Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets.
Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets.
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DOI：
10.1007/s00125-015-3837-8
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发表时间：
2016-03
期刊：
影响因子：
8.2
通讯作者：
Constância M
中科院分区：
文献类型：
--
作者：
Sandovici I;Hammerle CM;Cooper WN;Smith NH;Tarry-Adkins JL;Dunmore BJ;Bauer J;Andrews SR;Yeo GS;Ozanne SE;Constância M
衰老是2型糖尿病等代谢性疾病发展的主要风险因素。确定这种关联背后的机制可能有助于阐明与年龄相关的代谢健康渐进性丧失与2型糖尿病发展之间的关系。我们的目的是确定老化过程中内分泌胰腺的分子特征。采用Ilumina BeadChip阵列检测了幼龄和老年大鼠胰岛的整体基因转录。通过Sequenom MassArray检测46个随年龄差异表达的基因的启动子DNA甲基化，并建立其与表达的相关性。用免疫组织化学方法测定形态学和细胞过程随年龄的变化。在623个基因座中发现了与年龄相关的基因表达变化（>为1.5倍，错误发现率[FDR] <5%），其中显著（FDR < 0.05）富集了先前与胰岛细胞功能（Enpp1, Abcc8）， 2型糖尿病（Tspan8, Kcnq1），炎症过程（Cxcl9, Il33）和细胞外基质组织（Col3a1, Dpt）相关的基因。年龄相关的转录差异与炎症、葡萄糖稳态、细胞增殖和细胞-基质相互作用相关的几个位点的启动子DNA甲基化呈负相关（Il33、Cxcl9、Gpr119、Fbp2、Col3a1、Dpt、Spp1）。我们的研究结果表明，随着年龄的增长，很大一部分胰岛会发展为低级别的“慢性”炎症状态，这可能会引发功能可塑性的改变。此外，我们还发现了先前与2型糖尿病相关的基因表达的变化以及DNA甲基化的相关变化，这些变化可以解释它们与年龄相关的失调。这些发现为胰岛衰老过程的关键（epi）遗传特征提供了新的见解。本文的在线版本（doi:10.1007/s00125-015-3837-8）包含同行评审但未经编辑的补充材料，授权用户可使用。
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. 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. 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). 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. The online version of this article (doi:10.1007/s00125-015-3837-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.