Antagonistic effects of insulin and cortisol on coordinate control of metabolism and growth in cultured fibroblasts

A variety of metabolic and biosynthetic pathways in chick embryo fibroblasts are stimulated coordinately by many unrelated exogenous agents. Three of the best characterized components of this coordinate response are the uptake of 2-deoxy-D-glucose (2-dGlc) and of uridine and the incorporation of thymidine into DNA. Insulin stimulates and cortisol inhibits the coordinate response. In cortisol-treated cultures, as little as 10^?3 units/ml of insulin may stimulate thymidine incorporation 4-fold and 10^?1 units/ml may stimulate as much as 40-fold. The higher concentrations of insulin completely override the inhibitory effect of cortisol. They also cause about a 5-fold stimulation of the uptake of 2-dGlc and of uridine and a 2-fold stimulation of proline incorporation into protein. The uptake rates of 2-dGlc and uridine double within 30 minutes after addition of insulin to cortisol-inhibited cultures, but the incorporation of thymidine only begins to increase markedly after a 4-hour delay. When cortisol is added to cultures in the absence of insulin, the rates of uptake of 2-dGlc and uridine begin to decrease within two hours, but the incorporation of thymidine remains constant for two hours before beginning to decrease. Deprivation of Mg²⁺ inhibits the accelerated coordinate response maintained by insulin, but does not further the inhibition induced by cortisol. Results with metabolic inhibitors indicate that the stimulation of 2-dGlc and uridine uptake by insulin do not require RNA synthesis, and also suggest that they do not require protein synthesis. These and other findings can be explained by a model for coordinate control in which insulin increases and cortisol decreases the availability of Mg²⁺ for a wide spectrum of regulatory reactions in different metabolic pathways. In this model both hormones affect only the rates of ongoing reactions and do not instruct the cell to carry out specific new reactions unless the cell was predetermined to do so.