Laakso M, Malkki M, Kekäläinen P, Kuusisto J, Deeb S S
Department of Genetics, University of Washington, Seattle 98195.
J Clin Invest. 1994 Sep;94(3):1141-6. doi: 10.1172/JCI117429.
Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.
胰岛素受体底物-1（IRS-1）在胰岛素刺激的信号传导机制中发挥着重要作用。因此，我们研究了非胰岛素依赖型糖尿病（NIDDM）患者该基因编码区变异的频率及其临床意义。初步筛查纳入了40名芬兰典型NIDDM患者的人群样本。应用单链构象多态性分析，在40名NIDDM患者中发现了以下氨基酸替代：Gly818-Arg、Ser892Gly和Gly971Arg。前两个变异此前未见报道。另外对72名NIDDM患者和104名口服葡萄糖耐量试验完全正常且糖尿病家族史阴性的健康对照者进行了筛查。最常见的多态性是Gly971Arg替代，在112名NIDDM患者中有11名（9.8%）出现，在104名对照者中有9名（8.7%）出现。Gly818Arg替代在NIDDM患者中有2名（1.8%）出现，在对照者中有2名（1.9%）出现；Ser892Gly替代在NIDDM患者中有3名（2.7%）出现，在对照者中有1名（1.0%）出现。Gly971Arg替代与胰岛素分泌能力受损（通过口服葡萄糖耐量试验中的胰岛素反应或高血糖钳夹评估）或胰岛素作用（通过正常血糖钳夹评估）无关。在所观察到的三个氨基酸替代中，Ser892Gly最为有趣，因为它消除了一个潜在的丝氨酸磷酸化位点（SPGE），该位点位于生长因子受体结合蛋白（GRB2）唯一的SH2结合位点的紧邻氨基末端，因此可能会潜在影响信号转导的某些方面以及对胰岛素的代谢反应。
