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Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis. Elin Nyman Diabetes and Integrative Systems Biology Linköping University. MathCore Engineering AB. A Wolfram research company in Linköping Consultancy services in modeling and simulation
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Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology Linköping University
MathCore Engineering AB • A Wolfram research company in Linköping • Consultancy services in modeling and simulation • Develop MathModelica, an object-oriented modeling and simulation software
Insulin Signaling in Adipose Tissue • Primary human adipocytes • Insulin resistance, type 2 diabetes • Protein phosphorylation and glucose uptake • Compatible with the in vivo situation?
Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture
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.
Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture
Development of a Minimal Adipose Tissue Model module constraints
Module Constraints 20 % of total tissue glucose uptake
Simulations Compared to Experimental Data and Module Constraints
Simulations Compared to Experimental Data and Module Constraints Sub-physiological glucose concentration REJECTED Physiological glucose concentration
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
Our Approach to Multi-Level Modeling • Object-orientedmodeling • Minimal model to drawconclusions • Detailedmodels to complete the picture
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.
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]