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Elin Nyman Diabetes and Integrative Systems Biology Linköping University

Explore detailed multi-level models integrating insulin signaling in adipocytes for whole-body glucose control. Utilize MathModelica software for in vitro and in vivo simulations, questioning insulin resistance and type 2 diabetes.

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Elin Nyman Diabetes and Integrative Systems Biology Linköping University

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

  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. Examples of Models in MathModelica

  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. Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture

  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. Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture

  8. Development of a Minimal Adipose Tissue Model module constraints

  9. Module Constraints 20 % of total tissue glucose uptake

  10. Simulations Compared to Experimental Data and Module Constraints

  11. One Hypothesis – Many Models

  12. Development of a Minimal Adipose Tissue Model

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

  14. All Models Rejected => Rejection of the Hypothesis

  15. Summary of Tested Hypotheses

  16. Development of a Minimal Adipose Tissue Model

  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 ACCEPTED Insulin Bloodflow Glucose Uptake

  18. Summary of Tested Hypotheses

  19. Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture

  20. Insulin Signaling Details

  21. More Details

  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. The Final Hierarchical Model

  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]

  25. www.liu.se

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