title: Enterovirus infection of human islets of Langerhans affects β-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure.
abstract: OBJECTIVE
  In type 1 diabetes (T1D), most insulin-producing β cells are destroyed, but the trigger is unknown. One of the possible triggers is a virus infection and the aim of this study was to test if enterovirus infection affects glucose stimulated insulin secretion and the effect of virus replication on cellular macromolecules and organelles involved in insulin secretion.
  
  
  METHODS
  Isolated human islets were infected with different strains of coxsackievirus B (CVB) virus and the glucose-stimulated insulin release (GSIS) was measured in a dynamic perifusion system. Classical morphological electron microscopy, large-scale electron microscopy, so-called nanotomy, and immunohistochemistry were used to study to what extent virus-infected β cells contained insulin, and real-time PCR was used to analyze virus induced changes of islet specific genes.
  
  
  RESULTS
  In islets infected with CVB, GSIS was reduced in correlation with the degree of virus-induced islet disintegration. The expression of the gene encoding insulin was decreased in infected islets, whereas the expression of glucagon was not affected. Also, in islets that were somewhat disintegrated, there were uninfected β cells. Ultrastructural analysis revealed that virus particles and virus replication complexes were only present in β cells. There was a significant number of insulin granules remaining in the virus-infected β cells, despite decreased expression of insulin mRNA. In addition, no typical Golgi apparatus was detected in these cells. Exposure of islets to synthetic dsRNA potentiated glucose-stimulated insulin secretion.
  
  
  CONCLUSIONS
  Glucose-stimulated insulin secretion; organelles involved in insulin secretion and gene expression were all affected by CVB replication in β cells.
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory , Uppsala University , Uppsala , Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Hodik
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory , Uppsala University , Uppsala , Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Skog
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory , Uppsala University , Uppsala , Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lukinius
authors.affiliation: Department of Cell Biology , University Medical Center Groningen, University Groningen , Groningen , The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Isaza-Correa
authors.affiliation: Department of Cell Biology , University Medical Center Groningen, University Groningen , Groningen , The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kuipers
authors.affiliation: Department of Cell Biology , University Medical Center Groningen, University Groningen , Groningen , The Netherlands.
authors.forename: B N G
authors.initials: BN
authors.lastname: Giepmans
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory , Uppsala University , Uppsala , Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Frisk
keywords: Enterovirus; Human Islets; Transmission Electron Microscopy