Insulin receptor binding kinetics: modeling and simulation studies

Model Status

This version was created by James Lawson on 22/05/07 and is known to run in PCEnv. This file represents the receptor aggregation model described in Wanant and Quon 2000 'Insulin Receptor Binding Kinetics: Modeling and Simulation Studies.' Figures similar to those shown in the publication can be reproduced by graphing x1 (free insulin concentration, x axis) against 'scatchard,' which is a variable representing bound insulin over free insulin.

Model Structure

The binding of the hormone insulin to its receptors embedded in the plasma membrane of hepatocytes and myocytes, is the initial step in a signal transduction pathway that mediates glucose uptake and metabolism. The mature insulin receptor is a transmembrane glycoprotein with a dimeric structure capable of binding two insulin molecules at any given moment. The kinetics of insulin receptor binding are complex. The affinity of the receptor for the second insulin molecule is significantly lower than for the first bound molecule. This may explain the negative cooperative interactions observed at high insulin concentrations. That is, as the concentration of insulin increases and more receptors become occupied, the affinity of the receptors for insulin decreases. Conversely, at low insulin concentrations, positive cooperativity has been recorded. That is, the binding of insulin to its receptor at low insulin concentrations seems to enhance further binding. In addition, insulin receptor aggregation, or clustering of insulin receptors, occurs in response to ligand binding, and aggregation may also influence binding kinetics.

Sumanas Wanant and Michael J. Quon capture these features of insulin-receptor binding in their receptor aggregation model (see below). A system of differential equations represented the receptor-ligand binding and dissociation reactions. The assigned parameter values were based on experimental data. Model simulations recreated the positive and negative cooperativity observed in experiments, providing supporting evidence for the accuracy of the model.

The complete original paper reference is cited below:

Insulin Receptor Binding Kinetics: Modeling and Simulation Studies, Sumanas Wanant and Michael J. Quon, 2000, Journal of Theoretical Biology , 205, 355-364. PubMed ID: 10882558

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

A schematic diagram of Wanant and Quon's 2000 receptor aggregation model. This diagram shows a mature dimeric insulin receptor embedded in the plasma membrane. As it binds insulin molecules, the status of the ligand changes from an unbound state, to a singly bound state, to a doubly bound state. In addition, receptors are shown to cluster, or aggregate.