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Multi-level Modeling of Type 2 Diabetes. Elin Nyman Diabetes and Integrative Systems Biology Clinical and Experimental Medicine Linköping University. Workshop Hierarchical Modeling 2011-12-05. Glucose Homeostasis. Figure from: Evan D. Rosen and Bruce M. Spiegelman
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Multi-level Modeling of Type 2 Diabetes Elin Nyman Diabetes and Integrative Systems Biology Clinical and Experimental Medicine Linköping University Workshop Hierarchical Modeling 2011-12-05
Glucose Homeostasis Figure from: Evan D. Rosen and Bruce M. Spiegelman Adipocytes as regulators of energy balance and glucose homeostasis Nature 444, 847-853(14 December 2006)
Our Approach to Multi-Level Modeling • Minimal models to drawconclusions • Detailedmodels to complete the picture • Object-orientedmodeling to combine the different levels • MathModelica and the BioChem library
Development of a Minimal Model module constraints
Whole-body Level: Glucose Homeostasis Model • Meal simulation model • Based on high-quality data (>200 individuals) • Flows of glucose and insulin between the organs • Use model structure and parameters Dalla Man C, Rizza RA and Cobelli C Meal simulation model of the glucose-insulin system IEEE Trans Biomed Eng. 2007 Oct;54(10):1740-9
First Hypothesis - In Vivo and In Vitro is Direct Compatible
Simulations Compared to Experimental Data and Module Constraints Sub-physiological glucose concentration Physiological glucose concentration
Second Hypothesis – In Vivo/in Vitro Differences • Increased basal translocation of glucose transporters in the in vitro situation • Insulin effects on the bloodflow in the in vivo situation Insulin Bloodflow Glucose Uptake
Intracellular Level: Insulin Binding Details • Model for insulin-insulin receptor interactions • Binding and activation • Use model structure but estimate new parameters Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation Mol Syst Biol. 2009;5:243
Fatty Acids Interact with Glucose Homeostasis Figure from: Evan D. Rosen and Bruce M. Spiegelman Adipocytes as regulators of energy balance and glucose homeostasis Nature 444, 847-853(14 December 2006)
Acknowledgements Cecilia Brännmark Robert Palmér Jan Brugård Fredrik Nyström Peter Strålfors Gunnar Cedersund Fianne Sips Natal van Riel Martin Adiels
Nyman E, Brännmark C, Palmér R, Brugård J, Nystrom FH, Strålfors P, and Cedersund G A Hierarchical Whole Body Modeling Approach Elucidates the Link Between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis J Biol Chem. 2011 Jul 22;286(29):26028-41 www.liu.se