Antagonism was demonstrated between the effects of insulin and glucagon, added simultaneously to the perfusing blood, on phosphorylase activity, glucose output and urea production of the isolated rat liver. However, the degree of antagonism varied greatly, according to the action under study, and there appeared to be a clear-cut hierarchy in the effects of each hormone. For glucagon, this was (stimulation of): (1) phosphorylase activity, (2) glycogenolysis and glucose release, (3) urea production. For insulin, it was (inhibition of): (1) urea production, (2) glycogenolysis, (3) phosphorylase activation. Thus, high concentrations of insulin completely failed to inhibit the phosphorylase activation induced by 1.4 mμg./ml. of glucagon, while modest concentrations of insulin totally suppressed the stimulation of urea production induced by sustained glucagon concentrations at least ten times greater, and well above the biologic range. Our findings argue against a single common primary site of action of these two hormones.

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