Helicobacteria increases risk of Type 2 diabetes

From Medscape Education Clinical Briefs

Helicobacter pylori Infection May Increase Hemoglobin A1c Levels CME

News Author: Troy Brown
CME Author: Charles P. Vega, MD

 

Faculty and Disclosures

CME Released: 03/20/2012; Valid for credit through 03/20/2013

CME Information Earn CME Credit »

CLINICAL CONTEXT

Infection with Helicobacter pylori is most associated with gastrointestinal tract complications, but the authors of the current study explain how this infection may promote higher rates of type 2 diabetes as well. H pylori strainsplay a role in the homeostasis of leptin and ghrelin, 2 hormones critical to energy homeostasis and metabolism. In addition,H pylori infection is associated with chronic inflammation, particularly among H pylori strains which contain the cagantigen. There is evidence that this inflammation may extend beyond the gastrointestinal tract, affecting insulin and glucose metabolism.

Nonetheless, the effect of H pylori infection on the risk for incident type 2 diabetes is not completely clear. The current study by Chen and Blaser evaluates the relationship between H pylori infection and hemoglobin A1c (HbA1c) levels in a large population of adults.

STUDY SYNOPSIS AND PERSPECTIVE

Gastric H pylori infection is associated with elevated Hb1Ac levels in adults, according to a large study by Yu Chen, PhD, an associate professor of environmental medicine, and Martin Blaser, MD, a professor of internal medicine, at the New York University School of Medicine in New York City. The results of this study were published online March 14 and in the April 15 issue of the Journal of Infectious Diseases.

The researchers conducted cross-sectional analyses of data from 7417 participants in the National Health and Nutrition Examination Survey (NHANES) III (aged 18 years or older) and 6072 participants in NHANES 1999-2000 (aged 3 years or older) whose H pylori status was obtained, to study the association between H pylori infection and type 2 diabetes mellitus.

H pylori/Diabetes Status, HbA1c Measurement

In 1996, participants in the NHANES III phase 1 study who were aged 18 years or older were tested for H pyloriimmunoglobulin G (IgG) antibodies with 2 tests: the H pylori IgG enzyme-linked immunosorbent assay (Wampole ELISA), and the cagA IgG ELISA.

According to those results, study participants were classified into 3 groups:

• H pylori–positive and cagA-positive,
• H pylori–positive and cagA-negative, or
• H pylori–negative and cagA-negative.

H pylori status was established in NHANES 1999-2000 study participants with the Wampole ELISA. An immune status ratio (ISR) was calculated for each specimen by dividing the specimen optical density by the mean optical density of the cutoff controls. Specimens were given a negative value if the ISR was from 0 to 0.90, and a positive value if the ISR was higher than 0.90.

Participants received a positive diabetes status if they reported insulin use or a physician diagnosis of diabetes. HbA1c assays for both study groups were standardized to the reference method used in the Diabetes Control and Complications Trial, a large clinical study funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Because cagA status was only determined in NHANES III, the researchers only performed analyses of joint H pylori–cagA status in the NHANES III group.

They evaluated the effect of body mass index (BMI) on the association between H pylori status and HbA1c level, and performed stratified analyses using the standard definitions for overweight (≥25 kg/m²) and normal (<25 kg/m²) BMI.

H pylori Associated With Increased HbA1c Levels in Adults

In the NHANES 1999-2000 study overall, participants with H pylori had higher mean HbA1c levels (P = .02); this persisted when the researchers excluded those with known diabetes or insulin use (P = .02). The positive relationship was stronger in those 18 years of age or older (P = .01). There was no association in participants who were younger than 18 years.

After the adults were stratified according to BMI (<25 kg/m² and ≥25 kg/m²), the association between H pylori and HbA1c was only present in participants with a higher BMI. H pylori–associated increases in HbA1c were greater in those with a higher BMI (P for interaction < .01).

In NHANES III, the association between higher HbA1c levels with positive H pylori status was only apparent in participants without diabetes (P < .01). As in NHANES 1999-2000, H pylori–positivity was associated with higher HbA1c levels in participants with a high BMI who did not have diabetes (P < .01). Unlike in the earlier study, however, the association was also seen in participants with lower BMIs and no diabetes (P < .01).

H pylori cagA Associated With Increased HbA1c in Adults

Overall, there was a progressive increase in HbA1c when comparing participants who were H pylori–negative, H pylori–positive/cagA-negative, and H pylori–positive/cagA-positive (P = .02), especially after excluding participants who had diabetes or used insulin (P < .01). Positive H pylori cagA status was positively associated with HbA1c levels in both BMI groups after excluding people with a history of diabetes.

Association Between H pylori and Diabetes Unclear

In NHANES 1999-2000, H pylori was positively associated with diabetes (odds ratio [OR], 1.30; 95% confidence interval [CI], 0.94 - 1.80). This association was significant in people with higher BMIs (OR, 1.43; 95% CI, 1.00 - 2.03). There did not appear to be a difference between BMI levels (P for interaction = .21).

In NHANES III, H pylori was not associated with diabetes in either BMI group. CagA positivity was not associated with diabetes overall or in stratified analyses based on BMI. Neither H pylori nor H pylori cagA positivity was associated with current insulin use in the total population, or in participants stratified by BMI, although the sample size for this analysis was small.

The authors suspect that H pylori directly or indirectly increases HbA1c levels in adults, particularly those who are obese, as H pylori regulates leptin and ghrelin, which play a key role in energy homeostasis and metabolism.

In addition, H pylori causes gastric inflammation, which may be related to the development of metabolic syndrome, according to recent data.

"Given that the prevalence of H. pylori is decreasing, the proportion of diabetes that could be attributable to H. pyloriis likely to also decrease," write the authors. "However, among older individuals and especially those with a higher BMI, glucose intolerance associated with H. pylori could remain significant."

In an accompanying editorial, Dani Cohen, PhD, from Tel Aviv University in Israel, and Khitam Muhsen, PhD, from the University of Maryland School of Medicine, Baltimore, write: "Chen and Blaser utilized two independent large national samples of the general population. In addition, the use of a reliable biomarker of diabetes as a dependent variable confers originality to the article because prior studies on the association between H. pylori and HbA1c have been limited."

Noting that some adults might benefit from H pylori treatment, Dr. Cohen and Dr. Muhsen write: "Helicobacter pylori–infected adults with higher BMI, even if asymptomatic, may need anti–H. pylori therapy to control or prevent diabetes mellitus. With the continuous trend in the decline in H. pylori infection rates in developed countries, the relative importance of H. pylori in the etiology of diabetes mellitus will probably decrease. Nevertheless, there will be still many years in which older individuals, especially those with a higher BMI and glucose intolerance, will benefit from this new information."

The study was supported by grants from the National Institutes of Health and the Diane Belfer Program in Human Microbial Ecology. The authors and editorialists have disclosed no relevant financial relationships.

J Infect Dis. 2012:205:1183-1185, 1195-1202. Article abstract, Editorial extract

STUDY HIGHLIGHTS

• Researchers evaluated data from NHANES conducted in 1988 to 1994 and 1999 to 2000.
• Participants underwent testing for H pylori IgG antibodies by use of ELISA, including analysis for the cagAantigen.
• Participants also underwent evaluation for HbA1c values. The prevalence of clinical diabetes was determined by participant self-report or the use of insulin.
• The main study outcome was the relationship between positive testing results for H pylori IgG and HbA1c values. This result was adjusted to account for demographic and health habit variables as well as participants' BMI.
• Researchers evaluated 7417 participants from the first survey period and 6072 participants from the second survey period. The study cohort was fairly evenly divided according to sex and age groups represented.
• Variables associated with H pylori infection included older age, lower educational attainment, non-Hispanic black and Mexican American race/ethnicity, and higher BMI.
• In the 1999 to 2000 survey study cohort (NHANES 1999-2000), the mean HbA1c levels among participants with and without H pylori infection were 5.49% and 5.40% (P = .02). The difference in HbA1c levels based onH pylori infection was significant only among adults 18 years or older and among those with a BMI of 25 kg/m² or more.
• In the 1988 to 1994 survey study cohort (NHANES III), HbA1c levels were higher among participants with H pylori infection only among those without diabetes. H pylori infection was associated with higher HbA1c values regardless of BMI in this cohort.
• A positive testing result for the cagA antigen was associated with a more substantial increase in HbA1c values compared with positive H pylori status with a negative cagA testing result.
• There was no significant overall association between H pylori infection and the prevalence of diabetes, but H pylori infection was associated with a borderline increased risk for diabetes among participants with a BMI greater than 25 kg/m² in the 1999-2000 survey study cohort specifically.
• cagA positivity was also not associated with the prevalence of diabetes.
• Neither H pylori infection nor cagA positivity was associated with insulin use for diabetes.

CLINICAL IMPLICATIONS

• H pylori may increase the risk for type 2 diabetes by disturbing the homeostasis of leptin and ghrelin. In addition, H pylori infection is associated with chronic inflammation, which may be systemic and promote a higher risk for diabetes.
• The current study by Chen and Blaser demonstrates that H pylori infection, particularly with organisms with thecagA antigen, is associated with mild increases in HbA1c values in the general adult population. However, H pylori infection was generally unrelated to the prevalence of diabetes.