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Enterovirus Infection Reduces Beta-cell Function and Leads to Decreased Glucose Stimulated Insulin Secretion in Dissociated but not In Intact Pancreatic Human Islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Korsgren)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Korsgren)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Korsgren)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Korsgren)
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-204372OAI: oai:DiVA.org:uu-204372DiVA: diva2:638701
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2014-01-07Bibliographically approved
In thesis
1. Enterovirus Implications in Type 1 Diabetes
Open this publication in new window or tab >>Enterovirus Implications in Type 1 Diabetes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human enteroviruses (HEVs), particularly Coxsackie B viruses (CVBs), might trigger the onset of type 1 diabetes (T1D), either by direct infection of the insulin-producing beta-cells or by an indirect inflammatory response. The overall aim of this thesis was to study the tropism of HEVs in isolated human pancreatic cell clusters in vitro including virus effects on islet function, gene-expression and ultrastructure. Furthermore, the expression of the major CVB-receptor, CAR, was investigated in pancreatic tissue from T1D-related subjects and CVB-infected islets. Also, tissues and isolated islets from two adult organ-donors who died close to disease onset were studied.The results showed that beta-cells were destroyed through lytic infections with different strains of CVBs and that islets function did not depend on replication per se but on the degree of islet destruction. Virus particles were observed in beta-cells in association with insulin granules, however no virus replication or particles could be observed in the exocrine cell clusters, as opposed to in mice models. The virus-infected islets had a decreased expression of insulin mRNA and CAR mRNA/protein, possibly reflecting virus-killed beta-cells. Infected beta-cells contained a high number of insulin granules, which might indicate an impaired function.The in vivo studies showed presence of virus proteins in the islets of both donors who died close to onset of T1D and elevated expression of innate immunity genes, potentially indicating viral infection, but direct evidence is lacking. Both donors were immune-reactive for insulin but the isolated islets had an impaired or completely lacking glucose response. Ultrastructural analysis showed both damaged beta-cells and normal-looking beta-cells, indicating that the latter might still have the potential to function but were blocked. CAR-expression was significantly increased in T1D-related subjects which might indicate tissue damage and/or inflammation in these subjects.To conclude, these results showed that CVBs could infect human primary beta-cells, likely by binding to CAR and lead to functional abnormalities, indicating that they could cause T1D in vivo. Exocrine cells were not permissive to CVB, which raises the question if mice-models should be used to study human pancreatitis. Also, unique materials from two T1D organ-donors were described.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 918
Keyword
Enterovirus, Coxsackie B virus, Type 1 diabetes, Pancreatitis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204378 (URN)978-91-554-8709-6 (ISBN)
Public defence
2013-09-13, Rudbecklaboratoriet stora aulan, Dag Hammarskjöldsv 20, Uppsala, 09:15 (English)
Supervisors
Available from: 2013-08-30 Created: 2013-08-01 Last updated: 2014-01-07

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Skog, OskarHodik, MonikaKorsgren, OlleFrisk, Gun

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