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

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