The virtual NOD mouse: applying predictive biosimulation to research in type 1 diabetes

Type 1 diabetes is a complex, multifactorial disease characterized by T cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells. To facilitate research in type 1 diabetes, a large-scale dynamic mathematical model of the female non-obese diabetic (NOD) mouse was developed. In this model, termed the Entelos Type 1 Diabetes PhysioLab platform, virtual NOD mice are constructed by mathematically representing components of the immune system and islet beta cell physiology important for the pathogenesis of type 1 diabetes. This report describes the scope of the platform and illustrates some of its capabilities. Specifically, using two virtual NOD mice with either average or early diabetes-onset times, we demonstrate the reproducibility of experimentally observed dynamics involved in diabetes progression, therapeutic responses to exogenous IL-10, and heterogeneity in disease onset. Additionally, we use the Type 1 Diabetes PhysioLab platform to investigate the impact of disease heterogeneity on the effectiveness of exogenous IL-10 therapy to prevent diabetes onset. Results indicate that the inability of a previously published IL-10 therapy protocol to protect NOD mice who exhibit early diabetes onset is due to high levels of pancreatic lymph node (PLN) inflammation, islet infiltration, and beta cell destruction at the time of treatment initiation. Further, simulation indicates that earlier administration of the treatment protocol can prevent NOD mice from developing diabetes by initiating treatment during the period when the disease is still sensitive to IL-10's protective function.