Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells.
Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells.
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促进胰岛素对卵巢细胞营养作用的机制。
DOI：
10.1172/jci111029
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Demers,LM
中科院分区：
文献类型：
--
作者：
Veldhuis,JD;Kolp,LA;Toaff,ME;Strauss3rd,JF;Demers,LM
在体内很难证明胰岛素对性腺组织的直接作用。我们已经开发了一种体外系统，其中猪卵巢细胞对胰岛素的营养作用保持高度反应。纯化后的猪胰岛素能显著增强颗粒细胞对孕酮的合成和分泌。胰岛素的这些刺激作用是剂量和时间依赖性的，并且是饱和的。在血清限制条件下，胰岛素也显著增强雌二醇和8-溴环AMP刺激孕酮产生的能力。蛋白质和RNA合成抑制剂（环己亚胺、放线菌素D和α -amanatin）抑制胰岛素的作用。胰岛素刺激孕酮的产生是由于孕烯醇酮的生物合成增加，而不是孕酮对其主要代谢物20α-羟基孕酮-4-烯-3-酮的分解代谢减少。在可溶性甾醇底物5-胆固醇-3β，25-二醇存在的情况下，胰岛素也能促进黄体酮的产生，该底物很容易进入线粒体胆固醇侧链切割系统。此外，颗粒细胞暴露于胰岛素使线粒体细胞色素P-450含量增加3至7倍，通过差谱法测量，线粒体胆固醇侧链切割活性相应增加。胰岛素促进卵巢细胞合成黄体酮的能力被胰岛素样生长激素、增殖刺激活性所模仿，但不被表皮生长因子、成纤维细胞生长因子或猪松弛素所模仿。胰岛素对黄体酮产生的增强反映了对黄体酮生物合成的选择性作用，因为胰岛素显著抑制颗粒细胞对雌激素的生物合成。因此，我们的研究表明，胰岛素选择性地作用于卵巢细胞，刺激孕烯醇酮（而不是雌激素）的生物合成。胰岛素的作用是通过需要蛋白质和RNA合成的过程，以及通过增加线粒体细胞色素P-450含量和促进胆固醇在侧链切割反应中的利用的机制来发挥的。增殖刺激活动对胰岛素作用的惊人模仿表明胰岛素的作用可能是通过生长抑素受体介导的。此外，鉴于体内卵泡中存在高浓度的生长激素，我们的体外观察表明，胰岛素或胰岛素样生长因子的特异性营养作用可能会显著调节体内卵泡的分化功能。
Direct actions of insulin on gonadal tissues have been difficult to demonstrate in vivo. We have developed an in vitro system in which swine ovarian cells remain highly responsive to trophic actions of insulin. Purified porcine insulin significantly augmented the biosynthesis and secretion of progesterone by cultured granulosa cells. These stimulatory actions of insulin were dose- and time-dependent and saturable. Under serum-restricted conditions, insulin also significantly amplified the capacity of estradiol and 8-bromo cyclic AMP to stimulate progesterone production. Inhibitors of protein and RNA synthesis (cycloheximide, actinomycin D, and alpha-amanatin) inhibited insulin action. The stimulation of progesterone production by insulin was attributable to increased biosynthesis of pregnenolone, rather than diminished catabolism of progesterone to its principal metabolite, 20α-hydroxypregn-4-en-3-one. Insulin also enhanced progesterone production in the presence of a soluble sterol substrate, 5-cholesten-3β,25-diol, which readily gains access to the mitochondrial cholesterol side-chain cleavage system. Moreover, exposure of granulosa cells to insulin produced a three- to sevenfold increase in mitochondrial content of cytochrome P-450 measured by difference spectroscopy, with a corresponding increase in mitochondrial cholesterol side-chain cleavage activity.The capacity of insulin to facilitate progesterone biosynthesis by ovarian cells was mimicked by the insulinlike somatomedin, multiplication stimulating activity, but not by epidermal growth factor, fibroblast growth factor, or porcine relaxin. Insulin's augmentation of progesterone production reflected a selective action on progestin biosynthesis, since insulin significantly suppressed estrogen biosynthesis by granulosa cells.Thus, our investigations indicate that insulin acts on ovarian cells selectively to stimulate pregnenolone (but not estrogen) biosynthesis. The actions of insulin are exerted by processes that require protein and RNA synthesis, and by mechanisms that augment mitochondrial cytochrome P-450 content and facilitate the utilization of cholesterol in the side-chain cleavage reaction. The striking mimicry of insulin effect by multiplication stimulating activity suggests that insulin action may be mediated through somatomedin receptors. Moreover, in view of the high concentrations of somatomedin in ovarian follicles in vivo, our in vitro observations suggest that specific trophic actions of insulin or insulinlike growth factors are likely to significantly regulate the differentiated function of the Graafian follicle in vivo.
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DOI：
10.1016/0026-0495(68)90097-8
发表时间：
1968
期刊：
Metabolism: clinical and experimental
影响因子：
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作者：
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DOI：
--
发表时间：
1985
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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通讯作者：
Abumrad,NA
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DOI：
--
发表时间：
1980
期刊：
Biochemical and Biophysical Research Communications - BBRC
影响因子：
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作者：
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通讯作者：
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