In vivo and in vitro effect of sirolimus on insulin secretion.
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.
Marcelli-Tourvieille
Sophie
S
Department of Endocrinology and Metabolism and Endocrine Surgery, INSERM Unit-M859, Diabetes Cell Therapy, Lille University Hospital, Lille, France.
Hubert
Thomas
T
Moerman
Ericka
E
Gmyr
Valéry
V
Kerr-Conte
Julie
J
Nunes
Bertrand
B
Dherbomez
Michèle
M
Vandewalle
Brigitte
B
Pattou
François
F
Vantyghem
Marie-Christine
MC
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
D001786:Blood Glucose; D007328:Insulin; D000255:Adenosine Triphosphate; D004247:DNA; D005947:Glucose; D020123:Sirolimus