The Usefulness and Limitations of Diabetic Monkeys in Evaluating Pig Islet Transplantation Benefits in T1D

Various groups have reported prolonged diabetes reversal after the transplantation of pig islets into diabetic monkeys. This study aimed to identify the limitations of using monkeys to test the safety and efficacy of transplantation and to better understand the translational value of using it for T1D research and development. Metabolic incompatibilities in glycemic control between the pig and monkey underlie the chronic, mild hyperglycemia often observed in these transplanted monkeys. This phenomenon might not bear relevance for the pig-to-human species combination because the glycemic control in pigs and humans is similar and differs from that in the monkey. Weight loss observed in monkey transplant studies could be related to changes in the gastrointestinal tract associated with local high exposure to orally administered immunosuppressants; these must be given at higher dose levels in monkeys to achieve systemic exposure at therapeutic levels. This is also aggravated by insufficient graft insulin production in proportion to the needs of the monkey, so such findings in monkeys may have no translational value to the pig-to-human setting. Nutritional deficits can result in incorrect interpretation of blood glucose levels and C-peptide levels interpreted as measuring graft function. Likewise, nutritional status alters physiologic responses, influencing susceptibility to infectious and noninfectious complications. The limitations of the pig to monkey transplant model described in this review are important for the accurate interpretation of these experiments as predictors of the pig to human transplant outcome and highlight some caution in their translational value in predicting outcomes of pig-to-human islet cell transplant studies.

Ramifications for Individuals with T1D:
The pig-to-monkey preclinical model has long been viewed as a required study before bringing non-human islet transplantation concepts to human clinical testing (or potentially encapsulation product testing). This study shows some of the limitations of these monkey experiments and should significantly influence the planning of all preclinical non-human islet transplantation or encapsulation product experiments, and may help define the regulatory authorities’ requirements for preclinical data packages.

JDRF Involvement:
This study was funded in part by JDRF.

Investigators and Institutions:
This study was conducted by Dr. Melanie Graham and her colleagues at the University of Minnesota.

Reference:
Graham ML, Schuurman HJ. (2013) The usefulness and limitations of the diabetic macaque model in evaluating long-term porcine islet xenograft survival. Xenotransplantation. Jan-Feb;20(1):5-17. doi: 10.1111/xen.12012. Epub 2012 Nov 29.