Mode of Action of Glucocorticoids. I. Stimulation of Gluconeogenesis Independent of Synthesis De Novo of Enzymes.

The adrenal glucocorticoids regulate carbohydrate formation and protein synthesis (l-6), but the mechanism by which they influence either of these processes remains to be elucidated. The administration of glucocorticoids to rats is followed by increased formation of several liver enzymes that participate in amino acid degradation or gluconeogenesis; e.g. tyrosineol-ketoglutarate transaminase (7), glutamate-pyruvate transaminase (8), glucose 6-phosphatase (9, lo), fructose 1 ,B-diphosphatase (10, II), glycogen synthetase (12), tryptophan pyrrolase (13)) phosphoenolpyruvate carboxykinase (14, 15)) and pyruvic carboxylase (16). Karlson (17) has suggested that several hormones may function by stimulating enzyme synthesis and considerable evidence from the literature may be cited in support of this concept (18, 19). Greengard, Weber, and Singhal (20) have postulated that “the regulatory effect of glucocorticoids may be brought about by action on the cellular concentration of certain enzyme proteins.” Their proposal was based on data showing that glycogen formation in rats given cortisone plus either actinomycin D or puromycin was less than the amount of glycogen formed by rats given cortisone alone. Weber, Singhal, and Stamm (21) and Kenny and Ku11 (22) have reiterated this postulate. The concept that the primary effect of glucocorticoids is on enzyme induction is not in agreement with the previous findings of Kvam and Parks (10) that ethionine did not diminish the early effects of hydrocortisone on blood glucose and liver glycogen in fasted, adrenalectomized rats. Segal and Lopez (23) have questioned the proposal of Greengard et al. (20). The results of t,he present investigation indicate that the primary effect of glucocorticoids is not on induction of enzyme formation, although the latter process may be required for the maximum expression of the hormones’ activity.