title: Differential modulation of ACTH-stimulated cortisol and androstenedione secretion by insulin.
abstract: Results of previous clinical studies suggested counter regulatory actions between insulin and DHEA(S). The present studies were performed using primary monolayer cultures of bovine fasciculata-reticularis cells to test the hypothesis that insulin directly affects adrenal androgen secretion. Although having no independent effect, insulin exhibited complex time- and concentration-specific actions on ACTH-stimulated secretion of both C21 (cortisol) and C19 (androstenedione) corticosteroids. In the presence of low concentrations (0.05-0.1 nM) of ACTH, cortisol secretion during a 2 h incubation was about 2-fold greater in the presence than in the absence of insulin (0.01-100 ng/ml). In the presence of a maximal concentration (10 nM) of ACTH, on the other hand, cortisol secretion was not affected by insulin at concentrations less than or equal to 0.1 ng/ml, but was decreased at higher insulin concentrations. ACTH-stimulated androstenedione secretion was not significantly affected by insulin during a short-term (2 h) incubation. During a prolonged (24 h) incubation, insulin produced a concentration-dependent inhibition of ACTH-stimulated cortisol secretion. At an insulin concentration of 100 ng/ml, ACTH (10 nM)-stimulated cortisol secretion declined to a level only 30% of that produced by ACTH alone. In contrast, insulin exhibited biphasic effects on the secretion of androstenedione by cells maintained in the presence of ACTH for 24 h; an effect that was most dramatic in the presence of a maximal concentration of ACTH. At an insulin concentration of 0.1 ng/ml, androstenedione secretion by cells maintained in the presence of 10 nM ACTH was increased approximately 2.5-fold. At higher concentrations of insulin, ACTH-stimulated androstenedione secretion was inhibited to an extent comparable to that in cortisol secretion. The effects of insulin on ACTH-stimulated cortisol and androstenedione secretion could not be accounted for by changes in steroid degradation or a loss in 11 beta-hydroxylase activity. These results indicate that insulin interacts with ACTH to modulate the secretion of both C21 and C19 corticosteroids and that physiological concentrations (less than or equal to 1 ng/ml) of insulin may have a long-term effect to enhance selectively adrenal androgen secretion. These data are consistent with a servo mechanism between insulin and DHEA(S) in vivo and indicate that the correlations observed clinically result, at least in part, from a direct action of insulin to modulate the rate of adrenal androgen production.
authors.affiliation: Department of Pharmacology, University of Tennessee, Memphis 38163.
authors.forename: R E
authors.initials: RE
authors.lastname: Kramer
authors.forename: J E
authors.initials: JE
authors.lastname: Buster
authors.forename: R N
authors.initials: RN
authors.lastname: Andersen
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D000735:Androstenedione / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006854:Hydrocortisone / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007328:Insulin; D000735:Androstenedione; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone