Robust adaptation of PKC ζ-IRS1 insulin signaling pathways through integral feedback control

Abstract

Insulin signaling pathways in muscle tissue play a major role in maintaining glucose homeostasis. Dysregulation in these pathways results in the onset of serious metabolic disorders like type 2 diabetes. Robustness is an essential characteristic of insulin signaling pathways that ensures reliable signal transduction in the presence of perturbations as a result of several feedback mechanisms. Integral control, according to control engineering, provides reliable setpoint tracking and disturbance rejection. The presence of negative feedback and integrating process is crucial for biological processes to achieve integral control. The existence of an integral controller leads to the rejection of perturbations which resulted in the robust regulation of biochemical entities within acceptable levels. In the present in silico research work, the presence of integral control in the protein kinase C ζ -insulin receptor substrate-1 (PKC ζ-IRS1) pathway is identified, verified mathematically and model is simulated in Cell Designer. The data is exported to Minitab software and robustness analysis is carried out statistically using the Mann-Whitney test. The p-value of the results obtained with given parameters perturbed by ±1% is greater than the significance level of 0.05 (0.2132 for 1% error in k7(rate constant of IRS1 phosphorylation), 0.2096 for −1% error in k7, 0.9037 for both ±1% error in insulin and 0.9037 for ±1% error in k1(association rate constant of the first molecule of insulin to bind the insulin receptor), indicated that our hypothesis is proved The results satisfactorily indicate that even when perturbations are present, glucose homeostasis in muscle tissue is robust due to the presence of integral regulation in the PKC ζ-IRS1 insulin signaling pathways. In this paper, we have analysed the findings from the framework of robust control theory, which has allowed us to examine that how PKC ζ-IRS1 insulin signaling pathways produces desired output in presence of perturbations.