Awata T, Matsumoto C, Momomura K, Takahashi Y, Odawara M, Kasuga M, Kadowaki T, Iwamoto Y
Division of Endocrinology and Metabolism, Jichi Medical School, Tochigi, Japan.
J Clin Endocrinol Metab. 1994 Dec;79(6):1840-4. doi: 10.1210/jcem.79.6.7989492.
We studied a woman with acanthosis nigricans and insulin resistance. The patient's Epstein-Barr virus-transformed lymphocytes revealed slightly decreased insulin binding and markedly decreased insulin-stimulated autophosphorylation of the insulin receptor. The nucleotide sequence analysis of the patient's genomic DNA revealed a 3-basepair in-frame deletion in one allele, resulting in the loss of leucine at position 999 of the insulin receptor (delta Leu999). The messenger ribonucleic acid transcripts from the mutant allele in the patient's lymphocytes were not decreased. Insulin-stimulated autophosphorylation of the insulin receptor from cells expressing delta Leu999 mutant insulin receptor complementary DNA was markedly decreased. The proband, her mother, elder brother, and younger brother, who were heterozygous for this mutation, showed moderate or marked hyperinsulinemia during oral glucose tolerance tests. Although fasting glucose levels were normal and fasting insulin values were preserved in all subjects with the mutation for the 8-yr period of observation, a tendency of progressive increase in postload glucose levels was observed. These results suggest that the delta Leu999 mutation, which reduces tyrosine kinase activity, was responsible for insulin resistance and contributed to postload hyperglycemia.
我们研究了一名患有黑棘皮病和胰岛素抵抗的女性。患者的爱泼斯坦-巴尔病毒转化淋巴细胞显示胰岛素结合略有减少，胰岛素刺激的胰岛素受体自磷酸化显著减少。对患者基因组DNA的核苷酸序列分析显示，一个等位基因中有一个3碱基对的框内缺失，导致胰岛素受体第999位的亮氨酸缺失（δLeu999）。患者淋巴细胞中突变等位基因的信使核糖核酸转录本并未减少。表达δLeu999突变胰岛素受体互补DNA的细胞中，胰岛素刺激的胰岛素受体自磷酸化显著减少。该先证者及其母亲、哥哥和弟弟均为该突变的杂合子，在口服葡萄糖耐量试验期间表现出中度或显著的高胰岛素血症。尽管在8年的观察期内，所有携带该突变的受试者空腹血糖水平正常且空腹胰岛素值保持不变，但观察到负荷后血糖水平有逐渐升高的趋势。这些结果表明，降低酪氨酸激酶活性的δLeu999突变是胰岛素抵抗的原因，并导致负荷后高血糖。
