Sedaghat, Sherman, Quon, 2002

Model Structure

Insulin is a peptide hormone that influences metabolism by promoting glucose uptake into tissues. Insulin-stimulated glucose transport involves the translocation of glucose transporters (GLUT4) from an intracellular location to the plasma membrane (see the figure below). The identities of many of the intermediate components of the insulin signal transduction pathway have been elucidated. On binding insulin, the surface insulin receptor undergoes autophosphorylation and displays enhanced tyrosine kinase activity. Subsequently, downstream intracellular substances such as the insulin receptor substrate-1 (IRS-1) are phosphorylated, creating binding sites for SH2 containing proteins such as phosphatidylinositide 3-kinase (PI3K). This enzyme then catalyses the formation of phosphoinositol lipds such as PI(3,4,5)P₃, which in turn activate 3-phosphoinositide-dependent protein kinase (PDK)-1. This then phosphorylates and activates other kinases such as protein kinase C (PKC) and Akt that mediate translocation of GLUT4. The identities of the elements linking PKC and Akt with GLUT4 translocation are as yet unknown, therefore the mechanisms underlying the control of insulin metabolism are not yet completely understood.

Complete understanding is also hindered by the complexity of signalling pathways. Many substrates are shared components of several pathways, and feedback and other interactions link individual pathways into complex signalling networks. Alfred Gilman has founded The Alliance for Cellular Signaling with the aim of integrating experimental data into theoretical models and increasing understanding of cell signalling. With this in mind, Ahmad R. Sedaghat, Arthur Sherman, and Michael J. Quon have developed a mathematical model of metabolic insulin signaling pathways. Their model has four main parts:

Insulin receptor binding subsystem;
Insulin receptor recycling subsystem;
Postreceptor signalling subsystem; and
Glut4 translocation subsystem.

All rate constants and model parameters are constrained by published experimental data. Model simulations are consistent with published experimental data, and the authors concluded that the mathematical modelling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signalling.

The complete 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. (Full text and PDF versions of the article are available to subscribers on the American Journal of Physiology website.) PubMed ID: 12376338

The raw CellML descriptions of the model can be downloaded in various formats as described in .

Layout of the model elements.