Modelling of Detailed Insulin Receptor Kinetics Affects Sensitivity and Noise in the Downstream Signalling Pathway

Insulin resistance is a primary defect underlying the development of type II diabetes. In healthy conditions, insulin stimulates glucose uptake from the blood stream, but in diseased conditions the normal metabolic response is impaired. Identifying specific drug targets to restore insulin sensitivity at the cellular level and developing an effective treatment strategy require insight into both the biochemical mechanisms involved and the whole signalling network response to external cues. This study focuses on the consequences of integrating a detailed biochemical description of the insulin receptor trafficking compartment within a phenomenological model of the downstream signalling pathway. While the description of the experimental data is preserved by an iterative procedure of parameter fitting, the dynamic response of the network is highly modified, as shown by analyzing the complementary information derived from studying both connection sensitivities and node noise in the network. This is crucial considering the importance of network dynamics for identifying effective drug targets.