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Glucagon-like peptide-1 (GLP-1) promotes \u03b2-cell survival, proliferation, and differentiation; however, its developmental stage-specific effects on \u03b2-cell regeneration are not fully understood. To investigate this, we generated a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under the control of cytomegalovirus (CMV) promoter using the Multisite Gateway\n                    <jats:sup>\u00ae<\/jats:sup>\n                    recombination cloning system. The vector\u2019s ability to modulate \u03b2-cell differentiation and proliferation was subsequently assessed in neonatal and adult diabetic rat models. Type 2 Diabetes (T2DM) was induced in neonatal rats by administering low-dose streptozotocin (STZ), exploiting the intrinsic plasticity of the developing pancreas, whereas in adult rats, a high-fat diet combined with low-dose STZ was used. LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing \u03b2-cells in neonatal rats, accompanied by enhanced \u03b2-cell proliferation, demonstrating effective engagement of developmental plasticity. In adults, LentiGLP-1 partially restored \u03b2-cell populations through activation of residual progenitors and stimulation of replication in existing \u03b2-cells, improving glycemic control and insulin sensitivity. Notably, acinar cells did not contribute to \u03b2-cell generation in either neonatal or adult models. These results indicate that GLP-1 exerts developmentally regulated effects on \u03b2-cell differentiation, facilitating neogenesis in neonates and partially restoring regenerative capacity in adults. Long term GLP-1 expression, thus represents a promising strategy to restore \u03b2-cell mass by proliferation and differentiation, providing insight into its therapeutic potential for diabetes.\n                  <\/jats:p>","DOI":"10.1007\/s00109-026-02690-w","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T02:38:54Z","timestamp":1781231934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lentiviral GLP-1 gene therapy elicits developmental stage\u2013dependent \u03b2-cell regeneration in diabetic rats"],"prefix":"10.1007","volume":"104","author":[{"given":"Ezgi","family":"Erbasan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melike","family":"Aliciaslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulya","family":"Erendor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumeyye","family":"Sensoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Busra","family":"Cetin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Aydemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-5678","authenticated-orcid":false,"given":"Salih","family":"Sanlioglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"2690_CR1","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.1038\/s41467-023-40893-8","volume":"14","author":"Z Ma","year":"2023","unstructured":"Ma Z, Zhang X, Zhong W, Yi H, Chen X, Zhao Y, Ma Y, Song E, Xu T (2023) Deciphering early human pancreas development at the single-cell level. 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