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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. Glucose Homeostasis. Figure from: Evan D. Rosen and Bruce M. Spiegelman - PowerPoint PPT Presentation
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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
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
Insulin resistance
4
Type 2 diabetes
5
Insulin Signaling in Primary Human Adipocytes
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Combination of the in Vitro and in Vivo Systems
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
Development of a Minimal Model
module constraints
9
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
16
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)
21
In Summary
22
Acknowledgements
Cecilia Brännmark
Robert Palmér
Jan Brugård
Fredrik Nyström
Peter Strålfors
Gunnar Cedersund
Fianne Sips
Natal van Riel
Martin Adiels
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