DOI: 10.1101/509208Jan 2, 2019Paper

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

BioRxiv : the Preprint Server for Biology
Pramod Rajaram SomvanshiVenkatesh Kareenhalli


Insulin and glucagon control plasma macro-nutrient homeostasis through their signalling network composed of multiple feedback and cross-talk mechanisms. To understand how these interactions contribute to metabolic homeostasis and disease states, we analyzed 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 macro-nutrient 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 analysi...Continue Reading

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