Computational Analysis of Insulin-Glucagon Signalling Network: Implications of Bistability to Metabolic Homeostasis and Disease states.

Insulin and glucagon control plasma macronutrient homeostasis through their signalling network composed of multiple feedback and crosstalk interactions. To understand how these interactions contribute to metabolic homeostasis and disease states, we analysed the steady state response of metabolic regulation (catabolic or anabolic) with respect to structural and input perturbations in the integrated signalling network, for varying levels of plasma glucose. Structural perturbations revealed: the positive feedback of AKT on IRS is responsible for the bistability in anabolic zone (glucose >5.5 mmol); the positive feedback of calcium on cAMP is responsible for ensuring ultrasensitive response in catabolic zone (glucose <4.5 mmol); the crosstalk between AKT and PDE3 is responsible for efficient catabolic response under low glucose condition; the crosstalk between DAG and PKC regulates the span of anabolic bistable region with respect to plasma glucose levels. The macronutrient perturbations revealed: varying plasma amino acids and fatty acids from normal to high levels gradually shifted the bistable response towards higher glucose range, eventually making the response catabolic or unresponsive to increasing glucose levels. The analysis reveals that certain macronutrient composition may be more conducive to homeostasis than others. The network perturbations that may contribute to disease states such as diabetes, obesity and cancer are discussed.