A Mathematical Model of Metabolic Insulin Signalling Pathways
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This model runs in PCEnv, OpenCell and COR and the units are consistent throughout. It describes the complete model with feedback, and it is a close match to figures 8 and 9. However, a time delay was ignored in the eqaution for PKC, which prevents the model from completely matching the paper.
Model Structure
ABSTRACT: We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.
The original paper reference is cited below:
A mathematical model of metabolic insulin signaling pathways, Ahmad R. Sedaghat, Arthur Sherman, and Michael J. Quon, 2002,American Journal of Physiology, 283, E1084-E1101. PubMed ID: 12376338
reaction_diagram
Schematic diagram of the layout of the model elements.
signal transduction
metabolism
insulin
A mathematical model of metabolic insulin signaling pathways (with feedback)
The University of Auckland, Auckland Bioengineering Institute
Arthur
Sherman
American Journal of Physiology
c.lloyd@auckland.ac.nz
The University of Auckland
Auckland Bioengineering Institute
Catherine
Lloyd
May
12376338
Sedaghat, Sherman and Quon's 2002 mathematical model of metabolic insulin signaling pathways.
Catherine Lloyd
2007-05-30T00:00:00+00:00
The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
This is the CellML descripition of Sedaghat, Sherman and Quon's 2002
mathematical model of metabolic insulin signaling pathways.
2007-06-05T10:44:09+12:00
Michael
Quon
J
2002-11
A mathematical model of metabolic insulin signaling pathways
283
E1084
E1101
keyword
Catherine
Lloyd
May
Ahmad
Sedaghat
R
x1
insulin input
x2
concentration of unbound surface insulin receptors
x3
concentration of unphosphorylated once-bound surface receptors
x4
concentration of phosphorylated twice-bound surface receptors
x5
concentration of phosphorylated once-bound surface receptors
x6
concentration of unbound unphosphorylated intracellular receptors
x7
concentration of phosphorylated twice-bound intracellular receptors
x8
concentration of phosphorylated once-bound intracellular receptors
x9
concentration of unphosphorylated IRS-1
x10
concentration of tyrosine-phosphorylated IRS-1
x10a
concentration of serine-phosphorylated IRS-1
x11
concentration of unactivated PI 3-kinase
x12
concentration of tyrosine-phosphorylated IRS-1/activated PI 3-kinase complex
x13
percentage of PI(3,4,5)P3 out of the total lipid population
x14
percentage of PI(4,5)P2 out of the total lipid population
x15
percentage of PI(3,4)P2 out of the total lipid population
x16
percentage of unactivated Akt
x17
percentage of activated Akt
x18
percentage of unactivated PKC-zeta
x19
percentage of activated PKC-zeta
x20
percentage of intracellular GLUT4
x21
percentage of cell surface GLUT4