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

ABSTRACT: Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in Type 1 and Type 2 diabetes. 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 mo

SUBMITTER: Varghese SS 

PROVIDER: S-EPMC12642488 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature