title: AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice.
abstract: AEB071 (AEB, sotrastaurin), a specific inhibitor of protein kinase C, reduces T-lymphocyte activation and cytokine release. AEB delays islet allograft rejection in rats and prevents rejection when combined with cyclosporine. Since many immunosuppressive agents have toxic effects on the function of transplanted islets, we investigated whether this was also the case with AEB. Human islets were transplanted into Rag-knockout mice randomly assigned to vehicle control, AEB or sirolimus treatment groups. Non-fasting blood glucose levels, body weight and glucose tolerance was measured in recipients. In a separate experiment, human islets were cultured in the presence of AEB and assayed for glucose dependent insulin secretion and level of β-cell apoptosis. Eighty-six percent of the AEB-treated recipients achieved normoglycemia following transplant (compared with none in sirolimus-treated group, p < 0.05). AEB-treated recipients exhibited similar glucose homeostasis as vehicle-treated controls, which was better than in sirolimus-treated recipients. Human islets cultured with AEB showed similar rates of β-cell apoptosis (p = 0.98 by one-way ANOVA) and glucose stimulated insulin secretion (p = 0.15) as those cultured with vehicle. These results suggest that AEB is not associated with toxic effects on islet engraftment or function. AEB appears to be an appropriate immunosuppressive candidate for clinical trials in islet transplantation.
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Shaheed
authors.initials: S
authors.lastname: Merani
authors.forename: Michael
authors.initials: M
authors.lastname: McCall
authors.forename: Rena L
authors.initials: RL
authors.lastname: Pawlick
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Edgar
authors.forename: Joy
authors.initials: J
authors.lastname: Davis
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Emamaullee
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kin
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D011799:Quinazolines / Q000494:pharmacology* / Q000633:toxicity; D011897:Random Allocation
chemical_list: D001786:Blood Glucose; D007328:Insulin; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin