Effects of glucagon and glucagon-like peptide-1 on glucocorticoid secretion of dispersed rat adrenocortical cells

The effects of glucagon and glucagon-like peptide-1 (GLP-1) on the secretor y activity of rat adrenocortical cells have been investigated in vitro. Nei ther hormones affected basal or agonist-stimulated aldosterone secretion of dispersed rat zona glomerulosa cells or basal corticosterone production of zona fasciculata-reticularis (inner) cells. In contrast, glucagon and GLP- 1 partially (40%) inhibited ACTH (10(-9) M)-enhanced corticosterone secreti on of inner cells, maximal effective concentration being 10(-7) hi. The eff ect of 10(-7) M glucagon or GPL-1 was suppressed by 10(-6) M Des-His(1)-[Gl u(9)]-glucagon amide (glucagon-A) and exendin-4(3-39) (GPL-1-A), which are selective antagonists of glucagon and GLP-1 receptors, respectively. Glucag on and GLP-1 (10(-7) M) decreased by about 45-50% cyclic-AMP production by dispersed inner adrenocortical cells in response to ACTH (10(-9) M), but no t to the adenylate cyclase activator forskolin (10(-5) M) Again this effect was blocked by 10(-6) hi glucagon-A or GLP-1-A. The exposure of dispersed inner cells to 10(-7) M glucagon plus GLP-1 completely suppressed corticost erone response to ACTH (10(-9) M). However, they only partially inhibited ( by about 65-70%) both corticosterone response to forskolin(10(-5) M) or dib utyryl-cyclic-AMP (10(-5) M) and ACTH (10(-9) M)-enhanced cyclic-AMP produc tion. Quantitative HPLC showed that 10(-7) M glucagon or GLP-1 did not affe ct ACTH-stimulated pregnenolone production, evoked a slight rise in progest erone and 11-deoxycorticosterone release, and markedly reduced (by about 55 %) corticosterone secretion of dispersed inner adrenocortical cells. In lig ht of these findings the following conclusion are drawn: (i) glucagon and G LP-1, via the activation of specific receptors, inhibit glucocorticoid resp onse of rat adrenal cortex to ACTH, and (ii) the mechanism underlying the e ffect of glucagon and GLP-1 is probably two-fold, and involves both the inh ibition of the ACTH-induced activation of adenylate cyclase and the impairm ent of the late steps of glucocorticoid synthesis.