There has been an incredible amount of buzz recently in the diabetes community about the recent paper "Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies" published in The British Medical Journal: 2011;342:d35 doi:10.1136/bmj.d35. The authors: Yeung, Rawlinson and Craig, performed a meta-analysis and reviewed the association between current enterovirus infection diagnosed by molecular testing and the development of pancreatic autoimmunity or type 1 diabetes.
There is a long history of purported associations between viral infections and the development of type 1 diabetes. Epidemiologic studies have demonstrated a seasonal association with the development of clinical type 1 diabetes after enterovirus epidemics. Indeed, prior to the discovery of vaccines to prevent varicella, rubella, and mumps, many children were thought to present with type 1 diabetes after exposure to these viral infections. More recently coxsackie viral infections have been linked to type 1 diabetes onset as well. The authors of BMJ study note, "prospective studies have documented more enteroviral infections in children who developed Beta islet cell antibodies or diabetes as well as a temporal relation between infection and autoimmunity." However, according to the authors, the relationship between enteroviral infection and diabetes is not consistent across all studies and remains "controversial." Most importantly, a systematic review of Coxsackie B virus serological studies by the authors did not show an association with type 1 diabetes, however there had been no systematic review of molecular studies.
In a brief review of the theoretical etiology of type 1 diabetes, it is thought that people are low risk, moderate risk, or high risk. The risk is determined by alleles contributed from each parent to the HLA locus on chromosome 6. There is an association of other autoimmune diseases with these linked alleles including autoimmune thyroiditis, celiac disease and Addison's disease. To eventually develop type 1 diabetes, it is necessary to have this genetic susceptibility but it is not sufficient. The person must have another "hit" to develop the disease such as exposure to viral infections, toxins, antigens, or other environmental stimuli. Thus, the interest in proving which offending substance provokes the autoimmune response is important to possibly stop or prevent infection/exposure.
The authors systematically reviewed retrospective epidemiologic papers and meta-analyses of observational studies that were analyzed with random effects models. Cases eligible for the study were those that measured enterovirus RNA or viral protein in blood, stool or tissue with patients that had pre-diabetes or type 1 diabetes. What were the results?
After review of 33 prevalence studies involving 1,931 cases and 2,517 controls there appeared to be two separate outcomes: "1. diabetes related to autoimmunity or 2. type 1 diabetes." Meta-analysis demonstrated a significant association between enterovirus infection and type 1 diabetes- related autoimmunity and clinical type 1 diabetes. According to the authors, "the association between enteroviral infection, detected with molecular methods, and diabetes was strong, with almost 10 times the odds of enteroviral infection in children at diagnosis of type 1 diabetes compared with the controls. The odds of infection were also higher in children with prediabetes than in controls." In addition, it was also noted that persistent enterovirus infection was common among patients with type 1 diabetes.
Please note that the study did not prove that enteroviruses directly caused autoimmunity or type 1 diabetes; rather that there is an association between enteroviruses and autoimmunity/type 1 diabetes. The authors concluded that prospective studies will be required to determine a temporal causal effect between infection with enteroviruses and the development of autoimmunity and type 1 diabetes. Interestingly enough, the authors also commented on conflicting evidence as to whether the presence or absence of high-risk HLA genotypes (discussed above) alters the association between enterovirus infection and type 1 diabetes. Several researchers have reported higher rates of enterovirus infection in children with low risk HLA genotypes. The authors of this study did not perform an analysis of HLA genotypes in the diabetes studies and commented re the need for "future studies to include individuals with low and high HLA genotypes to determine whether genetic risk modifies the effect of enterovirus infection on the risk of type 1 diabetes."
In summary, this information has profound significance in the attempts to prevent autoimmune diabetes. Perhaps, work will now begun (or is already in progress) to develop a vaccine to prevent infection by coxsackie or other enterovirus infections.
Published On: February 15, 2011