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<p>Age is the strongest risk factor for type 2 diabetes, yet their independent contribution to pancreatic islet dysfunction remains unclear. We integrate DNA methylation, transcriptomic, and genotyping data from 144 islet donors. We identify 996 age- and 902 T2D-associated CpGs with minimal overlap, and 251 age- and 310 diabetes CpG target genes, usually distant from the CpG. Age-linked CpGs are enriched in promoters, form co-regulated gene modules, link to beta-cell function, including insulin secretion. Diabetes-associated CpGs are enriched in enhancer/non-regulatory regions, and modules suggest stress-induced epigenetic drift. CpG-gene associations are independent of genetic variation. Mendelian randomisation supports a causal role for age-associated CpGs regulating <i>KLHL42</i>, a T2D GWAS locus. A blood-based methylation risk score based on age-linked CpGs correlates with insulin secretion and improves diabetes classification when combined with genetic risk (AUC = 0.91). Altogether, age is associated with a coordinated epigenetic programme, whereas diabetes links to a heterogeneous, stress-related epigenetic signature.</p>

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Epigenetic landscapes in human pancreatic islets reveal distinct drivers for adaptation to age and type 2 diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Lucas Maurin,
  • Lorella Marselli,
  • Mathilde Boissel,
  • Vincent Pascat,
  • Mara Suleiman,
  • Emma Henriques,
  • Carmela De Luca,
  • Lijiao Ning,
  • Marie Fourcot,
  • Marta Tesi,
  • Bénédicte Toussaint,
  • Souhila Amanzougarene,
  • Mehdi Derhourhi,
  • Frédérik Oger,
  • Frederic Burdet,
  • Mickael Canouil,
  • Miriam Cnop,
  • Mark Ibberson,
  • Amélie Bonnefond,
  • Piero Marchetti,
  • Philippe Froguel,
  • Amna Khamis

摘要

Age is the strongest risk factor for type 2 diabetes, yet their independent contribution to pancreatic islet dysfunction remains unclear. We integrate DNA methylation, transcriptomic, and genotyping data from 144 islet donors. We identify 996 age- and 902 T2D-associated CpGs with minimal overlap, and 251 age- and 310 diabetes CpG target genes, usually distant from the CpG. Age-linked CpGs are enriched in promoters, form co-regulated gene modules, link to beta-cell function, including insulin secretion. Diabetes-associated CpGs are enriched in enhancer/non-regulatory regions, and modules suggest stress-induced epigenetic drift. CpG-gene associations are independent of genetic variation. Mendelian randomisation supports a causal role for age-associated CpGs regulating KLHL42, a T2D GWAS locus. A blood-based methylation risk score based on age-linked CpGs correlates with insulin secretion and improves diabetes classification when combined with genetic risk (AUC = 0.91). Altogether, age is associated with a coordinated epigenetic programme, whereas diabetes links to a heterogeneous, stress-related epigenetic signature.