An “Outbreak” of Juvenile Diabetes Mellitus: Consideration of a Viral Etiology

Huff, J. Clark; Hierholzer, John C.; Farris, William A.

doi:10.1093/oxfordjournals.aje.a112036

Cited by 37 publications

(17 citation statements)

References 30 publications

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“…Human enterovirus (HEV) infections have long been suspected as environmental triggers of human T1D (12,22,27); infections by common HEVs, such as the group B coxsackieviruses (CVB 1 to 6) and diverse echoviruses, have been implicated as triggers of T1D onset at the time of or shortly after infection (8,9,13,19,28,37,39,40,42,52,60). Nonetheless, it remains unclear whether HEV initiates T1D in humans (18,21,24,26); evidence supporting an etiologic connection between HEV infection and T1D onset is not as well-established as the links between, for example, specific HEV infections and poliomyelitis, aseptic meningitis, or myocarditis (43).…”

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confidence: 99%

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Kanno

Kim

Kono

et al. 2006

J Virol

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Group B coxsackieviruses can initiate rapid onset type 1 diabetes (T1D) in old nonobese diabetic (NOD) mice. Inoculating high doses of poorly pathogenic CVB3/GA per mouse initiated rapid onset T1D. Viral protein was detectable in islets shortly after inoculation in association with beta cells as well as other primary islet cell types. The virulent strain CVB3/28 replicated to higher titers more rapidly than CVB3/GA in the pancreas and in established beta cell cultures. Exchange of 5-nontranslated regions between the two CVB3 strains demonstrated a variable impact on replication in beta cell cultures and suppression of in vivo replication for both strains. While any CVB strain may be able to induce T1D in prediabetic NOD mice, T1D onset is linked both to the viral replication rate and infectious dose.Insulin-dependent (type 1) diabetes mellitus (T1D) is an autoimmune, largely T-cell-mediated disease typically diagnosed before the end of the teen years (5, 6). A predisposing, multigenic component has been described but accounts for fewer than 50% of cases (7,35,45); environmental factors (e.g., viral infections) have therefore been proposed to explain the remaining cases of T1D (3,6,32,57,58) that cannot be ascribed solely to host-driven pathogenic autoimmunity. Human enterovirus (HEV) infections have long been suspected as environmental triggers of human T1D (12,22,27); infections by common HEVs, such as the group B coxsackieviruses (CVB 1 to 6) and diverse echoviruses, have been implicated as triggers of T1D onset at the time of or shortly after infection (8,9,13,19,28,37,39,40,42,52,60). Nonetheless, it remains unclear whether HEV initiates T1D in humans (18,21,24,26); evidence supporting an etiologic connection between HEV infection and T1D onset is not as well-established as the links between, for example, specific HEV infections and poliomyelitis, aseptic meningitis, or myocarditis (43).The nonobese diabetic (NOD) mouse is widely used as a model for the study of T1D. Previous work demonstrated that CVB inoculation protects young NOD mice significantly better from T1D as they age than no treatment (mock infected) (55). Unlike all other treatments that protect NOD mice from T1D (reviewed in references 4 and 46), the CVB are widely thought to be instigators of T1D onset with no protective effect. The extent of protection from T1D onset correlates directly with replication efficiency of the specific CVB strain that is employed: CVB strains that replicate to higher titers protect more mice than do CVB strains which replicate to lower titers. As NOD mice age, naturally occurring, pathogenic autoimmune insulitis develops rapidly (4) with widespread islet inflammation (insulitis) present by week 12 to 15 of age, when T1D also begins to occur. T1D rapidly ensues following inoculation of old (Ͼ12 weeks of age) NOD mice with virulent CVB (14), a model that recapitulates observations of sudden T1D onset in humans reported to occur during or shortly after an infection (37, 52). Initiation of rapid T1D onset in older mice...

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Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Kanno

Kim

Kono

et al. 2006

J Virol

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“…Evidence for the contribution of Coxsackievirus B infections in the pathogenesis of type 1 diabetes abounds [13][14][15], yet several other EVs species, including Coxsackievirus A [16][17][18], echoviruses [16,17] and EVs of A-D species [19], may also have a role. Cases of new-onset type 1 diabetes occur in seasonal patterns [11,20], sometimes in clusters or small outbreaks, often peaking 1-2 months after high EV infection activity [21]. A recent study on intrafamilial spread of EV infections reported that 20% of siblings of diabetic probands acquired type 1 diabetes with a latency of 3-25 months [19].…”

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confidence: 99%

Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study

et al. 2014

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Aims/hypothesis This study compared the incidence rate of type 1 diabetes in children diagnosed with enterovirus (EV) infections with that in age-and sex-matched children without EV infection in a population-based cohort. In addition, we examined whether the direction or magnitude of the association between EV infection and type 1 diabetes differs according to atopic disease status in children.Methods We used insurance claims data from Taiwan's National Health Insurance Research Database to derive type 1 diabetes incidence in children aged up to 18 years with or without a diagnosis of EV infection during 2000-2008. Incidence rate ratios and HRs of type 1 diabetes for EV infection were estimated by Poisson regression and Cox's proportional hazard regression model. Results Overall incidence of type 1 diabetes was higher in the EV than in the non-EV infection cohort (5.73 vs 3.89 per 100,000 person-years; incidence rate ratio 1.48 [95% CI 1.19, 1.83]), with an adjusted HR of 1.48 (95% CI 1.19, 1.83). Among children without EV, incidence increased with age at diagnosis of EV infection, except in those aged 5-10 years. The HRs of type 1 diabetes in children with allergic rhinitis, bronchial asthma or either one of these atopic diseases showed more variation than in those children without these diseases. Conclusions/interpretation This nationwide retrospective cohort study found a positive correlation between type 1 diabetes and EV infection. The results suggest that a preventive strategy, such as an effective vaccine against EV infection, may lessen the incidence of type 1 diabetes in Taiwan.

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“…The CVB have been soundly implicated as causes of human myocarditis (1, 26, 42, 60-62, 73, 74, 108, 109) and pancreatitis (2,41,54,58,66,107) and, furthermore, cause these diseases readily in mice (9,40,43,85,86,105). Although CVB have been suggested as infectious triggers of human insulin-dependent (type 1) diabetes mellitus (T1D) (7,22,34,53,116), there is no consensus as to the etiologic role for CVB in T1D development (25,32,33,47,52,63,64,110). Unlike the readiness with which CVB cause pancreatitis and myocarditis in mice, very few CVB strains have been characterized that induce even transient glucose abnormalities or diabetes in inbred strains of mice (56,87,99).…”

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Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence

Tracy

Drescher

Chapman

et al. 2002

J Virol

147

164

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Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4-or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2-to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four-to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.The group B coxsackieviruses (CVB; family Picornaviridae, genus Enterovirus, species group B coxsackievirus; six serotypes, CVB1 to -6) are among the best studied of human enteroviruses (102). The CVB genome is a single strand of positive sense RNA 7,400 nucleotides in length that encodes 11 proteins in a single open reading frame (89). The CVB have been associated with diverse human diseases, among the more serious of which are myocarditis, pancreatitis, and aseptic meningitis. The CVB have been soundly implicated as causes of human myocarditis (1, 26, 42, 60-62, 73, 74, 108, 109) and pancreatitis (2,41,54,58,66,107) and, furthermore, cause these diseases readily i...

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An “Outbreak” of Juvenile Diabetes Mellitus: Consideration of a Viral Etiology

Cited by 37 publications

References 30 publications

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study

Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence

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