Epigenetic landscapes in human pancreatic islets reveal distinct drivers for adaptation to age and type 2 diabetes - PubMed
2 hours ago
- #Epigenetics
- #Type 2 Diabetes
- #Pancreatic Islets
- Age is the strongest risk factor for type 2 diabetes, but its independent effects on pancreatic islet dysfunction compared to diabetes are unclear.
- Integration of DNA methylation, transcriptomic, and genotyping data from 144 islet donors identified 996 age-associated and 902 T2D-associated CpGs with minimal overlap.
- Age-associated CpGs are enriched in promoters, form co-regulated gene modules, and link to beta-cell functions like insulin secretion.
- Diabetes-associated CpGs are enriched in enhancers or non-regulatory regions, with modules suggesting stress-induced epigenetic drift.
- CpG-gene associations are independent of genetic variation, and Mendelian randomization supports a causal role for age-associated CpGs regulating KLHL42, a T2D GWAS locus.
- A blood-based methylation risk score using age-linked CpGs correlates with insulin secretion and improves diabetes classification when combined with genetic risk (AUC = 0.91).
- Age is associated with a coordinated epigenetic programme, while diabetes links to a heterogeneous, stress-related epigenetic signature.