Developmental control of DNA damage responses in α- and β-cells shapes the selective beta-cell susceptibility in diabetes

Accumulation of DNA damage drives {beta}-cell dysfunction, senescence, and death in Type 1 and Type 2 diabetes. While -cell dysfunction also contributes to disease pathology, they remain remarkably resistant to senescence and cell-death. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both - and {beta}-cells during neonatal growth, with -cells exhibiting higher replication rates and DNA damage. We show that neonatal {beta}-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, while -cells compensate for their higher DNA damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that {beta}-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental epigenetic programs shape the differential DNA damage vulnerability of postnatal {beta}- and -cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of {beta}-cells from neonatal growth through adulthood. Our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal {beta}- and -cells during growth and diabetes. Article HighlightsO_LIMechanisms underlying the differential susceptibility of pancreatic {beta}- and -cells to diabetogenic stress remain unclear. C_LIO_LIDo replication dynamics, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal {beta}- and -cells to DNA damage, a key driver of {beta}-cell failure in diabetes? C_LIO_LIReplication introduces DNA damage vulnerability in both neonatal {beta}- and -cells, yet {beta}-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens {beta}-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic-stress preferentially compromises {beta}-cell repair fidelity. C_LIO_LIThese findings reveal how developmental programs shape {beta}-cell resilience and may influence lifelong diabetes risk. C_LI