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

While α-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 α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, while α-cells compensate for their higher DNA damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability.