TY - JOUR

T1 - Early differences in islets from prediabetic NOD mice

T2 - combined microarray and proteomic analysis

AU - Crèvecoeur, Inne

AU - Gudmundsdottir, Valborg

AU - Vig, Saurabh

AU - Marques Câmara Sodré, Fernanda

AU - D'Hertog, Wannes

AU - Fierro, Ana Carolina

AU - Van Lommel, Leentje

AU - Gysemans, Conny

AU - Marchal, Kathleen

AU - Waelkens, Etienne

AU - Schuit, Frans

AU - Brunak, Søren

AU - Overbergh, Lut

AU - Mathieu, Chantal

PY - 2017/3

Y1 - 2017/3

N2 - AIMS/HYPOTHESIS: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: We conclude that the pancreatic islets, irrespective of immune differences, may contribute to the initiation of the autoimmune process.DATA AVAILABILITY: All microarray data are available in the ArrayExpress database ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-5264.

AB - AIMS/HYPOTHESIS: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: We conclude that the pancreatic islets, irrespective of immune differences, may contribute to the initiation of the autoimmune process.DATA AVAILABILITY: All microarray data are available in the ArrayExpress database ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-5264.

KW - Animals

KW - Hydrolases

KW - Islets of Langerhans

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred NOD

KW - Models, Theoretical

KW - Oligonucleotide Array Sequence Analysis

KW - Prediabetic State

KW - Protein-Arginine Deiminases

KW - Proteomics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Two-Dimensional Difference Gel Electrophoresis

KW - Journal Article

U2 - 10.1007/s00125-016-4191-1

DO - 10.1007/s00125-016-4191-1

M3 - Journal article

C2 - 28078386

VL - 60

SP - 475

EP - 489

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 3

ER -