title: Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets.
abstract: OBJECTIVE
  Ageing is a major risk factor for development of metabolic diseases such as type 2 diabetes. Identification of the mechanisms underlying this association could help to elucidate the relationship between age-associated progressive loss of metabolic health and development of type 2 diabetes. We aimed to determine molecular signatures during ageing in the endocrine pancreas.
  
  
  METHODS
  Global gene transcription was measured in pancreatic islets isolated from young and old rats by Ilumina BeadChip arrays. Promoter DNA methylation was measured by Sequenom MassArray in 46 genes that showed differential expression with age, and correlations with expression were established. Alterations in morphological and cellular processes with age were determined by immunohistochemical methods.
  
  
  RESULTS
  Age-related changes in gene expression were found at 623 loci (>1.5-fold, false discovery rate [FDR] <5%), with a significant (FDR < 0.05) enrichment in genes previously implicated in islet-cell function (Enpp1, Abcc8), type 2 diabetes (Tspan8, Kcnq1), inflammatory processes (Cxcl9, Il33) and extracellular matrix organisation (Col3a1, Dpt). Age-associated transcriptional differences negatively correlated with promoter DNA methylation at several loci related to inflammation, glucose homeostasis, cell proliferation and cell-matrix interactions (Il33, Cxcl9, Gpr119, Fbp2, Col3a1, Dpt, Spp1).
  
  
  CONCLUSIONS
  Our findings suggest that a significant proportion of pancreatic islets develop a low-grade 'chronic' inflammatory status with ageing and this may trigger altered functional plasticity. Furthermore, we identified changes in expression of genes previously linked to type 2 diabetes and associated changes in DNA methylation that could explain their age-associated dysregulation. These findings provide new insights into key (epi)genetic signatures of the ageing process in islets.
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.|Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.|Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
authors.forename: Ionel
authors.initials: I
authors.lastname: Sandovici
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.|Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
authors.forename: Constanze M
authors.initials: CM
authors.lastname: Hammerle
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.|Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.|Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Cooper
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.
authors.forename: Noel H
authors.initials: NH
authors.lastname: Smith
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Tarry-Adkins
authors.affiliation: Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dunmore
authors.affiliation: Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Julien
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Bioinformatics Group, The Babraham Institute, Cambridge, UK.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Andrews
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK.|National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK. seo10@cam.ac.uk.|National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK. seo10@cam.ac.uk.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OQQ, UK. jmasmc2@cam.ac.uk.|Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK. jmasmc2@cam.ac.uk.|Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. jmasmc2@cam.ac.uk.|National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK. jmasmc2@cam.ac.uk.
authors.forename: Miguel
authors.initials: M
authors.lastname: Constância
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D054370:Chemokine CXCL9 / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D051381:Rats; D064233:Sulfonylurea Receptors / Q000235:genetics; D059470:Tetraspanins / Q000235:genetics
chemical_list: C577509:Abcc8 protein, rat; C577828:COL3A1 protein, rat; C505723:CXCL9 protein, rat; D054370:Chemokine CXCL9; D024061:Collagen Type III; D051657:KCNQ1 Potassium Channel; D064233:Sulfonylurea Receptors; D059470:Tetraspanins; C111874:Tspan8 protein, rat; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases
keywords: Ageing; DNA methylation; Epigenetics; Inflammageing; Pancreatic islets; Type 2 diabetes