Quantification of the effect of amino acids on an integrated mTOR and insulin signaling pathway.

Integration of nutrient and growth factor signaling pathways through mammalian TOR (mTOR) plays a central role in the regulation of cell growth. However, the mechanism of integration of these two signals in mTOR activation is largely unknown. Moreover, the nutritional input involving amino acids is yet to be characterized. Excess amino acid conditions, such as in obesity and protein-rich diets, are known to regulate insulin signaling through mTOR activation resulting in insulin resistance. Here, we develop a dynamic model to identify the regulatory role of amino acids in mTOR activation and to study its effect on insulin signaling in relation to multiple feedback loops present in the insulin signaling pathway. The analysis revealed that amino acids bring about multiple effects in the regulation of mTOR that might be represented by a single mechanism. Insulin signaling was demonstrated to operate between two extreme conditions involving tumor growth and insulin resistance, with multiple feedback loops tightly controlling and maintaining a robust insulin response. The state of insulin resistance was characterized by a decrease in the time lag or an increase in the magnitude of the negative feedback loop facilitated through perturbations such as excess input of amino acids. Such a condition disturbs the delicate balance between positive and negative feedback loops to yield an insulin-resistant state.