title: The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study.
abstract: The use of immunosuppressive drugs in transplanted patients is associated with the development of diabetes, possibly due to β-cell toxicity. To better understand the mechanisms leading to post-transplant diabetes, we investigated the actions of prolonged exposure of isolated human islets to therapeutical levels of tacrolimus (Tac) or cyclosporin A (CsA). Islets were isolated from the pancreas of multiorgan donors by enzymatic digestion and density gradient centrifugation. Functional, survival and molecular studies were then performed after 4 days of incubation with therapeutical concentrations of Tac or  CsA. Glucose-induced insulin secretion was significantly decreased in Tac, but not in CsA exposed islets, which was associated with a reduction of the amount of insulin granules as shown by electron microscopy. The percentage of apoptotic β-cells was higher in Tac than CsA exposed islets. Microarray experiments followed by Gene Set Enrichment Analysis revealed that gene expression was more markedly affected upon Tac treatment. In conclusion, Tac and CsA affect features of beta-cell differently, with several changes occurring at the molecular level.
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.forename: Matilde
authors.initials: M
authors.lastname: Masini
authors.forename: Robin
authors.initials: R
authors.lastname: Liechti
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Franco
authors.initials: F
authors.lastname: Filipponi
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Masiello
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000368:Aged; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus