Differences in glucose‐stimulated insulin secretion in vitro of islets from human, nonhuman primate, and porcine origin

Abstract

Background Porcine islet xenotransplantation is considered a potential cell-based therapy for type 1 diabetes. It is currently being evaluated in diabetic nonhuman primates (NHP) to assess safety and efficacy of the islet product. However, due to a variety of distinct differences between the respective species, including the insulin secretory characteristics of islets, the suitability and predictive value of the preclinical model in the extrapolation to the clinical setting remains a critical issue. Methods Islets isolated from human (n=3), NHP (n=2), adult pig (AP, n=3) and juvenile pig (JP, n=3) pancreata were perifused with medium at basal glucose (2.5mM) followed by high glucose (16.7mM) concentrations. The total glucose-stimulated insulin secretion (GSIS) was calculated from generated insulin secretion profiles. Results NHP islets exhibited GSIS 3-fold higher than human islets, while AP and JP islets exhibited GSIS 1/3 and 1/16 of human islets, respectively. The insulin content of NHP and AP islets was similar to that of human islets, whereas that of JP islets was 1/3 of human islets. Conclusion Despite the fact that human, NHP, and AP islets contain similar amounts of insulin, the much higher GSIS for NHP islets than for human, AP and JP islets suggests the need for increased dosing of islets from JP and AP in pig-to-NHP transplantation which may be substantially higher than that required for humans. Finally, porcine islet xenotransplantation to humans may require significantly higher dosing given the lower GSIS of AP islets compared to human islets.

Factors Affecting Transplant Outcomes in Diabetic Nude Mice Receiving Human, Porcine, and Nonhuman Primate Islets

“…It is possible that the 100% cure rate achieved by NHP islets is due to the intrinsically higher insulin secretory capacity of NHP islets (14-16) and is supported by their observed high total insulin content. So our recommendation form this analysis was, whenever NHP islets are tested in nude mice, 1000 IEQ would be the optimal number to test islet function.…”

Virus safety of islet cell transplantation from transgenic pigs to marmosets

“…Glucose levels in pigs and humans are similar and differ significantly from those in non-human primates. Monkeys maintain a lower set point of normoglycaemia and higher insulin and C-peptide secretion than pigs and humans (Casu et al, 2008;Mueller et al, 2013). And second, non-human primates are not optimal with regard to testing for virus safety, since the PERV receptor is mutated (Mattiuzzo and Takeuchi, 2010).…”

Progress in Clinical Encapsulated Islet Xenotransplantation

“…35–38 However, after stimulation with 15mM glucose, isolated porcine islets secrete 6 to 3 times less insulin than human islets during the first and second phases, respectively; for perifused human islets the stimulation index is 13 during the first phase and 8 during the second phase, compared to 2 during both phases for porcine islets (Figure 2). This difference in the amplitude of islet secretory response cannot be explained by lower insulin content of pig islets (Table 2).…”