Abstract
Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26–74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.
Highlights
Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk
While aging was associated with elevated HbA1c levels (P 1⁄4 0.028 as analysed by linear regression, Supplementary Fig. 1a), there were no significant associations between age and body mass index (BMI) or in vitro glucose-stimulated insulin secretion (Supplementary Fig. 1b,c)
The association analyses were adjusted for sex, body mass index (BMI) and family
Summary
Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. We demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D. One possible factor may be that aging causes epigenetic changes that affect gene expression and thereby potentially insulin secretion in pancreatic islets[3] Epigenetic alterations, such as changes in DNA methylation, have been linked to several diseases, including T2D2–8. We analysed DNA methylation genome-wide in islets from diabetic subjects and non-diabetic controls and identified multiple genes with altered methylation and expression in diabetic islets[3] These epigenetic changes were further associated with perturbed islet hormone secretion, and likely contribute to hyperglycaemia. It remains unknown if aging is associated with genome-wide changes in DNA methylation of human islets and if these changes have any effect on islet function and development of T2D
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