Nonhuman primate models for beta cell replacement in diabetes research

Diabetes Mellitus (DM) is metabolic disease related to defects in insulin action, secretion, or both resulting in hyperglycemia. The two most common forms are Type 1 diabetes (T1D), caused by autoimmune destruction of the insulin producing β-cells that induces absolute insulin deficiency, and Type 2 diabetes (T2D), where severe insulin resistance leads to β-cell failure. β-cell replacement, so far demonstrated by islet cell transplantation, can effectively reverse diabetes and eliminate the need for repeated insulin injections. Animal models have been instrumental in advancing successful treatment strategies for diabetes, especially nonhuman primate (NHP) models of T1D for immunology and transplantation. Owing to the clinical success of pancreas and islet cell allotransplantation, there are ongoing efforts to advance β-cell replacement. Innovative approaches using immunomodulation or immunotolerance, gene therapy, macro- or microencapsulated devices for transplantation, and novel cell sources are being pursued with the aim to improve safety and efficacy as well as increase access to the majority of patients. Therapies that meet successful benchmarks in vitro or in rodent screening assays often require additional modeling in the NHP to properly evaluate the immune response with high predictive validity to the clinical situation. The use of NHPs brings challenges that are similar to the clinical situation since diabetes imposes physical, psychological, and social challenges related to complications of the disease and its management. The T1D state together with complex experimental treatments, potential treatment-induced toxicities, and uncertain experimental outcomes can add burden that can negatively impact welfare and relationships with caregivers. This burden can be mitigated by optimizing disease induction and management together with a careful experimental design strategy that avoids additive insults and brings the model closer to planned clinical trials. The use of animal-focused refined methods to mitigate the impact of diabetes and model-imposed confounding improves welfare which can enhance validity for proper interpretation of scientific outcomes.