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Impaired \u03b2\u2010cell function is associated with loss of \u03b2\u2010cell identity, resulting in \u03b2\u2010cell dedifferentiation or trans\u2010differentiation to other endocrine cells. We have shown that \u03b2\u2010cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of \u03b2\u2010cell dedifferentiation in\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice independent of their effect on body weight.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      After 4\u2009weeks of treatment, 12\u2010week\u2010old\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic \u03b2\u2010cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice. After a 4\u2010week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic \u03b2\u2010cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3\n                      <jats:sup>+<\/jats:sup>\n                      or FOXO1 translocation. Furthermore, the number of \u03b2\u2010cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The findings highlight that the early glucose\u2010lowering effects of semaglutide and tirzepatide in\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice occur independently of changes to \u03b2\u2010cell identity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70141","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:30:13Z","timestamp":1765153813000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of Weight\u2010Neutral Treatment With Semaglutide or Tirzepatide on \u03b2\u2010Cell Identity in\n                    <i>db<\/i>\n                    \/\n                    <i>db<\/i>\n                    Mice"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4278-8178","authenticated-orcid":false,"given":"Zhaobin","family":"Deng","sequence":"first","affiliation":[{"name":"Naomi Berrie Diabetes Center and Department of Medicine Vagelos College of Physicians &amp; Surgeons of Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsook","family":"Son","sequence":"additional","affiliation":[{"name":"Naomi Berrie Diabetes Center and Department of Medicine Vagelos College of Physicians &amp; Surgeons of Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Du","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy M.","family":"McKimpson","sequence":"additional","affiliation":[{"name":"Naomi Berrie Diabetes Center and Department of Medicine Vagelos College of Physicians &amp; Surgeons of Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingli","family":"Liu","sequence":"additional","affiliation":[{"name":"Naomi Berrie Diabetes Center and Department of Medicine Vagelos College of Physicians &amp; Surgeons of Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Accili","sequence":"additional","affiliation":[{"name":"Naomi 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