title: mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: Jordi
authors: J
authors: Rovira
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: María Jose
authors: MJ
authors: Ramírez-Bajo
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: Elisenda
authors: E
authors: Banon-Maneus
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: Daniel
authors: D
authors: Moya-Rull
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: Pedro
authors: P
authors: Ventura-Aguiar
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: Natalia
authors: N
authors: Hierro-Garcia
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
authors: Marta
authors: M
authors: Lazo-Rodriguez
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: Ignacio
authors: I
authors: Revuelta
authors: Department of Nephrology, Hospital Universitario de Canarias, Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Univesidad de La Laguna, Santa Cruz de Tenerife, Spain.
authors: Armando
authors: A
authors: Torres
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: Federico
authors: F
authors: Oppenheimer
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: Josep M
authors: JM
authors: Campistol
authors: Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: Fritz
authors: F
authors: Diekmann