Diabetes Linked to Nearly 10-Fold Increase in Cold-Like Enterovirus Infection

Laurie Barclay, MD

February 11, 2011

February 11, 2010 — Type 1 diabetes is linked to nearly a 10-fold increase in cold-like enterovirus infection, according to the results of a systematic review and meta-analysis of observational molecular studies reported in the February 3 issue of the BMJ.

"Type 1 diabetes is believed to result from a complex interplay between genetic predisposition, the immune system, and environmental factors," write Wing-Chi G. Yeung, from the University of New South Wales in Sydney, Australia, and colleagues. "...Prospective studies have also shown more enterovirus infections in children who developed islet autoantibodies or subsequent diabetes, or both; as well as a temporal relation between infection and autoimmunity. The relation between enterovirus infection and diabetes is not consistent across all studies, however, and the subject remains controversial."

The goal of the study was to examine the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes.

The investigators searched PubMed to May 2010 and EMBASE to May 2010 for human studies without language restrictions. They also searched bibliographies of identified articles and contacted the study authors. Inclusion criteria for the studies were cohort or case-control design measuring enterovirus RNA or viral protein in blood, stool, or tissue of patients with prediabetes and diabetes, with sufficient data to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

There were 24 studies and 2 abstracts meeting inclusion criteria; these were all case-control studies enrolling a total of 4448 participants. However, great variance in the study designs resulted in a high degree of statistical heterogeneity. Diabetes-related autoimmunity or type 1 diabetes was considered as 2 separate outcomes. Enterovirus infection was significantly associated with type 1 diabetes–related autoimmunity (OR, 3.7; 95% CI, 2.1 - 6.8; heterogeneity χ2/df = 1.3) and clinical type 1 diabetes (OR, 9.8; 95% CI, 5.5 - 17.4; heterogeneity χ2/df = 3.2), based on meta-analysis using random-effects models.

"There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes," the study authors write. "Larger prospective studies would be needed to establish a clear temporal relation between enterovirus infection and the development of autoimmunity and type 1 diabetes."

Limitations of this study include meta-analysis of observational studies unable to prove causality, high proportion of included studies from European countries, significant heterogeneity in study design and methods used, and possible unmeasured confounding factors. In addition, enterovirus polymerase chain reaction primers had varying sensitivity and specificity, and not all studies reported the validation and limits of detection of their polymerase chain reaction method.

In an accompanying editorial, Didier Hober and Famara Sane, from University Lille 2 in France, note that type 1 diabetes and enterovirus infection are clearly linked, but the mechanism is yet to be explained.

"The link between enteroviruses and the pathogenesis of type 1 diabetes probably involves an interplay between viruses, pancreatic beta cells, the innate and adaptive immune systems, and the genotype of the patient," Drs. Hober and Sane write. "Further studies are needed to tease out the association of these factors and to establish the pathogenic mechanisms of enterovirus infections. The association between enteroviruses and type 1 diabetes opens up the possibility of developing new preventive and therapeutic strategies to fight this disease."

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The study authors and editorialists have disclosed no relevant financial relationships.

BMJ. 2011;342:d35. Full text

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