Dynamic sensitivity and control analyses of metabolic insulin signalling pathways

Abstract

The authors have applied the dynamic sensitivity and control analyses to study the GLUT4 metabolic insulin signalling pathways, based on the models developed by Sedaghat et al. They have calculated the time-dependent sensitivities of the concentration of the membrane GLUT4 with respect to all reaction parameters (reaction rate constants and initial concentrations of the effectors). These time-dependent sensitivities provide dynamic information about pathways, in particular, the separate roles of the negative and positive feedbacks in the network. In addition, the integrated sensitivities of the membrane GLUT4 have been used to rank the potential drug targets according to the accumulated influence of each reaction rate or initial concentration on the membrane GLUT4. The results are consistent with experimental facts and predictions of drug targets in the literature. Furthermore, a strategy is developed using dynamic sensitivities to control the accumulated amount of membrane GLUT4 over a period of time for a fixed amount of insulin input. This strategy is then applied to rank possible mechanisms of insulin resistance. The results are also in agreement with those suggested in the literature.