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

Published version
Peer-reviewed

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Authors

Hammerle, Constanze M 
Cooper, Wendy N 
Smith, Noel H 
Tarry-Adkins, Jane L 

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.

Description

Keywords

Ageing, DNA methylation, Epigenetics, Inflammageing, Pancreatic islets, Type 2 diabetes, Aging, Animals, Chemokine CXCL9, Collagen Type III, DNA Methylation, Diabetes Mellitus, Type 2, Epigenesis, Genetic, Inflammation, Islets of Langerhans, KCNQ1 Potassium Channel, Male, Phosphoric Diester Hydrolases, Pyrophosphatases, Rats, Sulfonylurea Receptors, Tetraspanins

Journal Title

Diabetologia

Conference Name

Journal ISSN

0012-186X
1432-0428

Volume Title

59

Publisher

Springer Science and Business Media LLC
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/D01235X/2)
Biotechnology and Biological Sciences Research Council (BB/H003312/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/4)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/5/B)
Medical Research Council (MC_PC_12012)
Biotechnology and Biological Sciences Research Council (Grant ID: BB/H003312/1), British Heart Foundation, FP6 Epigenome Network of Excellence programme, GlaxoSmithKline, Nuffield Foundation, Royal Society, Medical Research Council (Grant ID: MRC_MC_UU_12012/4)
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