Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes

Willcox, Abby; Richardson, Sarah J.; Aj, Bone; Foulis, Alan K.; Morgan, Noel G.

doi:10.1007/s00125-011-2192-7

Cited by 53 publications

(49 citation statements)

References 14 publications

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“…Many studies since then have used rodent models of spontaneous diabetes, and much attention has been focused on EVs, especially Coxsackievirus B4 [15]. Moreover, concrete evidence illustrates a range of EVs infecting, replicating and lysing cultured human islets and insulin-producing cell lines in vitro [49], and markers of EV have also been found in the pancreas of patients with type 1 diabetes [24].…”

Section: Discussionmentioning

confidence: 99%

“…Evidence for this association is supported by detection of EVs in the blood [13,14,17,22], pancreas [15,[23][24][25][26] and gut mucosa [27] of patients with type 1 diabetes. Histopathologic evidence indicates that expression of enteroviral capsid protein VP1 in islet cells of patients with type 1 diabetes is related to induction of protein kinase R and downregulation of Mcl-1 [23,24].…”

Section: Introductionmentioning

confidence: 95%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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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“…This was strongly associated with the presence of insulitis suggesting that factors released from the immune cells could be driving an attempt by the beta cells to increase their numbers in the face of the attack [70]. The presence of proliferating endocrine cells was also frequently observed in islets with VP1 staining, implying that a viral infection could be inducing the recruitment of the immune cells, which in turn release factors that promote endocrine cell proliferation [71]. The finding that endocrine cell proliferation was increased in some islet autoantibody positive organ donors with evidence of insulitis [72] and that proliferation was not observed in adult, longer duration type 1 diabetes patients [73] who rarely have evidence of insulitis, lends support to this hypothesis.…”

Section: Are the Beta Cells Trying To Fight Back?mentioning

confidence: 97%

Pancreatic Pathology in Type 1 Diabetes Mellitus

2014

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“…The majority of published studies have made use of pancreatic tissues collected at autopsy from type 1 diabetic patients with varying durations of diabetes (8)(9)(10). Much of the material was affected by postmortem changes and was preserved in the form of formalin-fixed, paraffin-embedded blocks, which means that many of the more modern techniques used to detect viruses cannot be applied with confidence.…”

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confidence: 99%

Detection of a Low-Grade Enteroviral Infection in the Islets of Langerhans of Living Patients Newly Diagnosed With Type 1 Diabetes

et al. 2014

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The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3–9 weeks after onset of type 1 diabetes in six adult patients (age 24–35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh-frozen whole pancreatic tissue using PCR and sequencing. Nondiabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetic patients (two of nine controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (one of nine controls). Enterovirus-specific RNA sequences were detected in four of six patients (zero of six controls). The results were confirmed in various laboratories. Only 1.7% of the islets contained VP1+ cells, and the amount of enterovirus RNA was low. The results provide evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, which is consistent with the possibility that a low-grade enteroviral infection in the pancreatic islets contributes to disease progression in humans.

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Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes

Abstract: Ki67(+) cells were frequently observed in islets that also contained VP1(+) cells, suggesting that the factors facilitating viral replication may also drive islet cell proliferation. However, in an individual cell, VP1 production does not require concurrent beta cell proliferation.

Cited by 53 publications

References 14 publications

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

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

Pancreatic Pathology in Type 1 Diabetes Mellitus

Detection of a Low-Grade Enteroviral Infection in the Islets of Langerhans of Living Patients Newly Diagnosed With Type 1 Diabetes

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