Modelling Insulin Signalling – Harmonic Oscillators and Translocation
Insulin has profound effects on cell metabolism, growth, proliferation and anti-apoptosis in mammalian cells. As a consequence, dysregulation of the insulin signalling pathway is implicated not only in diabetes but also in the development of cancer and cardiovascular disease. Biological systems are notorious for having multiple and complex interacting pathways. The system can be considered as a black box where key biochemical players in the networks are known, but the structure and interactions between them are not.
A key mediator in downstream glucose transport is the molecule Akt. Akt derives signalling specificity from both its biochemical state and its cellular location. Phosphorylation and activation of Akt occurs at the plasma membrane and is a relatively fast process. On the other hand, the translocation of Akt from the cytosol, where it is synthesised, to the plasma membrane, is a slower and crucial step in downstream signalling. However, this process is currently not well understood.
The arrival of Akt at the plasma membrane can be measured by total internal reflection fluorescence (TIRF) microscopy. The aim of this mathematical modelling is to determine where different effectors and perturbations impinge on the signalling network, giving valuable biological insight into the operation of the system. Using the TIRF data as a guide, we have developed a compartmental model of Akt translocation to minimally encode the response to insulin stimulation. The structure of the model can be demonstrated to be equivalent to a damped harmonic oscillator, allowing the analysis of the structure and transient dynamics in terms of the different regimes of this system. The modelling also allows the exploration of a variety of scenarios that are difficult or impossible to implement experimentally. The downstream action of Akt activation in glucose transport is then explored.
Associate Professor Adelle Coster, University of New South Wales