1. Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology Linköping University

2. 2 MathCore Engineering AB  A Wolfram research company in Linköping  Consultancy services in modeling and simulation  Develop MathModelica, an object-oriented modeling and simulation software

3. 3 Examples of Models in MathModelica

4. 4 Insulin Signaling in Adipose Tissue  Primary human adipocytes  Insulin resistance, type 2 diabetes  Protein phosphorylation and glucose uptake  Compatible with the in vivo situation?

5. 5 Our Approach to Multi-Level Modeling  Object-oriented modeling  Minimal model to draw conclusions  Detailed models to complete the picture

6. 6 The Dalla Man Model  Meal simulation model  Based on high-quality data (>200 individuals)  Flows of glucose and insulin  Use as whole-body level 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.

7. 7 Our Approach to Multi-Level Modeling  Object-oriented modeling  Minimal model to draw conclusions  Detailed models to complete the picture

8. 8 Development of a Minimal Adipose Tissue Model module constraints

9. 9 Module Constraints 20 % of total tissue glucose uptake

10. 10 Simulations Compared to Experimental Data and Module Constraints

11. 11 One Hypothesis – Many Models

12. 12 Development of a Minimal Adipose Tissue Model

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

14. 14 All Models Rejected => Rejection of the Hypothesis

15. 15 Summary of Tested Hypotheses Hypothesis Original dataset Exteded dataset Intracellular signalling enoughOKRejected

16. 16 Development of a Minimal Adipose Tissue Model

17. 17 In Vivo/in Vitro Differences  Increased basal translocation of GLUT4 in the in vitro situation  Insulin effects on the bloodflow in the in vivo situation Insulin Bloodflow Glucose Uptake ACCEPTED

18. 18 Summary of Tested Hypotheses Hypothesis Original dataset Exteded dataset Intracellular signalling enoughOKRejected In vitro/in vivo difference in basal GLUT4 translocation OKRejected In vitro/in vivo difference in blood-flow OKRejected Multiple in vitro/in vivo differences OK

19. 19 Our Approach to Multi-Level Modeling  Object-oriented modeling  Minimal model to draw conclusions  Detailed models to complete the picture

20. 20 Insulin Signaling Details

21. 21 More Details

22. 22 Insulin Binding Details  Model for insulin – insulin receptor interactions  Binding and activation  Use model structure, estimate 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. Epub 2009 Feb 17.

23. 23 The Final Hierarchical Model

24. 24 Acknowledgements  Diabetes and Integrative Systems Biology  Gunnar Cedersund  Peter Strålfors  Cecilia Brännmark  Robert Palmér  Medical and Health Sciences  Fredrik Nyström  MathCore Engineering AB  Jan Brugård 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 May 13. [Epub ahead of print]

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