Type 1 Diabetes Associated With Enterovirus in Children

A recent study confirms that frequent enterovirus infection may contribute to the development of type 1 diabetes in children.

Children with type 1 diabetes had 3 times more enterovirus infections than children without type 1 diabetes, according to research published in Diabetologia.1

Type 1 diabetes is caused by an immune response that attacks insulin-producing cells in the pancreas and that can be predicted by identifying islet autoimmunity.

Previous studies have identified the association between enterovirus and type 1 diabetes2; this study, conducted by Hannah Honkanen, PhD, from the University of Tampere in Finland, and colleagues explores that link in greater depth.1

The researchers performed a case-control study of a prospective birth cohort of children participating in the Type 1 Diabetes Prediction and Prevention study in Finland. They analyzed stool from 129 case children (1673 samples) and 282 control children (3108 samples), using reverse‐transcriptase polymerase chain reaction to detect viral RNA, which was genotyped by sequencing.

Coxsackievirus A4 was the most common genotype identified, at 28%, followed by type A2 at 14% and type A16 at 11%.

Of children in the control group, 169 were diagnosed with enterovirus, whereas the case group had 108 infections (mean, 0.6 and 0.8, respectively). Researchers noted this difference occurred (mean, 0.4 and 0.6, respectively) before the detection of autoantibodies.

In case children, enterovirus infections happened more than 12 months before autoantibodies were first identified in samples. During this period, a mean 6.3 infections were diagnosed per case child vs 2.1 infections per control child per 10 follow-up years. These results suggest there is a lag between infection and the development of islet autoantibodies. “No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion,” the researchers wrote.

One study limitation the researchers acknowledged was that research was only conducted in a single country, and thus additional study is needed to see whether similar results occur elsewhere. Another limitation cited was lack of respiratory samples. Many enteroviruses present as respiratory infections, and only examining stool samples may underestimate their frequency. In addition, the researchers noted that, “we cannot exclude the possibility that some other non-HLA genes could influence the detection of enteroviruses.”

“This autoimmune process seems to start several months after the infection, suggesting that slowly operating mechanisms are involved,” Dr Honkanen said in an interview with Endocrinology Advisor. “This fits with other studies showing that enterovirus proteins are detected in insulin-producing cells in the majority of type 1 diabetic patients. Thus, these viruses can directly infect insulin-producing cells, which in turn may cause cell damage. The infection may become chronic and induce inflammation, which promotes autoimmune responses to insulin and other autoantigens. However, further studies are needed to elucidate the underlying mechanisms in more detail.”

Dr Honkanen said that enteroviruses are common in children, and that other factors, such as genes, play a role in which children develop type 1 diabetes. “It seems that only certain specific enterovirus types show an association with diabetes…. [T]here is still not enough evidence to conclude that enteroviruses really cause diabetes. The complex nature of type 1 diabetes makes it difficult to exclude the effects of possible confounding factors, and the causality of the observed associations needs to be proven in further studies,” she concluded.

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  1. Honkanen H, Oikarinen S, Nurminen N, et al. Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity [published online January 9, 2017]. Diabetologia. doi: 10.1007/s00125-016-4177-z
  2. Yeung WC, Rawlinson WD, Craig ME. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ. 2011;342:d35. doi: 10.1136/bmj.d35