1. 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

2. 2 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)

3. 3 Insulin resistance

4. 4 Type 2 diabetes

5. 5 Insulin Signaling in Primary Human Adipocytes

6. 6 Combination of the in Vitro and in Vivo Systems

7. 7 Our Approach to Multi-Level Modeling  Minimal models to draw conclusions  Detailed models to complete the picture  Object-oriented modeling to combine the different levels  MathModelica and the BioChem library

8. 8 Development of a Minimal Model module constraints

9. 9 Module Constraints

10. 10  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 Whole-body Level: Glucose Homeostasis Model

11. 11 Cellular Level: Insulin Signaling in Adipocytes

12. 12 First Hypothesis - In Vivo and In Vitro is Direct Compatible

13. 13 Simulations Compared to Experimental Data and Module Constraints Physiological glucose concentration Sub-physiological glucose concentration

14. 14 First Hypothesis Rejected

15. 15 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

16. 16 Extend the Minimal Insulin Signaling Model

17. 17 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

18. 18 The Multi-level Model

19. 19 Ongoing Work: Including Fatty Acids at the Whole-body Level

20. 20 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)

21. 21 In Summary

22. 22 Acknowledgements Cecilia Brännmark Robert Palmér Jan Brugård Fredrik Nyström Peter Strålfors Gunnar Cedersund Fianne Sips Natal van Riel Martin Adiels

23. www.liu.se 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