Rovira Juárez, JordiRamírez Bajo, María JoséBañón Maneus, ElisendaMoya Rull, DanielVentura Abreu Aguiarà, PedroHierro García, NataliaLazo Rodríguez, MartaRevuelta Vicente, IgnacioTorres, ArmandoOppenheimer Salinas, FedericoCampistol Plana, Josep M.Diekmann, Fritz2025-12-022025-12-022016-02-012373-8731https://hdl.handle.net/2445/224589Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and ? -cell toxicity.Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, ?-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression.After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated.In conditions that require adaptive ? -cell proliferation, SRL might reveal harmful effects by blocking ? -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.9 p.application/pdfengcc-by-nc-nd (c) Rovira Juárez, Jordi et al., 2016http://creativecommons.org/licenses/by-nc-nd/4.0/Receptors d'insulinaComplicacions de la diabetisRegulació del metabolismeInsulin receptorsDiabetes complicationsMetabolic regulationinfo:eu-repo/semantics/article2025-10-30info:eu-repo/semantics/openAccess263371627500257