Periodic insulin stimulation of Akt: Dynamic steady states and robustness

Abstract

The periodic secretion of insulin is a salient feature of the blood glucose control system in vivo. Insulin levels in the blood exhibit oscillations on multiple time scales - rapid, ultradian, and circadian - and the improved metabolic regulation resulting from pulsatile insulin release has been well established. Although numerous mathematical models investigating the causal mechanisms of insulin oscillations have appeared in the literature, to date there has been comparatively little attention given to the influence of periodic insulin stimulation on downstream components of the insulin signalling pathway. In this paper, we explore the effect of high frequency periodic insulin stimulation on Akt (also known as PKB), a crucial crosstalk node in the insulin signalling pathway that coordinates metabolic and mitogenic processes in the cell. We analyse a mathematical model of Akt translocation to the plasma membrane under both single step insulin perturbations and periodic insulin stimulation with an emphasis on - but not limited to - the physiological range of parameter values. It was shown that the system rapidly attains a robust dynamic steady state entrained to the periodic insulin stimulation. Moreover, the translocation of Akt to the plasma membrane in the model permits a sufficient level of phosphorylation to trigger downstream metabolic regulators. However, the modelling also indicated that further investigation of this activation process is required to determine whether the response of Akt is a key determinant of the enhanced metabolic control observed under periodic insulin stimulation.

Keywords: Akt/PKB; Insulin signalling; ODE model; Periodic stimulation; Signalling.