(620c) Modeling the Complex Interactions Between the Insulin and Angiotensin II Signalling Systems

The cross-talk between insulin and Angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. Systems biology provides a useful framework to study the behavior of complex cellular networks associated with diabetes and hypertension. In [1] Wang developed a mathematical model for the AKT signalling pathway to investigate system-level mechanisms of cell growth and metabolism. The model centers on mTOR which senses the level of nutrients, insulin growth factor which activates the pathway, and pAKT (phosphorylated AKT) that adjusts the growth.

In this work we have advanced Wang’s model by including the interactions of AKT signaling pathway with the Angiotensin signalling pathway. The chemical reaction network of the biomolecules involved in the cross-talk is modeled using mass-action kinetics and conservation laws. The resulting model represents a nonlinear dynamical system which is in the form of ordinary differential equations. We show that the complex dynamic intearctions are regulated by a combination of positive and negative feedback loops. These nested feedback loops are studied to understand their role in important biological mechanisms such as glucose uptake and vasodilation-vasoconstriction balance.

Using this new dynamic model, bistability and parameter sensitivity analysis is carried and the system behavior is mapped to the parameter space to give insight into the development of diabetes and hypertension. The normal regulatory response of insulin signalling is identified to be bistable so that AKT can switch between low and high levels to maintain normal phenotype. The proposed mathematical model predicts that Ang II can impair the insulin signalling pathway  through several mechanisms: by direct inhibition of pAKT by ONOO, by directly inhibiting pIRS1 or by activating mTOR. It is shown that the interaction parameters in the model, the balance of positive and negative feedback loops are important in preserving the desired bistability and normal phenotype.

The model delineates that systems with over activated Ang II as a result of disfunction (e.g diseased kidneys can stimulate Ang II) can promote diabetes. The model also predicts that poor glyceamic control induced by diabetes contributes to hypertension by activating the Renin Angiotensin System.

1. Wang G: Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases. Physical Biology 2010, 7:046015.