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Diabetologia. 2016 Mar;59(3):502-11. doi: 10.1007/s00125-015-3837-8. Epub 2015 Dec 23.

Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets.

Author information

1
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.
2
Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
3
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
4
Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
5
Bioinformatics Group, The Babraham Institute, Cambridge, UK.
6
National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK.
7
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.
8
National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK. seo10@cam.ac.uk.
9
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.
10
Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK. jmasmc2@cam.ac.uk.
11
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. jmasmc2@cam.ac.uk.
12
National Institute of Health Research, Cambridge Biomedical Research Centre, Cambridge, UK. jmasmc2@cam.ac.uk.

Abstract

AIMS/HYPOTHESIS:

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/INTERPRETATION:

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.

KEYWORDS:

Ageing; DNA methylation; Epigenetics; Inflammageing; Pancreatic islets; Type 2 diabetes

PMID:
26699651
PMCID:
PMC4742511
DOI:
10.1007/s00125-015-3837-8
[Indexed for MEDLINE]
Free PMC Article

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