Hormonal regulation of insulin receptor gene expression. Hydrocortisone and insulin act by different mechanisms

Incubation of cultured human (IM-9) lymphocytes with glucocorticoids increases the number of insulin receptors on the cell surface. Recently it has been shown that this results from a 3-fold increase in the rate of proreceptor synthesis. In the case of homologous insulin receptor down-regulation, a moderate rise in proreceptor biosynthesis has also been demonstrated. To further delineate the mechanisms of insulin receptor regulation, we have measured insulin receptor mRNA levels in hydrocortisone-treated and insulin-treated IM-9 lymphocytes. An increase in insulin receptor mRNA could be detected after 2 h of incubation with hydrocortisone and a plateau was reached by 4-6 h. The response was dose-dependent, being detectable with 50 nM hydrocortisone and reaching a maximal 3.7-fold increase at 200 nM. Actinomycin D completely suppressed the effect, whereas cycloheximide inhibited the effect by no more than 50%. These findings were extended by performing in vitro nuclear transcription assays which revealed that the 3-4-fold increase in insulin receptor mRNA could be attributed to increases in transcription. In contrast, homologous down-regulation was not associated with any change in total insulin receptor mRNA levels. The present study demonstrates that hydrocortisone, but not insulin, stimulates insulin receptor biosynthesis by increasing the rate of transcription and that de novo protein synthesis is probably required for a maximal effect.