Dynamic flux balance analysis of whole-body metabolism for type 1 diabetes

Type 1 diabetes (T1D) mellitus is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that induce organ-wide, long-term metabolic effects. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify therapeutic interventions but is limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model of organ-specific regulation and metabolism that highlighted chronic inflammation as a hallmark of the disease, identified processes related to neurodegenerative disorders and suggested calcium channel blockers as adjuvants for diabetes control. In addition, whole-body modeling of a patient population allowed for the assessment of between-individual variability to insulin and suggested that peripheral glucose levels are degenerate biomarkers of the internal metabolic state. Taken together, the organ-resolved, dynamic modeling approach enables modeling and simulation of metabolic disease at greater levels of coverage and precision and the generation of hypothesis from a molecular level up to the population level. A dynamic organ-resolved model is developed by integrating metabolic and regulatory processes in type 1 diabetes, providing a depiction of network dynamics, regulation and response to perturbations in relation to variability in insulin response.