Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body

Glucose HomeostasisElin Nyman

Diabetes and Integrative Systems Biology

Linköping University

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MathCore Engineering AB

A Wolfram research company in Linköping

Consultancy services in modeling and simulation

Develop MathModelica, an object-oriented modeling and simulation software

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Examples of Models in MathModelica

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Insulin Signaling in Adipose Tissue

Primary human adipocytes

Insulin resistance, type 2 diabetes

Protein phosphorylation and glucose uptake

Compatible with the in vivo situation?

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Our Approach to Multi-Level Modeling

Object-oriented modeling

Minimal model to draw conclusions

Detailed models to complete the picture

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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.

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Our Approach to Multi-Level Modeling

Object-oriented modeling

Minimal model to draw conclusions

Detailed models to complete the picture

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Development of a Minimal Adipose Tissue Model

module constraints

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Module Constraints

20 % of total tissue glucose uptake

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Simulations Compared to Experimental Data and Module Constraints

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One Hypothesis – Many Models

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Development of a Minimal Adipose Tissue Model

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Simulations Compared to Experimental Data and Module Constraints

Physiological glucose concentration

Sub-physiological glucose concentration REJECTED

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All Models Rejected => Rejection of the Hypothesis

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Summary of Tested Hypotheses

Hypothesis

Original dataset

Exteded dataset

Intracellular signalling enough OK Rejected

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Development of a Minimal Adipose Tissue Model

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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

Insulin Bloodflow Glucose Uptake

ACCEPTED

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Summary of Tested Hypotheses

Hypothesis

Original dataset

Exteded dataset

Intracellular signalling enough OK Rejected

In vitro/in vivo difference in basal GLUT4 translocation

OK Rejected

In vitro/in vivo difference in blood-flow

OK Rejected

Multiple in vitro/in vivo differences

OK OK

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Our Approach to Multi-Level Modeling

Object-oriented modeling

Minimal model to draw conclusions

Detailed models to complete the picture

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Insulin Signaling Details

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More Details

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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.

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The Final Hierarchical Model

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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]

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