Background: Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model.
Methods: Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month.
Results: There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group.
Conclusions: IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation.
1 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
2 Clinical Islet Transplant Laboratory, University of Alberta, Edmonton, Alberta, Canada.
M.D.M. is supported by an Alberta Innovates Healthcare Solutions (AIHS) Clinical Fellowship, and A.M.J.S. is the recipient of a Senior Clinical Scholarship from AIHS. The clinical islet transplant program is supported through Alberta Health Services and through grants from the Juvenile Diabetes Research Foundation and from the Clinical IsletTransplant Consortium of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes, Digestive Diseases, and Kidney. These preclinical studies were supported through additional support from the Diabetes Research Institute Foundation of Canada. A.M.J.S. is a member of the Alberta Diabetes Institute.
IDN6556 was provided free of charge through a material transfer agreement from Pfizer, Inc, USA, and, more recently, from Conatus Pharmaceuticals, Inc, San Diego, CA.
The authors declare no other conflicts of interest.
3 Address correspondence to: Michael D. McCall, M.D., BSc, 5-040 Li Ka Shing Centre for Health Research Innovation, 112 St and 87 Ave, Edmonton, AB, Canada T6G 2E1.
M.D.M., R.P., J.E., and A.M.J.S. participated in research design. M.D.M., A.M.M., T.K., R.P., R.E., and A.M.J.S. participated in performing the research. M.D.M., A.M.M., and A.M.J.S. participated in writing the article. M.D.M., R.P., and A.M.J.S. participated in data analysis.
Received 5 October 2011. Revision requested 27 October 2011.
Accepted 25 March 2012.