Cama A, de la Luz Sierra M, Ottini L, Kadowaki T, Gorden P, Imperato-McGinley J, Taylor S I
Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Endocrinol Metab. 1991 Oct;73(4):894-901. doi: 10.1210/jcem-73-4-894.
Insulin resistance is frequently associated with acanthosis nigricans and hyperandrogenism. In patients with type A insulin resistance, this has been shown to be due to genetic defects in insulin receptor function. However, other patients with a similar clinical syndrome have been reported to have a variant of this syndrome, in which assays of insulin receptor function were normal. We have sequenced a portion of the insulin receptor gene in one such patient, a 29-yr-old woman with obesity and insulin resistance. The patient is heterozygous for a mutation substituting isoleucine for methionine at position 1153. Met1153 is located in the intracellular domain of the receptor near the cluster of tyrosine phosphorylation sites at positions 1158, 1162, and 1163. Studies of the mutant receptor expressed in NIH-3T3 cells demonstrated that the Ile1153-mutation impairs the ability of insulin to stimulate autophosphorylation of solubilized insulin receptors. In addition, the mutation impairs the ability of insulin to stimulate receptor tyrosine kinase activity to phosphorylate an artificial substrate [poly(Glu-Tyr)]. It seems likely that this defect in receptor tyrosine kinase activity explains the defect in the ability of the patient's insulin receptors to mediate insulin action in vivo. Furthermore, this patient provides a paradigm in which genetic factors act in concert with other risk factors, such as obesity, to cause clinically important insulin resistance.
胰岛素抵抗常与黑棘皮症和高雄激素血症相关。在A型胰岛素抵抗患者中，已证实这是由于胰岛素受体功能的基因缺陷所致。然而，据报道，其他具有类似临床综合征的患者患有该综合征的一种变体，其中胰岛素受体功能检测结果正常。我们对一名这样的患者（一名患有肥胖症和胰岛素抵抗的29岁女性）的胰岛素受体基因的一部分进行了测序。该患者在第1153位密码子处存在杂合突变，导致异亮氨酸取代甲硫氨酸。甲硫氨酸1153位于受体的细胞内结构域，靠近第1158、1162和1163位酪氨酸磷酸化位点簇。对在NIH-3T3细胞中表达的突变受体的研究表明，异亮氨酸1153突变损害了胰岛素刺激可溶性胰岛素受体自身磷酸化的能力。此外，该突变损害了胰岛素刺激受体酪氨酸激酶活性以磷酸化人工底物[聚（谷氨酸-酪氨酸）]的能力。受体酪氨酸激酶活性的这种缺陷似乎可以解释患者胰岛素受体在体内介导胰岛素作用的能力缺陷。此外，该患者提供了一个范例，即遗传因素与其他风险因素（如肥胖）共同作用，导致临床上重要的胰岛素抵抗。
