Hedo J A, Moncada V Y, Taylor S I
J Clin Invest. 1985 Dec;76(6):2355-61. doi: 10.1172/JCI112247.
In some patients with genetic forms of extreme insulin resistance, the cause of insulin resistance is a marked (greater than or equal to 90%) reduction in the number of insulin receptors on the cell surface. In the present work, we describe studies of insulin receptor biosynthesis in Epstein-Barr virus (EBV)-transformed lymphocytes from three patients (A-1, A-5, and A-8) with type A extreme insulin resistance. Insulin receptors are composed of two major glycoprotein subunits (apparent molecular weight [Mr] of 135 and 95 kD), which are both derived from a common precursor molecule with Mr of 190 kD. In one patient (A-1), there was a marked reduction in the biosynthesis of both the 190-kD precursor and the mature receptor. Thus, in this patient, the defect appears to occur early in the biosynthetic pathway (i.e., before the synthesis of the 190-kD precursor). In contrast, in two sisters (A-5 and A-8) with type A extreme insulin resistance, biosynthesis of the 190-kD precursor proceeds at a normal rate. However, there appears to be a defect subsequent to the biosynthesis of the 190-kD precursor, but before the insertion of the mature receptor in the plasma membrane. Our observations suggest the existence of at least two distinct types of biosynthetic defects which may give rise to a marked reduction in the number of insulin receptors on the cell surface. In addition, for comparison, we have studied receptor biosynthesis in cultured EBV lymphocytes from a fourth patient (A-7) with type A extreme insulin resistance. Although the cells of patient A-7 have a normal number of insulin receptors, we have detected subtle abnormalities in the posttranslational processing of the insulin receptor precursor, which may be a biochemical marker for a postbinding defect that causes insulin resistance in this patient.
在一些患有遗传性极端胰岛素抵抗的患者中，胰岛素抵抗的原因是细胞表面胰岛素受体数量显著减少（大于或等于90%）。在本研究中，我们描述了对三名患有A型极端胰岛素抵抗患者（A-1、A-5和A-8）的爱泼斯坦-巴尔病毒（EBV）转化淋巴细胞中胰岛素受体生物合成的研究。胰岛素受体由两个主要的糖蛋白亚基组成（表观分子量[Mr]分别为135和95 kD），这两个亚基均来自一个Mr为190 kD的共同前体分子。在一名患者（A-1）中，190-kD前体和成熟受体的生物合成均显著减少。因此，在这名患者中，缺陷似乎发生在生物合成途径的早期（即在190-kD前体合成之前）。相比之下，在两名患有A型极端胰岛素抵抗的姐妹（A-5和A-8）中，190-kD前体的生物合成速率正常。然而，在190-kD前体生物合成之后，但在成熟受体插入质膜之前，似乎存在缺陷。我们的观察结果表明，至少存在两种不同类型的生物合成缺陷，这可能导致细胞表面胰岛素受体数量显著减少。此外，为了进行比较，我们研究了第四名患有A型极端胰岛素抵抗患者（A-7）培养的EBV淋巴细胞中的受体生物合成。尽管患者A-7的细胞胰岛素受体数量正常，但我们在胰岛素受体前体的翻译后加工过程中检测到了细微异常，这可能是该患者导致胰岛素抵抗的结合后缺陷的生化标志物。
