Glucocorticoid-induced insulin resistance: the importance of postbinding events in the regulation of insulin binding, action, and degradation in freshly isolated and primary cultures of rat hepatocytes.
Glucocorticoid-induced insulin resistance: the importance of postbinding events in the regulation of insulin binding, action, and degradation in freshly isolated and primary cultures of rat hepatocytes.
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糖皮质激素诱导的胰岛素抵抗：结合后事件在新鲜分离的大鼠肝细胞和原代培养物中胰岛素结合、作用和降解调节中的重要性。
DOI：
10.1172/jci110526
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发表时间：
1982
期刊：
影响因子：
--
通讯作者：
Amatruda,JM
中科院分区：
文献类型：
--
作者：
Caro,JF;Amatruda,JM
我们最近提出，胰岛素受体的“下调”可能是细胞对胰岛素的许多生物反应之一。为了进一步探讨这一假设，我们研究了胰岛素的作用，结合，和降解的新鲜分离的肝细胞从大鼠造成胰岛素抵抗的地塞米松，1.0毫克/公斤，每隔一天，1和4周，在地塞米松治疗的（0.1 μM，24小时）正常大鼠肝细胞原代培养物。与年龄和体重相比，地塞米松治疗1周和4周导致显著的高胰岛素血症和正常。匹配的对照动物。从地塞米松处理1周的大鼠新鲜分离的肝细胞比对照动物的细胞结合更少的胰岛素。这种胰岛素结合的减少反映在细胞溶解后细胞胰岛素受体总数的减少。通过胰岛素刺激α-氨基异丁酸摄取的能力评价胰岛素作用。地塞米松治疗1周后，新鲜分离的肝细胞中氨基异丁酸摄取的基础速率增强，尽管胰岛素刺激的氨基异丁酸摄取的剂量-反应曲线明显向右偏移，但在无胰岛素浓度时，对照组和地塞米松治疗组动物的肝细胞摄取存在显著差异。无论是以高于基础值的百分比还是绝对增量表示，这都是正确的。地塞米松处理1周的动物肝细胞中胰岛素降解增强，但不能解释所观察到的胰岛素结合变化。地塞米松处理4周的动物肝细胞在氨基异丁酸摄取方面对胰岛素有抗性，然而，胰岛素结合和胰岛素降解都恢复到对照动物肝细胞中观察到的水平。地塞米松0.1 μM体外处理24 h后的肝细胞与地塞米松处理4周的大鼠肝细胞相似，因为它们在氨基异丁酸摄取方面具有胰岛素抵抗，并且具有正常至增加的胰岛素结合。胰岛素降解也相似。这些细胞对0.1 μM胰岛素下调其受体的能力具有抵抗性，而在没有地塞米松的情况下用胰岛素处理的平行培养物的胰岛素结合减少了52%。这些数据表明，对胰岛素有反应的肝细胞通过减少胰岛素受体的数量和增加胰岛素降解来对体内高胰岛素血症作出反应。在体内和体外对胰岛素产生抗性的肝细胞对胰岛素的这些作用具有抗性。这些研究强调了后结合事件在胰岛素结合、作用和降解调节中的重要性，并支持了肝细胞胰岛素受体下调是胰岛素众多生物学作用之一的假设。它们还有助于解释细胞如何产生胰岛素抵抗，以及在高胰岛素血症的情况下如何具有正常数量的胰岛素结合位点。
We have recently proposed that “down regulation” of the insulin receptor may be one of the many biological responses of a cell to insulin. In an attempt to further explore this hypothesis we have studied insulin action, binding, and degradation in freshly isolated hepatocytes from rats rendered insulin resistant by the administration of dexamethasone, 1.0 mg/kg every other day, for 1 and 4 wk, and in dexamethasone-treated (0.1 μM for 24 h) primary cultures of hepatocytes from normal rats.Dexamethasone treatment for 1 and 4 wk resulted in significant hyperinsulinemia and euglycemia when compared with age- and weight-matched control animals. Freshly isolated hepatocytes from rats treated with dexamethasone for 1 wk bound less insulin than cells from control animals. This decrease in insulin binding was reflected in a decrease in the total number of cellular insulin receptors upon solubilization of the cells. Insulin action was evaluated by the ability of insulin to stimulate the uptake of α-aminoisobutyric acid. The basal rate of aminoisobutyrate uptake in freshly isolated hepatocytes was enhanced by 1 wk of dexamethasone treatment, and although there was an apparent shift to the right in the dose-response curve for insulin-stimulated aminoisobutyrate uptake, at no insulin concentration was there a significant difference in the uptake by hepatocytes from control and dexamethasone-treated animals. This was true whether expressed as a percentage or absolute increment above basal. Insulin degradation was enhanced in hepatocytes from animals treated with dexamethasone for 1 wk but could not account for the observed changes in insulin binding.Hepatocytes from animals treated with dexamethasone for 4 wk were resistant to insulin with regard to aminoisobutyrate uptake, yet both insulin binding and insulin degradation returned to the levels observed in hepatocytes from control animals.Primary cultures of hepatocytes from normal rats exposed to dexamethasone, 0.1 μM, in vitro for 24 h were similar to hepatocytes from rats treated with dexamethasone for 4 wk in that they were insulin resistant with regard to aminoisobutyrate uptake and had normal to increased insulin binding. Insulin degradation was also similar. These cells were resistant to the ability of insulin, 0.1 μM, to down regulate its receptor whereas parallel cultures treated with insulin in the absence of dexamethasone had a 52% decrease in insulin binding.These data indicate that hepatocytes that are insulin responsive respond to in vivo hyperinsulinemia by a decrease in the number of insulin receptors and by increased insulin degradation. Hepatocytes rendered resistant to insulin both in vivo and in vitro are resistant to these effects of insulin. These studies emphasize the importance of postbinding events in the modulation of insulin binding, action, and degradation, and support the hypothesis that down regulation of the hepatocyte insulin receptor is one of the many biological actions of insulin. They also help explain how a cell can be insulin resistant and have a normal number of insulin binding sites in the presence of hyperinsulinemia.