Pan-organ model integration of metabolic and regulatory processes in type 1 diabetes

Type 1 diabetes mellitus (T1D) is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that disrupts the glucose-insulin-glucagon system and induces organ-wide, long-term effects on glycolytic and nonglycolytic processes. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify intervention points to ensure better control of T1D but was limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model using a novel integrative modeling framework that links organ-specific regulation and metabolism. The developed framework allowed the correct prediction of disrupted metabolic processes in T1D, highlighted pathophysiological processes common with neurodegenerative disorders, and suggested calcium channel blockers as potential adjuvants for diabetes control. Additionally, the model predicted the occurrence of insulin-dependent rewiring of interorgan crosstalk. Moreover, a simulation of a population of virtual patients allowed an assessment of the impact of inter and intraindividual variability on insulin treatment and the implications for clinical outcomes. In particular, GLUT4 was suggested as a potential pharmacogenomic regulator of intraindividual insulin efficacy. Taken together, the organ-resolved, dynamic model may pave the way for a better understanding of human pathology and model-based design of precise allopathic strategies.