Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes.
Although a number of previous studies have suggested that glucocorticoids influence somatostatin (SS) function at the peptide level in some tissues and SS mRNA levels in thyroid tumor cells, there has been no systematic investigation of the effects of glucocorticoids on SS gene expression in normal tissues. In the present study, we have examined the effect of dexamethasone (DEX) on SS secretion and gene expression in rat tissues using as models DEX-treated rats in vivo, primary cultures of rat islet and cerebrocortical cells, and a SS-producing rat islet tumor cell line (1027B2). In vivo DEX administration (0.5 mg/kg) for 3 or 8 days augmented SS-mRNA 2- to 3-fold in peripheral tissues (stomach, pancreas, and jejunum), but reduced it by 50-60% in brain. The DEX effect was time dependent, being more pronounced after 8 days than after 3 days of treatment. In all tissues, SS mRNA levels returned to control values 2 weeks after cessation of DEX. Changes in tissue content of immunoreactive SS paralleled those in SS mRNA. In cultured rat islet cells, 18-h incubation with DEX induced dose-dependent biphasic effects on immunoreactive SS and SS mRNA; low doses (10(-10) M) were stimulatory, and high doses (10(-8)-10(-5) M) were inhibitory. Insulin secretion displayed dose-dependent stimulation by DEX, whereas glucagon release was inhibited. The effect of DEX on SS mRNA levels in primary cultures of brain cells was solely inhibitory. 1027B2 cells responded to DEX with augmented immunoreactive SS secretion and SS mRNA levels at low concentration (10(-10) M), followed by a dose-dependent inhibition of both parameters with increasing DEX concentrations. We conclude that glucocorticoids exert significant effects on SS peptide production and steady state mRNA levels in normal SS-producing tissues in vivo, in vitro, and in cultured 1027B2 cells. The glucocorticoid effect is time and dose dependent, tissue specific, and at least in part due to a direct action of the steroid hormone on SS-producing cells.