Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial

Abstract

This study evaluated the possible role of enterovirus infections in the pathogenesis of type I (insulin-dependent) diabetes in a prospective dietary intervention trial. Children participated in the second pilot of the Trial to Reduce IDDM in Genetically at Risk (TRIGR) project. They were randomized into two groups receiving either a casein hydrolysed formula (Nutramigen) or a regular formula, whenever breast milk was not available over the first 6-8 months of life. Altogether 19 children who turned positive for autoantibodies associated with type I diabetes by 2 years of age and 84 matched control children were analysed for enterovirus antibodies and enterovirus RNA in serum. Enterovirus infections were common during the first 2 years of life and more frequent among boys than girls (P = 0.02). Autoantibody-positive children had more enterovirus infections than autoantibody-negative children before the appearance of autoantibodies (0.83 versus 0.29 infection per child, P = 0.01). The average levels of IgG antibodies to echovirus antigen were also higher in autoantibody-positive than in autoantibody-negative children (P = 0.0009). No difference was found in the frequency of enterovirus infections between children receiving the casein hydrolysed formula or regular formula. These results suggest that enterovirus infections are associated with the induction of beta-cell autoimmunity in young children with increased genetic susceptibility to type I diabetes.

Figures

Fig. 1

Frequency of enterovirus infections in relation to age during the follow-up of 103 children. (a) Enterovirus infections diagnosed by serology. (b) Infections diagnosed by the presence of viral RNA in serum using RT-PCR. CB = cord blood, MS = maternal sera.

Fig. 2

Antibody levels and viral RNA in serum during the follow-up of three children. ♦, CBV4 IgG; ◊, CBV4 IgA; ▪, EV11 IgG; □, EV11 IgA; •, peptide IgG; ○, peptide IgA. Case 119, who had enterovirus RNA in two consecutive samples followed by the appearance of diabetes-associated autoantibodies (marked by arrows). (b) Control child who had an IgG response of long duration to the CBV4 antigen after infection by the CBV4 serotype (confirmed by neutralization assay and marked by arrow). (c) Control child who had an IgG response of short duration to the CBV4 antigen after infection by the CBV3 serotype (confirmed by neutralization assay and marked by arrow).

Fig. 3

Average levels of IgG class antibodies to echovirus 11 in case and control children during the follow-up. Horizontal bars on the top of the figure represent the time period where P-values are analysed. ▪, cases; □, controls.