mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome

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 ? -cell toxicity.Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5,...

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Bibliographic Details
Authors: Rovira Juárez, Jordi, Ramírez Bajo, María José, Bañón Maneus, Elisenda, Moya Rull, Daniel, Ventura Abreu Aguiarà, Pedro, Hierro García, Natalia, Lazo Rodríguez, Marta, Revuelta Vicente, Ignacio, Torres, Armando, Oppenheimer Salinas, Federico, Campistol Plana, Josep M., Diekmann, Fritz
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/224589
Online Access:https://hdl.handle.net/2445/224589
Access Level:Open access
Keyword:Receptors d'insulina
Complicacions de la diabetis
Regulació del metabolisme
Insulin receptors
Diabetes complications
Metabolic regulation
Description
Summary: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 ? -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.

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