Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets.
Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic beta-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD*scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucose-stimulated insulin release. Together, our results demonstrate that immunosuppressants impair human beta-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.
Johnson
James D
JD
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. jimjohn@interchange.ubc.ca
Ao
Ziliang
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Ao
Peter
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Li
Hong
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Dai
Long-Jun
LJ
He
Zehua
Z
Tee
May
M
Potter
Kathryn J
KJ
Klimek
Agnieszka M
AM
Meloche
R Mark
RM
Thompson
David M
DM
Verchere
C Bruce
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Warnock
Garth L
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007328:Insulin; D009173:Mycophenolic Acid; D005947:Glucose; D020123:Sirolimus; D016559:Tacrolimus