Manduchi, E.; Descamp, H.; Liu, J.; Schug, J.; Da, T.; Lahori, D.; El-Mekkoussi, H.; Lee, M.; Feleke, E.; Liu, C.; Naji, A.; Glaser, B.; Kaestner, K. H.; Avrahami, D.

Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycemia despite rising insulin resistance, largely due to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here, leveraging cell-type-specific methylome data from the Human Pancreas Analysis Program (HPAP), we investigate the epigenomic basis of beta cell adaptation by mapping genome-wide DNA methylation (DNAm) patterns across the human lifespan. In healthy donors, we identify progressive age-related demethylation enriched in cis-regulatory elements at beta cell identity and function genes, suggesting that epigenetic remodeling supports functional adaptation to metabolic demand over time. In contrast, alpha cells show the opposite trajectory, with subtle, age-related hypermethylation. In T2D beta but not alpha cells we observed further demethylation compared to healthy controls, underscoring a unique capacity of beta cells to respond to changes in metabolic demand. Together, our findings suggest that DNAm remodeling in healthy beta cells reflects a long-term adaptation to metabolic demand, which in T2D is accelerated as part of a compensatory response that ultimately fails under sustained insulin resistance.