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Although \u03b1-cell dysfunction also contributes to disease pathology, \u03b1-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. 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 \u03b1- and \u03b2-cells during neonatal growth, with \u03b1-cells exhibiting higher replication rates and DNA damage. We show that neonatal \u03b2-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas \u03b1-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that \u03b2-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 and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal \u03b2- and \u03b1-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of \u03b2-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in \u03b2-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal \u03b2- and \u03b1-cells during growth and diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Mechanisms underlying the differential susceptibility of pancreatic \u03b2- and \u03b1-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal \u03b2- and \u03b1-cells to DNA damage, a key driver of \u03b2-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal \u03b2- and \u03b1-cells, yet \u03b2-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens \u03b2-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises \u03b2-cell repair fidelity. These findings reveal how developmental programs shape \u03b2-cell resilience and may influence lifelong diabetes risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1027","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:13:38Z","timestamp":1784124818000},"page":"1612-1628","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Developmental Control of DNA Damage Responses in \u03b1- and \u03b2-Cells Shapes the Selective \u03b2-Cell Susceptibility in Diabetes"],"prefix":"10.2337","volume":"75","author":[{"given":"Sneha S.","family":"Varghese","sequence":"first","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute 1 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro Giovanni","family":"Hernandez-De La Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Biomedical and Biological Sciences Program, Keck School of Medicine, University of Southern California 2 , Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine 3 , Scottsdale, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute 1 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma","family":"Tixi","sequence":"additional","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute 1 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparamita","family":"Pandey","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles 4 , Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Anchondo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute 5 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute 1 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Integrative Genomics Core 6 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-7866","authenticated-orcid":false,"given":"Senta K.","family":"Georgia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Keck School of Medicine, University of Southern California 7 , Los Angeles, CA"},{"name":"Center for Endocrinology, Diabetes, and Metabolism, The Saban Research Institute, Children\u2019s Hospital Los Angeles 8 , Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Ping","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute 1 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-0101","authenticated-orcid":false,"given":"Zong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine 3 , Scottsdale, AZ"},{"name":"Division of Endocrinology 9 , Mayo Clinic, Scottsdale, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriyo","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute 10 , City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-7899","authenticated-orcid":false,"given":"Sangeeta","family":"Dhawan","sequence":"additional","affiliation":[{"name":"Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism 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