The acute and chronic effects of glucocorticoids on insulin receptor and insulin responsiveness. Transient fluctuations in intracellular receptor level parallel transient fluctuations in responsiveness.

The treatment of confluent embryonic Swiss mouse fibroblasts (3T3-C2 cells) with glucocorticoids has been shown to result in a time- and dose-dependent increase in the number of cellular insulin receptors (Knutson, V. P., Ronnett, G. V., and Lane, M. D. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 2822-2826). Cellular events relating to the insulin receptor and insulin responsiveness which occur over the time course of the transition to the "up-regulated" steady state are described. Over the 48-h transition from the basal to the up-regulated steady state, a transient increase in the level of intracellular receptor was detected with a 3-5-fold increase in intracellular receptor found 12 h after steroid administration. Through the use of the heavy isotope density shift, this increase in the intracellular receptor population was preceded by a decrease in the rate of receptor inactivation, with no change in receptor synthesis. Insulin-induced receptor down-regulation was abolished after 12 h of dexamethasone treatment, when the intracellular receptor level was elevated. Nevertheless, the cells maintained the ability to internalize receptor in response to insulin binding. The hormonal responsiveness of the cells over the glucocorticoid-induced transition was assessed by the ability of insulin to stimulate the cellular uptake of 2-deoxyglucose and aminoisobutyric acid. Glucose transport was transiently increased at a time when the intracellular population of receptor was transiently elevated. Glucocorticoid treatment ultimately led to a loss of insulin-sensitive glucose transport. Insulin-stimulated amino acid transport was transiently abolished when the intracellular population of receptor was high. With chronic steroid treatment, the sensitivity of the amino acid transporter was increased above control levels. These data would indicate that glucocorticoids have no short- or long-term effect on insulin receptor synthesis; the insulin-induced internalization of insulin receptor alone is not sufficient to induce a cellular response to insulin; and the cellular events leading to the transient accumulation of intracellular receptor are coupled to the cellular responsiveness of the cells to insulin.