Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose...
-
Upload
gladys-miles -
Category
Documents
-
view
213 -
download
0
Transcript of Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose...
![Page 1: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/1.jpg)
Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body
Glucose HomeostasisElin Nyman
Diabetes and Integrative Systems Biology
Linköping University
![Page 2: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/2.jpg)
2
MathCore Engineering AB
A Wolfram research company in Linköping
Consultancy services in modeling and simulation
Develop MathModelica, an object-oriented modeling and simulation software
![Page 3: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/3.jpg)
3
Examples of Models in MathModelica
![Page 4: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/4.jpg)
4
Insulin Signaling in Adipose Tissue
Primary human adipocytes
Insulin resistance, type 2 diabetes
Protein phosphorylation and glucose uptake
Compatible with the in vivo situation?
![Page 5: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/5.jpg)
5
Our Approach to Multi-Level Modeling
Object-oriented modeling
Minimal model to draw conclusions
Detailed models to complete the picture
![Page 6: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/6.jpg)
6
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.
![Page 7: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/7.jpg)
7
Our Approach to Multi-Level Modeling
Object-oriented modeling
Minimal model to draw conclusions
Detailed models to complete the picture
![Page 8: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/8.jpg)
8
Development of a Minimal Adipose Tissue Model
module constraints
![Page 9: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/9.jpg)
9
Module Constraints
20 % of total tissue glucose uptake
![Page 10: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/10.jpg)
10
Simulations Compared to Experimental Data and Module Constraints
![Page 11: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/11.jpg)
11
One Hypothesis – Many Models
![Page 12: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/12.jpg)
12
Development of a Minimal Adipose Tissue Model
![Page 13: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/13.jpg)
13
Simulations Compared to Experimental Data and Module Constraints
Physiological glucose concentration
Sub-physiological glucose concentration REJECTED
![Page 14: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/14.jpg)
14
All Models Rejected => Rejection of the Hypothesis
![Page 15: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/15.jpg)
15
Summary of Tested Hypotheses
Hypothesis
Original dataset
Exteded dataset
Intracellular signalling enough OK Rejected
![Page 16: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/16.jpg)
16
Development of a Minimal Adipose Tissue Model
![Page 17: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/17.jpg)
17
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
![Page 18: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/18.jpg)
18
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
![Page 19: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/19.jpg)
19
Our Approach to Multi-Level Modeling
Object-oriented modeling
Minimal model to draw conclusions
Detailed models to complete the picture
![Page 20: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/20.jpg)
20
Insulin Signaling Details
![Page 21: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/21.jpg)
21
More Details
![Page 22: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/22.jpg)
22
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.
![Page 23: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/23.jpg)
23
The Final Hierarchical Model
![Page 24: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/24.jpg)
24
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]
![Page 25: Multi-Scale Modeling Incorporating Insulin Signaling in Adipocytes and Whole-body Glucose Homeostasis Elin Nyman Diabetes and Integrative Systems Biology.](https://reader038.fdocuments.us/reader038/viewer/2022110210/56649e9e5503460f94b9fee2/html5/thumbnails/25.jpg)
www.liu.se