally, individuals with diabetes are more frequently exposed to pathogens than their healthy counterparts as they regularly attend hospital settings[49]. However, there are also indications that H. pylori infection may contribute to the development of diabetes. Whereas insulin insensitivity is an early phenomenon, pancreatic β-cell function declines gradually over time before the onset of clinical hyperglycemia, the result of many factors that can be influenced by infection, such as insulin resistance (IR), glucotoxicity, lipotoxicity, β-cell dysfunction, chronic inflammation, and genetic and epigenetic factors[23,50].

H. pylori and IR

A growing body of evidence has linked H. pylori infection to IR[51-54], which is defined by a state where insulin can no longer effectively induce glucose disposal in skeletal muscle or suppress endogenous glucose production in the liver[55]. Insulin resistance and abnormal insulin secretion are central to the development of T2DM, and most studies support the view that IR precedes defects in insulin secretion[56]. The first direct evidence for an association between chronic H. pylori infection and IR came from a study by Aydemir et al[53] showing higher homeostatic model assessment-estimated insulin resistance (HOMA-IR) scores in H. pylori-positive individuals. Furthermore, a Japanese study in 2009 that included a large population of 1107 asymptomatic subjects also showed that H. pylori significantly and independently contributed to IR[52].

A recent systematic review of evidence for the association between H. pylori infection and quantitative indexes of IR shows a trend toward a positive association between H. pylori infection and IR, independent of several confounders[51]. However, Gillum et al[57] maintain that there are no consistent associations between H. pylori infection and diabetic prevalence or variables of the IR syndrome in American men 40-74 years of age. Furthermore, Park et al[58] reported that metabolic and inflammatory parameters, including blood sugar, lipid profiles, IR, white blood cell count, and C-reactive protein (CRP) levels, were not changed after H. pylori eradication. It is important to note that H. pylori infection was not determined in all studies by histologic detection of organisms in mucosal biopsy specimens, which is considered the diagnostic gold standard. Although the diagnostic utility of serum H. pylori-specific IgG antibodies is well established[59], the inclusion of false-positive or false-negative detections is unavoidable. As anti-H. pylori IgGs can be detected even after eradication, it is difficult to determine whether H. pylori merely initiates, or chronic active H. pylori infection is required to promote, IR[60]. However, serologic tests are widely available, noninvasive, and inexpensive, and thus suitable for screening and large epidemiologic studies. As IR can develop in the presence of inflammation[61] or as a result of alterations in counter-regulatory hormones that affect insulin[62], H. pylori may thus promote IR by inducing chronic inflammation and affecting insulin-regulating gastrointestinal hormones[53].

H. pylori and inflammation

It is commonly believed that the chronic inflammation induced by H. pylori infection is strongly linked to the pathogenesis of T2DM, which is associated with a general activation of the innate immune system, and a chronic, cytokine-mediated state of low-grade inflammation. Many tissues are affected by pro-inflammatory cytokines, which cause recognizable features of T2DM[63]. Inflammation of the adipose tissue is considered a key factor in the pathogenesis of IR, and β-cell autoinflammation mediated by interleukin (IL)-1β impairs insulin secretion in T2DM. This inflammation is characterized by an increased infiltration of bone marrow-derived macrophages and increased expression of chemokines and cytokines such as IL-1β[64], CRP and IL-6[65], as well as tumor necrosis factor (TNF)[66-69]. These and other macrophage-secreted factors exert paracrine effects that result in the activation of serine kinases such as c-jun N-terminal kinases (c-JNK) and the inhibitor of nuclear factor kappa B kinase β, which phosphorylate insulin receptor substrate proteins and create a state of IR in adipose tissue[70].

Some epidemiological studies have suggested that pathogen burden is a risk factor for the inflammation that leads to IR[71,72]. Colonization of the gastric epithelium by H. pylori brings about active chronic inflammation by infiltrating gastric submucosal neutrophils and monocytes, which can lead to gastric mucosal damage and epithelial remodeling[73]. The host immune response to H. pylori infection is complex and involves upregulation of several proinflammatory cytokines, such as CRP[74-76], IL-6, and TNF-α[77], which are implicated in IR and the development of diabetes[78]. Human CRP is primarily synthesized by hepatocytes and regulated by inflammatory cytokines (mostly TNF-α and IL-6), and levels of high-sensitive CRP (hsCRP) have been the main focus of investigation for diabetes risk. Of 11 prospective studies, seven reported a significant positive association between hsCRP levels and diabetes risk[65,79-84], and four studies found no association[85-88]. However, it is not known whether hsCRP itself directly influences IR or diabetes. IL-6 is produced in a variety of tissues, including activated leukocytes, adipocytes, and endothelial cells[89,90]. Approximately 25% of in vivo systemic IL-6 originates from subcutaneous adipose tissue[89] and is thought to modify adipocyte glucose and lipid metabolism and body weight[91-93]. Pradhan et al[65] state that elevated levels of IL-6 predict the development of T2DM and further support a possible role for inflammation in diabetogenesis, an idea also supported by Spranger et al[69]. Increased production of TNF-α in adipose tissue may be a critical mechanism by which fat cells induce peripheral IR[94], by the indirect increase in free fatty acid oxidation, stimulation of insulin counter-regulatory hormones or cytokines (e.g., IL-6 and CRP), impairment of endothelial function, or direct inhibitory effects on glucose transporter protein GLUT4, insulin receptor substrates, or glucose-stimulated insulin release by pancreatic β-cells[84]. Furthermore, H. pylori in the gut microbiota leads to increased production of lipopolysaccharide, a constituent of the bacterial cell wall, which also activates innate inflammatory processes[95]. Concentrations of circulating lipopolysaccharide are higher in obese patients with T2DM than in non-diabetic, lean individuals and correlate with the degree of IR[96].

Despite the evidence implicating a link between H. pylori infection and inflammation that predisposes individuals to T2DM, there are some contradictory data. A study by Jeon et al[35] failed to find any significant association between levels of inflammatory mediators (CRP and IL-6) and H. pylori infection or T2DM. Studies by Danesh et al[97] and Ridker et al[98] also found no significant association. Therefore, more investigation is needed to determine whether inflammation triggered by H. pylori infection contributes to the development of T2DM.

H. pylori and hormones

H. pylori-induced gastritis can potentially affect the secretion of gastric-related hormones such as leptin and ghrelin[99,100], as well as gastrin and somatostatin[101], which may influence a predisposition to diabetes. Gastrin increases food-related and glucose-stimulated insulin release[102,103], and somatostatin regulates pancreatic insulin secretion and inhibits insulin release[104,105]. Patients with H. pylori infections could therefore have altered insulin release, as they have elevated basal and stimulated serum concentrations of gastrin and decreased somatostatin[101,106]. The regulation of leptin and ghrelin, which are produced in the stomach and are involved in energy homeostasis[107,108], affects obesity, insulin sensitivity, and glucose homeostasis[109,110]. Increasing evidence indicates H. pylori can influence the production of leptin and ghrelin, and thus could promote obesity and the development of diabetes[100,111-114]. Ghrelin decreases energy expenditure and promotes weight gain[115], whereas leptin, which is expressed mainly by adipocytes, reduces food intake and increases energy expenditure[116]. H. pylori infection has been shown to impair ghrelin production[117,118] and enhance the production of leptin[119]. Low ghrelin levels are associated with elevated fasting insulin concentrations, IR, and T2DM[120]. Leptin has also been implicated in the development of IR[121], and elevated levels correlate with IR in lean men[122] and patients with T2DM[123]. Elevation of leptin levels is likely deleterious to human islet function, as a clinical study revealed that improved pancreatic β-cell function was independently associated with the decreased leptin and increased adiponectin levels in obese women after standardized weight reduction[124]. There is evidence that in addition to mitigating the effects of insulin through phosphorylation of Ser-318 of insulin receptor substrate 1[125], high levels of leptin may also impair glucose-stimulated insulin secretion and induce apoptosis of β cells in human islets via activation of c-JNK[126]. However, a study by Brown et al[127] indicated that leptin has a protective role on pancreatic β cell function, showing that leptin could prevent apoptosis of pancreatic β cells through modulation of the Bcl protein family.

H. pylori and insulin secretion

Decreased insulin secretion is one of the major pathophysiological defects in T2DM. The progression from normal glucose tolerance to prediabetes and T2DM is characterized by continuing defects in β-cell function[128]. A study by So et al[129] found that H. pylori titer could independently predict abnormal pancreatic β-cell function in Chinese men. Additionally, Rahman et al[130] also described a positive association between H. pylori infection and impaired insulin secretion. The insulin-producing pancreatic β-cells are especially susceptible to damage by inflammation and oxidative stress[131], therefore it is plausible that inflammation caused by H. pylori infection results in deficits in insulin secretion. Furthermore, it was reported in a study by Hsieh et al[40] that patients with H. pylori infection were more likely to have had impaired insulin secretion at a young age, which may increase the risk for T2DM.

Accumulating evidence indicates that cytokines play important roles in β-cell failure, as chronic exposure to IL-1β, TNF-α, and IFN-γ inhibits insulin secretion and induces apoptosis of β cells[132,133]. In addition, H. pylori vacuolating cytotoxin stimulates mitochondrial-dependent apoptosis in diabetic patients through downregulation of anti-apoptotic Bcl-2, upregulation of pro-apoptotic Bax, and increased activation of caspase-9 and -3[134]. Despite these studies, more studies are needed to elucidate the role of H. pylori infection in insulin secretion and the incidence of T2DM.

H. PYLORI ERADICATION AND DIABETES

There are limited and conflicting data regarding the effect of H. pylori eradication on glucose metabolism and insulin sensitivity[58,135-137]. However, it may be beneficial for patients at risk of diabetes to be checked for the presence of H. pylori infection, as a report by Zojaji et al[136] showed that H. pylori treatment can improve the mean HbA1c and the metabolic abnormalities in patients with T2DM. Additionally, Gen et al[137] demonstrated that successful H. pylori eradication significantly decreased fasting insulin and HOMA-IR levels. Other studies focused on the effects of eradication on H. pylori-stimulated inflammatory cytokines. Some reports indicate that CRP levels are decreased after H. pylori eradication, suggesting a beneficial effect on low-grade inflammation[33,137]. However, there are also reports showing no effect of H. pylori eradication on mean HOMA-IR and CRP levels[58] or HbA1c levels[135]. Recently, Vafaeimanesh et al[138] found that in patients with T2DM, the mean decrease in HbA1c and fasting plasma glucose levels in eradicated cases was similar to non-eradicated subjects three and six months after treatment.

H. PYLORI-ASSOCIATED FACTORS AND DIABETES

Many additional factors are likely involved in the relationship between H. pylori infection and diabetes. For example, lifestyle is a critical factor affecting both chronic H. pylori infection and T2DM, as it has been shown that older subjects with a low-risk lifestyle are less likely to develop T2DM[139]. Gastroduodenal conditions resulting from H. pylori infection could delay gastric emptying, which has been postulated to cause mismatch between the onset of insulin action and the absorption of carbohydrates in insulin-dependent children with diabetes[140,141]. However, it has also been suggested that delayed gastric emptying is a potential advantage, rather than a disadvantage, in relation to glycemic control in T2DM patients not treated with insulin[142], and others maintain that H. pylori infection does not affect the rate of gastric emptying in diabetic patients[143]. H. pylori infection has also been implicated in platelet activation and aggregation, increases in pro-atherogenic factors such as homocysteine, production of reactive oxygen species, and increases in lipid peroxides[144].

Obesity

There is now solid evidence that obesity is the main etiological cause of T2DM, with new, controlled, clinical trials showing that a weight loss of as little as 5% is sufficient to prevent most obese subjects with impaired glucose tolerance from developing the disease[145]. However, there is no clear evidence linking obesity and H. pylori infection. According to some studies, obesity[146] and/or a high BMI[112] may be associated with an increased incidence of H. pylori colonization, likely resulting from reduced gastric motility. A study by Cohen et al[147] demonstrated that adults infected with H. pylori had higher BMI levels, even if asymptomatic, and further suggested that H. pylori therapy may lead to weight loss and improve diabetic control. In contrast, other studies showed no association between H. pylori seropositivity or CagA antibody status and BMI[148,149], or even an inverse relationship between morbid obesity and H. pylori seropositivity[150]. Nevertheless, there are data demonstrating that H. pylori eradication significantly increases the incidence of obesity in patients with peptic ulcer disease, as it increases BMI[151,152], and/or enhances the appetite of asymptomatic patients by elevating plasma ghrelin[113] and reducing leptin[153] levels.

Dyslipidemia

Disturbances in the production and clearance of plasma lipoproteins are among the metabolic abnormalities that commonly accompany diabetes. Moreover, dyslipidemia may foster the development of diabetes[154]. High concentrations of plasma triglyceride and low-density lipoprotein cholesterol (LDL-c), along with low concentration of high-density lipoprotein cholesterol (HDL-c), are attributed mostly to IR and insulin deficiency[155,156]. H. pylori infection may induce dyslipidemia, as it leads to elevated plasma levels of total cholesterol[157,158], LDL-c[158] and triglyceride concentrations[159] and decreased levels of HDL-c[160,161]. It was postulated that chronic H. pylori infection may promote atherogenic lipid profiles through the action of pro-inflammatory cytokines, such as IL-6, interferon-α and TNF-α, which activate adipose tissue lipoprotein lipase, stimulate hepatic fatty acid synthesis and influence lipolysis[158,162]. However, as not all studies found significant changes in plasma levels of total cholesterol, triglycerides, and LDL-c with H. pylori infection[163,164], further studies are needed to verify this association.

Age

Although there have been indications that T2DM may predispose an individual to H. pylori infection[35,47-49], this seems unlikely, considering the age at which the disease is typically acquired. A model of age-related pleiotropy, or life-course perspective, with respect to H. pylori colonization has been proposed by Atherton et al[165]. The potential benefits of H. pylori occur predominantly earlier in life, including reduced risks for asthma[166,167], tuberculosis reactivation[168], childhood diarrhea[169], and gastroesophageal reflux disease[170-172]. However, among older individuals, H. pylori can promote adverse health effects, such as peptic ulcer disease, gastric cancer, and perhaps increased glucose intolerance.

CONCLUSION

Since the discovery of H. pylori, a variety of epidemiological studies, therapeutic trials, and case reports have evaluated the direct or indirect involvement of this bacterium in the pathogenesis of various extragastric disorders. Although no current data provide concrete evidence that H. pylori plays a role in diabetes mellitus, the possibility cannot be ruled out. The evidence concerning an association between H. pylori infection and IR, chronic inflammation, the secretion of gastric-related hormones, and insulin secretion deficiency implicate H. pylori in a predisposition to diabetes (Figure 1). However, the pathophysiology of T2DM is complex, and many other factors could contribute to this process after H. pylori infection, such as lifestyle, changes in gastric emptying, dyslipidemia and so on. Diabetes mellitus is a multifaceted and multistep disease that is unlikely to result from a single cause, though risk factors that deserve attention include gastrointestinal infections and the composition of intestinal microbiota. Larger prospective studies investigating the impact of H. pylori infection on diabetes and corresponding mediating factors are warranted. Meanwhile, large interventional studies are urgently needed to evaluate the long-term benefit of H. pylori eradication for prevention and progression of diabetes. Evidence supporting an etiological role of H. pylori in the development of T2DM would indicate that preventive measures, such as increased hygiene and treatments using antibiotics and proton pump inhibitor combinations, should be explored as targets of intervention in high-risk communities.

Figure 1 Potential mechanisms for contribution of Helicobacter pylori to type 2 diabetes mellitus. Insulin resistance and abnormal insulin secretion are central to the development of type 2 diabetes mellitus (T2DM). On the one hand, Helicobacter pylori (H. pylori) infection brings about chronic low-grade inflammation with upregulation of several cytokines such as C-reactive protein (CRP), tumor necrosis factor (TNF) and interleukin (IL)-1β, which may influence insulin action and pancreatic β cell secretion. On the other hand, H. pylori-induced gastritis can potentially affect the secretion of gastric hormones, including leptin, ghrelin, gastrin, and somatostatin, which could affect insulin sensitivity and glucose homeostasis. In addition, other mechanisms and mediators may be involved in the possible causative relationship between H. pylori infection and T2DM.