title: In vivo and in vitro effect of sirolimus on insulin secretion.
abstract: BACKGROUND
  The effects of sirolimus on insulin secretion are still debated. Our aim was to investigate the effects of sirolimus, both (1) in vivo in healthy minipigs; and (2) in vitro on human islets.
  
  
  METHODS
  (1) Ten minipigs were evaluated during three successive stages: (a) basal; (b) at the end of a 4-week period of treatment with sirolimus; and (c) after a 4-week period of wash-out. We evaluated insulin secretion with the acute insulin response (AIR), and glucose tolerance with the glucose disposal rate (GDR). (2) Insulin content, stimulation index, adenosine triphosphate (ATP), and apoptosis were measured in human islets treated in vitro with sirolimus at therapeutic and supratherapeutic concentrations.
  
  
  RESULTS
  (1) Basal and stimulated insulin levels and GDR increased during sirolimus administration and returned to baseline after a wash-out period; (2) regardless of culture duration, sirolimus dose-dependently decreased apoptosis and increased insulin content. Stimulation indexes and ATP were also significantly enhanced but only at therapeutic concentrations.
  
  
  CONCLUSIONS
  This study suggests that sirolimus, at plasma-drug concentrations usually targeted in clinical practice, (1) increases basal and stimulated insulin levels in vivo and insulin content in vitro regardless of culture duration; (2) is able to reduce apoptosis. These findings may partly underlie the improved results of islet transplantation.
authors.affiliation: Department of Endocrinology and Metabolism and Endocrine Surgery, INSERM Unit-M859, Diabetes Cell Therapy, Lille University Hospital, Lille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Marcelli-Tourvieille
authors.forename: Thomas
authors.initials: T
authors.lastname: Hubert
authors.forename: Ericka
authors.initials: E
authors.lastname: Moerman
authors.forename: Valéry
authors.initials: V
authors.lastname: Gmyr
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nunes
authors.forename: Michèle
authors.initials: M
authors.lastname: Dherbomez
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vandewalle
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005947:Glucose / Q000502:physiology; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D020123:Sirolimus / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000255:Adenosine Triphosphate; D004247:DNA; D005947:Glucose; D020123:Sirolimus