Multi-level Modeling of Type 2 Diabetes
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Multi-level Modeling of Type 2 Diabetes
Elin NymanDiabetes and Integrative Systems Biology
Clinical and Experimental Medicine
Linköping University
Workshop Hierarchical Modeling 2011-12-05
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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)
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Insulin resistance
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Type 2 diabetes
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Insulin Signaling in Primary Human Adipocytes
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Combination of the in Vitro and in Vivo Systems
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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
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Development of a Minimal Model
module constraints
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Module Constraints
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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
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Cellular Level: Insulin Signaling in Adipocytes
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First Hypothesis - In Vivo and In Vitro is Direct Compatible
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Simulations Compared to Experimental Data and Module Constraints
Physiological glucose concentration
Sub-physiological glucose concentration
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First Hypothesis Rejected
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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
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Extend the Minimal Insulin Signaling Model
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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
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The Multi-level Model
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Ongoing Work: Including Fatty Acids at the Whole-body Level
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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)
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In Summary
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Acknowledgements
Cecilia Brännmark
Robert Palmér
Jan Brugård
Fredrik Nyström
Peter Strålfors
Gunnar Cedersund
Fianne Sips
Natal van Riel
Martin Adiels
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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