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

Abstract

The effects of glucagon and glucagon-like peptide-1 (GLP-1) on the secretory activity of rat adrenocortical cells have been investigated in vitro Neither 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-I partially (40%) inhibited ACTH (10 −9 M)-enhanced corticosterone secretion of inner cells, maximal effective concentration being 10 −7 M. The effect of 10 −7 M glucagon or GPL-1 was suppressed by 10 −6 M Des-His 1-[Glu 9]-glucagon amide (glucagon-A) and exendin-4(3-39) (GPL-1-A), which are selective antagonists of glucagon and GLP-1 receptors, respectively Glucagon 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 not to the adenylate cyclase activator forskolin (10 −5 M). Again this effect was blocked by 10 −6 M glucagon-A or GLP-1-A. The exposure of dispersed inner cells to 10 −7 M glucagon plus GLP-1 completely suppressed corticosterone response to ACTH (10 −9 M) However, they only partially inhibited (by about 65–70%) both corticosterone response to forskolin (10 −5 M) or dibutyryl-cyclic-AMP (10 −7 M) and ACTH (10 −9 M)-enhanced cyclic-AMP production. Quantitative HPLC showed that 10 −7 M glucagon or GLP-1 did not affect ACTH-stimulated pregnenolone production, evoked a slight rise in progesterone and 11-deoxycorticosterone release, and markedly reduced (by about 55%) corticosterone secretion of dispersed inner adrenocortical cells. In light of these findings the following conclusion are drawn: (i) glucagon and GLP-1, via the activation of specific receptors, inhibit glucocorticoid response of rat adrenal cortex to ACTH; and (ii) the mechanism underlying the effect of glucagon and GLP-1 is probably two-fold, and involves both the inhibition of the ACTH-induced activation of adenylate cyclase and the impairment of the late steps of glucocorticoid synthesis.