title: Rapamycin impairs proliferation of transplanted islet β cells.
abstract: BACKGROUND
  The cause for a progressive attrition of islet graft function observed over the years after islet transplantation is not well defined but may be in part the result of adverse effects of immunosuppressive agents. In this study, we examined the effect of rapamycin, a key component of the immunosuppressive regimen, on β-cell replication of transplanted islets.
  
  
  METHODS
  Mice transplanted with rat islets under kidney capsule received bromodeoxyuridine for 7 days. Mice were treated with rapamycin or appropriate vehicle. β-cell replication was determined by double immunofluorescence staining for insulin and bromodeoxyuridine. For in vitro studies, apoptosis, glucose-stimulated insulin secretion, and proliferation were determined in islet cells incubated with EdU in the presence or absence of rapamycin.
  
  
  RESULTS
  In our islet transplant model, rapamycin impaired glucose tolerance and β-cell proliferation of transplanted and host islets. In vitro, rapamycin reduced glucose-stimulated insulin secretion and reversibly decreased β-cell replication. The inhibitory effect of rapamycin on β-cell proliferation was not due to the decrease in insulin release. Additionally, in islet cells, expression of cell cycle proteins was significantly modified by rapamycin, suggesting a blockade of cell cycle progression. Inhibition of p38MAPK partially reverted rapamycin effect on β-cell proliferation.
  
  
  CONCLUSIONS
  Rapamycin, at concentration usually used to prevent islet graft rejection, is able to reduce the rate of β-cell proliferation in transplanted rat islets but also in host murine islets. These data suggest that the progressive islet graft dysfunction observed under immunosuppressive therapy may result in part from an impairment of β-cell regeneration.
authors.affiliation: Department of Surgery, Cell Isolation and Transplantation Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Nadja
authors.initials: N
authors.lastname: Niclauss
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Laurianne
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Geraldine
authors.initials: G
authors.lastname: Parnaud
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D007328:Insulin; D020123:Sirolimus