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

Abstract

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.Therefore, systematic analyses of disrupted metabolic processes beyond glycolysis in T1D require extended approaches. To better capture metabolism, we used an whole-body organresolved reconstruction of human metabolism (WBM reconstruction) (Thiele et al., 2018), which was built using the comprehensive, but generic human metabolic reconstruction (Brunk et al., 2018). The male WBM reconstruction includes the comprehensively known metabolic pathways for 20 organs, two sex organs, and six blood cells, which are anatomically accurately interconnected. Through the integration of condition-specific information, aka constraints, such as diet, gene expression, or physiological parameters, the WBM reconstruction can be converted into a personalized, condition-specific WBM model . Consequently, the male WBM model enables the simulation of carbohydrate disorders and the investigation of their impact on nonglycolytic pathways. Thereby, the WBM reconstruction provides a complete picture of organ-resolved human metabolism. However, addressing the disease dynamics and patient responses to insulin requires the modeling of metabolic pathways and nonmetabolic processes as well as insulin receptor binding, signal transduction, and internalization of receptors. Recently, multiscale, multialgorithm, whole-organism dynamic models in biology, primarily models of microbiology (Bauer and Thiele, 2018; Bauer et al., 2017; Covert et al., 2008; Karr et al., 2012), plant physiology (Grafahrend-Belau et al., 2013), human physiology and xenobiotic metabolism (Cordes et al., 2018; Gueb...