title: Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis.
abstract: Type 1 diabetes is an endocrine disease where a long preclinical phase, characterised by immune cell infiltration in the islets of Langerhans, precedes elevated blood glucose levels and disease onset. Although several studies have investigated the role of the immune system in this process of insulitis, the importance of the beta cells themselves in the initiation of type 1 diabetes is less well understood. The aim of this study was to investigate intrinsic differences present in the islets from diabetes-prone NOD mice before the onset of insulitis.
  
  
  
  The islet transcriptome and proteome of 2-3-week-old mice was investigated by microarray and 2-dimensional difference gel electrophoresis (2D-DIGE), respectively. Subsequent analyses using sophisticated pathway analysis and ranking of differentially expressed genes and proteins based on their relevance in type 1 diabetes were performed.
  
  
  
  In the preinsulitic period, alterations in general pathways related to metabolism and cell communication were already present. Additionally, our analyses pointed to an important role for post-translational modifications (PTMs), especially citrullination by PAD2 and protein misfolding due to low expression levels of protein disulphide isomerases (PDIA3, 4 and 6), as causative mechanisms that induce beta cell stress and potential auto-antigen generation.
  
  
  
  We conclude that the pancreatic islets, irrespective of immune differences, may contribute to the initiation of the autoimmune process.
  
  
  
  All microarray data are available in the ArrayExpress database ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-5264.
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Inne
authors.initials: I
authors.lastname: Crèvecoeur
authors.affiliation: Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Valborg
authors.initials: V
authors.lastname: Gudmundsdottir
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Vig
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques Câmara Sodré
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Wannes
authors.initials: W
authors.lastname: D'Hertog
authors.affiliation: Department of Information Technology, IMinds, Faculty of Sciences, Ghent University, Ghent, Belgium.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Fierro
authors.affiliation: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Leentje
authors.initials: L
authors.lastname: Van Lommel
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: Department of Information Technology, IMinds, Faculty of Sciences, Ghent University, Ghent, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Marchal
authors.affiliation: SyBioMa, KU Leuven, Leuven, Belgium.|Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.affiliation: Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark.|The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium. lutgart.overbergh@kuleuven.be.
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 bus 902, 3000, Leuven, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008962:Models, Theoretical; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011236:Prediabetic State / Q000378:metabolism* / Q000473:pathology; D000076342:Protein-Arginine Deiminases; D040901:Proteomics / Q000379:methods*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057825:Two-Dimensional Difference Gel Electrophoresis
chemical_list: D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: 2D-DIGE; Beta cells; Intrinsic differences; Microarray; NOD mice; Pathway analysis; Post-translational modifications; Type 1 diabetes