Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: A prospective study

Abstract

Recent prospective studies have documented serologically an increased frequency of enterovirus infections in prediabetic children, indicating that these infections may initiate and accelerate the beta-cell damaging process several years before the clinical manifestation of type 1 diabetes. The aim of the present study was to establish whether these serological findings would be supported by the detection of enterovirus RNA in a unique prospective series of sera collected from prediabetic children 0-10 years before the manifestation of clinical type 1 diabetes. Reverse transcription followed by polymerase chain reaction employing highly conserved primers among enteroviruses were used to amplify enteroviral sequences. Viral RNA was found in 22% (11/49) of follow-up samples from prediabetic children but in only 2% (2/105) of those from controls (OR 14.9, P < 0.001). Persisting RNA positivity was not observed in any of these children. The presence of enterovirus RNA was associated with concomitant increases in the levels of autoantibodies against islet cells (OR 21.7, P < 0.01) and glutamic acid decarboxylase (OR 15.4, P < 0.05), but not in the levels of antibodies against insulin or the tyrosine phosphatase-like IA-2 protein. In contrast to the prediabetic children, those with newly diagnosed type 1 diabetes were negative for enterovirus RNA. The results thus complement previous serological data, suggesting that enterovirus infections are an important risk factor underlying type 1 diabetes and associated with the induction of beta-cell autoimmunity even years before symptoms appear.

The role of viruses in human diabetes

“…Moreover, infections were also clustered immediately preceding the appearance of autoantibodies even several years before the diagnosis of clinical diabetes [56,57,58,34]. The frequency of other virus infections such as cytomegalovirus, adenovirus and Epstein Barr virus did not differ between the groups [13,56,59].…”

“…Others have detected enteroviruses by PCR methods in the serum of children genetically at risk for diabetes some months or years before the clinical condition developed [34,35].…”

“…Contamination can create difficulties as well as cause false positives [36] and repeated freezing and thawing of specimens can also interfere with results [34]. Nevertheless, results using these tests from three western European countries show consistency, especially in diabetic children compared with control subjects with very low levels of infection.…”

“…Non-insulin dependent diabetic patients were negative for enteroviruses when tested in this system. [30] 1997 whole blood adults coxsackie B3B4 [29] 1999 serum children younger than 15 years of age coxsackie B viruses and echoviruses [23] 2000 whole blood children and adults coxsackie B2B3B4 [34] 2000 serum prediabetic children not determined [35] 2000 serum prediabetic children not determined [33] 2000 serum diabetic children - [31] 2001 mononuclear cells diabetic children coxsackie B4B5 cells enterovirus infection has been associated with the onset of insulin requiring diabetes. In an earlier review of 11 such cases who were mainly children, all six coxsackie viruses were implicated.…”

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells

“…The process, which finally leads to complete beta-cell loss and onset of clinical disease, starts years before any clinical symptoms and is thought to result from several factors involving host genes, autoimmune responses and cytokines, as well as environmental factors. Results from previous cross-sectional and prospective studies on patients with Type 1 diabetes and/or prediabetic individuals have suggested that enterovirus infections are involved in the development of the disease [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15].…”