The role of cyclic AMP in the control of liver metabolism

Abstract

1. 1.|Gluconeogenesis from lactate in the perfused liver is stimulated by blood levels of glucagon and high levels of catecholamines. This effect of the hormones appears to be mediated by cyclic AMP. The changes in intermediary metabolites produced by the hormones or cyclic AMP with lactate or amino acids as substrate are consistent with the activation of a reaction or reactions between pyruvate and P-pyruvate in the gluconeogenic pathway. The absence of any effect of glucagon on glucose or lactate formation from fructose suggests that cyclic AMP does not produce any significant effect on reactions between triose-P and glucose or on the conversion of P-pyruvate to pyruvate. 2. 2.|Gluconeogenesis appears to be as sensitive as glycogenolysis to stimulation by glucagon, catecholamines and cyclic AMP. The nucleotide mimics the actions of the hormones on urea production and K + release by the perfused liver. 3. 3.|The accumulation of cyclic AMP in the liver is promoted by much lower levels of glucagon than catecholamines and the maximum cyclic AMP concentration with glucagon is 20 to 30 fold higher than that with epinephrine. Isopropyl norepinephrine stimulates glycogenolysis and cyclic AMP formation in the liver and the effects of epinephrine are blocked by pronethalol. The liver receptors therefore appear to resemble β-adrenergic receptors more closely than α-receptors. 4. 4.|Insulin deficiency produced by anti-insulin serum or alloxan causes an elevation of the liver cyclic AMP level in vivo which can be reversed by insulin treatment. Perfused livers from antiserum-treated rats also show an increase in cyclic AMP and this probably accounts for the increased rates of glycogenolysis, gluconeogenesis, urea production and K + release. 5. 5.|Insulin added to the perfusion medium reverses the effects of antiserum treatment. It also inhibits many processes in normal livers which are stimulated by cyclic AMP and it antagonizes the actions of glucagon and epinephrine on glucose output. It lowers the level of cyclic AMP in normal livers and in those treated with glucagon or obtained from rats injected with antiserum. 6. 6.|Adrenal glucocorticoids are required for a normal effect of glucagon on lactate gluconeogenesis. They appear to exert a permissive action by increasing the sensitivity of a reaction or reactions in gluconeogenesis to activation by cyclic AMP.