DNA methylation patterns associated with ageing differ markedly from those linked to type 2 diabetes, according to a new multiomics study that provides fresh insight into pancreatic islet dysfunction and disease risk.
Researchers integrated DNA methylation, transcriptomic, and genotyping data from 144 pancreatic islet donors to investigate how ageing and type 2 diabetes independently influence epigenetic regulation. While advancing age remains the strongest risk factor for type 2 diabetes, the biological mechanisms connecting the two have remained poorly understood.
Distinct Epigenetic Signatures Identified
The analysis identified 996 age associated cytosine phosphate guanine (CpG) sites and 902 diabetes associated CpG sites, with minimal overlap between the two groups. Researchers also identified 251 age- related and 310 diabetes related CpG target genes, most of which were located at considerable distances from the associated methylation sites.
Age associated DNA methylation changes were predominantly found in gene promoter regions and formed coordinated gene modules linked to beta cell function, including insulin secretion. In contrast, diabetes associated DNA methylation changes were enriched in enhancer and non-regulatory regions, suggesting a more heterogeneous pattern consistent with stress related epigenetic alterations.
Importantly, the observed relationships between CpG sites and target genes appeared independent of underlying genetic variation, indicating that these epigenetic mechanisms may exert effects beyond inherited genetic risk.
Potential Biomarkers for Diabetes Risk
Further analysis using Mendelian randomisation supported a potential causal role for age associated DNA methylation changes regulating KLHL42, a genetic locus previously linked to type 2 diabetes risk through genome wide association studies.
Researchers also developed a blood-based methylation risk score using age associated CpG sites. The score correlated with insulin secretion and improved classification of type 2 diabetes when combined with genetic risk information. The combined model achieved strong discriminatory performance: area under the curve (AUC): 0.91.
Implications For Diabetes Research
The findings suggest that ageing and type 2 diabetes are characterised by fundamentally different epigenetic programmes within pancreatic islets. Ageing appears to drive a coordinated biological process affecting beta cell function, whereas diabetes is associated with a more variable and stress related epigenetic signature.
The authors conclude that DNA methylation markers may offer valuable opportunities for identifying individuals at risk of diabetes and for improving understanding of the biological pathways linking ageing to metabolic disease.
Reference
Maurin L et al. Epigenetic landscapes in human pancreatic islets reveal distinct drivers for adaptation to age and type 2 diabetes. Nature Communications. 2026;17:4811.
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