Kramer R E, Buster J E, Andersen R N
Department of Pharmacology, University of Tennessee, Memphis 38163.
J Steroid Biochem. 1990 Jun;36(1-2):33-42. doi: 10.1016/0022-4731(90)90111-5.
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.
以往临床研究结果提示胰岛素与脱氢表雄酮（DHEA[S]）之间存在对抗调节作用。本研究采用牛束状带-网状带细胞原代单层培养来验证胰岛素直接影响肾上腺雄激素分泌这一假说。胰岛素虽无独立作用，但对促肾上腺皮质激素（ACTH）刺激的C21（皮质醇）和C19（雄烯二酮）皮质类固醇分泌表现出复杂的时间和浓度特异性作用。在低浓度（0.05 - 0.1 nM）ACTH存在时，2小时孵育期间，存在胰岛素（0.01 - 100 ng/ml）时的皮质醇分泌比不存在胰岛素时约高2倍。另一方面，在最大浓度（10 nM）ACTH存在时，浓度小于或等于0.1 ng/ml的胰岛素对皮质醇分泌无影响，但在更高胰岛素浓度时皮质醇分泌减少。短期（2小时）孵育期间，胰岛素对ACTH刺激的雄烯二酮分泌无显著影响。在延长（24小时）孵育期间，胰岛素对ACTH刺激的皮质醇分泌产生浓度依赖性抑制。在胰岛素浓度为100 ng/ml时，ACTH（10 nM）刺激的皮质醇分泌降至仅为单独ACTH所产生分泌水平的30%。相反，胰岛素对在ACTH存在下维持24小时的细胞的雄烯二酮分泌表现出双相作用；在最大浓度ACTH存在时这种作用最为显著。在胰岛素浓度为0.1 ng/ml时，在10 nM ACTH存在下维持的细胞的雄烯二酮分泌增加约2.5倍。在更高胰岛素浓度时，ACTH刺激的雄烯二酮分泌受到抑制，其程度与皮质醇分泌情况相当。胰岛素对ACTH刺激的皮质醇和雄烯二酮分泌的影响不能用类固醇降解变化或11β-羟化酶活性丧失来解释。这些结果表明胰岛素与ACTH相互作用以调节C21和C19皮质类固醇的分泌，并且生理浓度（小于或等于1 ng/ml）的胰岛素可能具有长期作用以选择性增强肾上腺雄激素分泌。这些数据与体内胰岛素和DHEA[S]之间的伺服机制一致，并表明临床上观察到的相关性至少部分源于胰岛素调节肾上腺雄激素产生速率的直接作用。
