Alterations in insulin binding induced by changes in vivo in the levels of glucocorticoids and growth hormone.
Alterations in insulin binding induced by changes in vivo in the levels of glucocorticoids and growth hormone.
复制标题
体内糖皮质激素和生长激素水平的变化引起胰岛素结合的改变。
作者：
C. Kahn;I. Goldfine;D. Neville;P. De Meyts
先前的研究表明，组织对胰岛素的敏感性在糖皮质激素和GH过量的状态下降低，而当这些激素缺乏时则增加。为了评价胰岛素受体在这些状态中的作用，我们研究了[125 I]胰岛素与纯化的肝质膜的结合，这些质膜是从糖皮质激素和GH的各种扰动的大鼠中获得的。通过给予ACTH（40 U/天，持续4天）或地塞米松（1 mg/天，持续4天）在大鼠中产生糖皮质激素过量。这导致了胰岛素抵抗状态。与这种胰岛素抵抗相关的是，与肝脏中其特异性受体结合的胰岛素减少了50-60%。相反，肾上腺切除术，产生胰岛素敏感性的增加，与胰岛素结合到肝脏的增加。计算机辅助Scatchard分析使用了一个负合作模型的菊粉受体相互作用表明，与我们的研究结果与肥胖，在这些国家的胰岛素结合的变化很可能是完全由于受体亲和力的变化，没有变化的受体浓度。GH给药也产生轻度胰岛素抵抗和受体浓度降低。这与受体亲和力的相互增加有关，因此，在低生理胰岛素浓度下，胰岛素结合没有发生重大变化。垂体切除大鼠，另一方面，表现出受体浓度的增加和亲和力的降低，和GH治疗只有部分纠正这些变化。植入MtT肿瘤（分泌ACTH、GH和PRL）的大鼠具有过量糖皮质激素和GH的联合作用，并且具有非常强的胰岛素抵抗。从这些大鼠制备的肝膜显示胰岛素结合和受体亲和力的降低，类似于在糖皮质激素过量的其他状态下观察到的。此外，肾上腺切除术的荷瘤大鼠导致胰岛素结合的增加，尽管持续的GH，ACTH和PRL水平升高。这些研究结果表明，胰岛素受体亲和力和数量的改变可能在伴随糖皮质激素过量和缺乏的胰岛素敏感性改变的状态中发挥重要作用，并遵循垂体切除术。相反，与GH过量相关的胰岛素抵抗在胰岛素结合位点远端的受体上的位点（即转导）或在胰岛素作用中重要的一个或多个细胞内反应中介导。
Previous studies have shown that the sensitivity of tissues to insulin is diminished in states of glucocorticoid and GH excess and is increased when these hormones are deficient. To evaluate the role of the insulin receptor in these states, we have studied [125I]insulin binding to purified liver plasma membranes obtained from rats with a variety of perturbations of both glucocorticoids and GH. Glucocorticoid excess was produced in rats by administration of ACTH (40 U/day for 4 days) or dexamethasone (1 mg/day for 4 days). This resulted in an insulin-resistant state. Associated with this insulin resistance, there was a 50-60% decrease in insulin binding to its specific receptors in liver. Conversely, adrenalectomy, which produces an increase in insulin sensitivity, was associated with an increase in insulin binding to liver. Computer-assisted Scatchard analysis using a negative cooperative model for the inulin-receptor interaction indicated that, in contrast to our findings with obesity, the changes in insulin binding in these states were most likely due entirely to changes in receptor affinity, with no change in receptor concentration. GH administration also produced mild insulin resistance and a decrease in receptor concentration. This was associated with a reciprocal increase in receptor affinity and thus, no major alteration in insulin binding occurred at low physiological insulin concentrations. Hypophysectomized rats, on the other hand, showed an increase in receptor concentration and a decrease in affinity, and GH treatment only partially corrected these changes. Rats implanted with the MtT tumor (which secretes ACTH, GH, and PRL) have the combined effects of excess glucocorticoids and GH and are very insulin resistant. Liver membranes prepared from these rats showed a decrease in insulin binding and receptor affinity similar to that observed in other states of glucocorticoid excess. Further, adrenalectomy of the tumor-bearing rats resulted in an increase in insulin binding despite the persistence of the elevated levels of GH, ACTH, and PRL. These findings suggest that alterations in insulin receptor affinity and number may play a major role in the states of altered insulin sensitivity which accompany glucocorticoid excess and deficiency, and follow hypophysectomy. In contrast, the insulin resistance associated with GH excess is mediated at either a site on the receptor distal to the insulin-binding site (i.e. transduction) or at one or more of the intracellular reactions important in insulin action.