Portal de Periódicos da CAPES

mTOR Inhibition

2016; Wolters Kluwer; Volume: 2; Issue: 2 Linguagem: Inglês

10.1097/txd.0000000000000576

2373-8731

Jordi Rovira, María José Ramírez-Bajo, Elisenda Bañón-Maneus, Daniel Moya‐Rull, Pedro Ventura‐Aguiar, Natalia Hierro-Garcia, Marta Lazo-Rodríguez, Ignacio Revuelta, Armando Torres, Federico Oppenheimer, Josep M. Campistol, Fritz Diekmann,

PI3K/AKT/mTOR signaling in cancer

Sirolimus (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 β -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, β-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 β -cell proliferation, SRL might reveal harmful effects by blocking β -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.