Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

Abstract

Aims/hypothesis Attempts to use an alternative source of islets to restore glucose homeostasis in diabetic patients require preclinical islet xenotransplantation models to be tested. These models raise questions about metabolic compatibility between species and the most appropriate metabolic parameters to be used to monitor graft function. The present study investigated and compared relevant gluco-metabolic parameters in pigs, monkeys and the pig-to-monkey islet transplantation model to gain insight into the potential clinical outcome of pig-to-human islet transplantation. Methods Basal and IVGTT-stimulated blood glucose, Cpeptide, insulin and glucagon levels were assessed in nondiabetic pigs and monkeys. The same parameters were used to evaluate the performance of porcine islet xenografts in diabetic monkeys. Results Non-diabetic cynomolgus monkeys showed lower levels of fasting and stimulated blood glucose but higher levels of C-peptide and insulin than non-diabetic pigs. The reported levels in humans lie between those of monkeys and pigs, and differences in metabolic parameters between pigs and humans appear to be smaller than those between pigs and cynomolgus monkeys. The transplantation data indicated that the degree of graft function (evaluated by the measurement of C-peptide levels) necessary to normalise blood glucose in the recipient was determined by the recipient levels rather than by the donor levels. Conclusions/interpretation The differences between donor and recipient species may affect the transplantation outcome and need to be considered when assessing graft function in xenotransplantation models. Given the differences between monkeys and humans as potential recipients of pig islets, it should be easier to reach glucose homeostasis in pig-to-human than in pig-to-non-human primate islet xenotransplantation.

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts

“…expand their beta cell mass following transplantation (23). Notably, porcine islets have been shown to maintain long-term function following intraportal transplantation into nonhuman primates with production of detectable porcine C-peptide and restoration of normoglycemia (24)(25)(26)(27)(28). In a limited number of case reports, xenotransplantation of porcine islets into diabetic humans has improved glycemic control (29).…”

Treatment of diabetes with encapsulated pig islets: an update on current developments

“…Nevertheless, the primary obstacle is that the cell density in this device needs to be quite low to ensure an adequate oxygen supply. This indicates that if large numbers of pig islets (25 000-100 000 IEQs/kg) are required to achieve insulin independence in diabetic NHPs (Hering et al, 2006;Casu et al, 2008;van der Windt et al, 2009;Thompson et al, 2011a;Zhu et al, 2014a), numerous or larger devices must be implanted. However, it is impossible to find a suitable surgical site to accommodate such macrodevices.…”

Use of genetically-engineered pig donors in islet transplantation

“…In the last decade, several groups from around the world have shown success in restoring insulin independence for a period > 6 mo in diabetic nonhuman primate recipients of pig islets, a breakthrough achievement in xenotransplantation [9][10][11][12][13][14][15][16][17] . While the results of pigto-nonhuman primate models cannot fully predict the pig-to-human results due to dissimilarities among the different donors and recipient species, they are necessary steps to reach clinical application [18,19] . These results provide evidence that porcine islets would very likely function to restore glycemic control in humans.…”