multi-scale modeling incorporating insulin signaling in adipocytes and whole-body glucose...
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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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