A Mathematical Model of Metabolic Insulin Signalling Pathways
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This model runs in OpenCell and COR and the units are consistent throughout. It describes the complete model without feedback, and recreates figures 6 and 7 from 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
Layout of the model elements.
x15percentage of PI(3,4)P2 out of the total lipid population12376338x10concentration of tyrosine-phosphorylated IRS-1x21percentage of cell surface GLUT4x3concentration of unphosphorylated once-bound surface receptors2007-06-05T10:44:09+12:00JMichaelQuon283E1084E1101A mathematical model of metabolic insulin signaling pathwaysx7concentration of phosphorylated twice-bound intracellular receptorsx14percentage of PI(4,5)P2 out of the total lipid populationkeywordx16percentage of unactivated Aktx19percentage of activated PKC-zeta0.01x17percentage of activated AktAmerican Journal of Physiology2007-05-30T00:00:00+00:00The University of AucklandAuckland Bioengineering Institutex11concentration of unactivated PI 3-kinasex20percentage of intracellular GLUT4x6concentration of unbound unphosphorylated intracellular receptorsArthurShermanx13percentage of PI(3,4,5)P3 out of the total lipid populationx4concentration of phosphorylated twice-bound surface receptorsc.lloyd@auckland.ac.nzx8concentration of phosphorylated once-bound intracellular receptorsx18percentage of unactivated PKC-zeta
Sedaghat, Sherman and Quon's 2002 mathematical model of metabolic insulin signaling pathways.
x9concentration of unphosphorylated IRS-1x1insulin inputRAhmadSedaghatA mathematical model of metabolic insulin signaling pathways (without feedback)The University of Auckland, Bioengineering InstituteThe 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.x12concentration of tyrosine-phosphorylated IRS-1/activated PI 3-kinase complexx2concentration of unbound surface insulin receptorsx5concentration of phosphorylated once-bound surface receptorsCatherine LloydThis is the CellML descripition of Sedaghat, Sherman and Quon's 2002
mathematical model of metabolic insulin signaling pathways.2002-11MayCatherineLloydmetabolisminsulinsignal transductionMayCatherineLloyd