@article{0cca3263537d45beb77e496157861fed,
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.",
keywords = "AEB071, Islet transplant, Sotrastaurin, Toxicity",
author = "Shaheed Merani and Michael McCall and Pawlick, {Rena L.} and Edgar, {Ryan L.} and Joy Davis and Christian Toso and Emamaullee, {Juliet A.} and Tatsuya Kin and Shapiro, {A. M.James}",
note = "Funding Information: Recipients were treated starting on the day of transplant and Funding for this project was provided by charitable donations from continuously thereafter with either AEB at 30 mg/kg po bid, the Roberts family, the Diabetes Research Institute Foundation sirolimus 0.2 mg/kg ip daily or vehicle (saline 100 ul po bid). of Canada, and the Victor family. We would like to thank Drs. Non-fasting blood glucose of recipients was monitored daily fol-Jurgen Wagner, Walter Schuler and Colin Anderson for their lowing islet transplantation for two weeks, and on alternate days contribution to experimental design and thoughtful contribution thereafter using a One Touch Ultra (LifeScan Inc.,) glucometer. to interpretation of data. A.M.J.S. is a Senior Clinical Scholar Primary graft function (a return to normoglycemia after trans-supported through the Alberta Heritage Foundation for Medical plantation) was defined as a minimum of 3 d of blood glucose Research (AHFMR). S.M. is a recipient of the AHFMR M.D./ levels less than 12.0 mM. Animals were investigated for six post-Ph.D., Studentship, the CIHR Walter and Jessie Boyd and Charles operative weeks, at which time their islet graft was retrieved by Scriver M.D./Ph.D., Studentship and Lionel E. McLeod Award. nephrectomy and their return to hyperglycemia used to confirm C.T. is supported by the Swiss National Science Foundation, a graft dependent normoglycemic status vs. spontaneous remis-F.S. Chia award and the AHFMR. M.M. is the recipient of an sion. No animals showed spontaneous remission from diabetes. Alberta Diabetes Foundation/Wirtanen Scholarship. S.M., C.T., Oral glucose tolerance test. At post-operative week two and J.A.E. and A.M.J.S. participated in research design. S.M., M.M., four, islet transplant recipients who exhibited a non-fasting blood C.T., J.A.E. and A.M.J.S. participated in writing of the paper. glucose less than 20 mM were challenged with a 3 g/kg body S.M., M.M., R.L.P., R.L.E., J.D. and T.K. participated in per-weight oral dextrose bolus following an 18 h fast. Blood glucose formance of the research. S.M., R.L.E. and M.M. participated in was monitored before glucose bolus and after 5, 15, 30, 60 and data analysis.",
year = "2011",
month = nov,
doi = "10.4161/isl.3.6.17766",
language = "English (US)",
volume = "3",
pages = "338--343",
journal = "Islets",
issn = "1938-2014",
publisher = "Taylor and Francis Ltd.",
number = "6",
}