A multiscale, model-based analysis of the multi-tissue interplay underlying blood glucose regulation in type I diabetes

Annu Int Conf IEEE Eng Med Biol Soc. 2016 Aug:2016:1417-1421. doi: 10.1109/EMBC.2016.7590974.

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.

Publication types

  • Clinical Trial

MeSH terms

  • Blood Glucose / metabolism*
  • Carbohydrate Metabolism
  • Diabetes Mellitus, Type 1 / blood*
  • Glucagon
  • Glucose / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Insulin / blood*
  • Liver / metabolism
  • Metabolic Networks and Pathways
  • Models, Biological
  • Muscles / metabolism

Substances

  • Blood Glucose
  • Insulin
  • Glucagon
  • Glucose