title: A multiscale, model-based analysis of the multi-tissue interplay underlying blood glucose regulation in type I diabetes.
abstract: A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels. Simulations of diabetes associated gene knockouts and impaired cellular glucose metabolism, resulted in elevated whole body blood-glucose levels, but also in a metabolic shift within the cell's reaction network. Such multiscale models have the potential to be employed in the exploration of novel drug-targets or to be integrated into control algorithms for artificial pancreas systems.
authors.forename: Federico
authors.initials: F
authors.lastname: Wadehn
authors.forename: Stephan
authors.initials: S
authors.lastname: Schaller
authors.forename: Thomas
authors.initials: T
authors.lastname: Eissing
authors.forename: Markus
authors.initials: M
authors.lastname: Krauss
authors.forename: Lars
authors.initials: L
authors.lastname: Kupfer
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005934:Glucagon; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood*; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D005947:Glucose