IRCCS Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy.
Nat Rev Endocrinol. 2009 Dec;5(12):682-93. doi: 10.1038/nrendo.2009.215.
Type 2 diabetes mellitus (T2DM) is a complex disorder that has a heterogeneous genetic and environmental background. In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. The biological relevance of these three polymorphisms has been very thoroughly characterized both in vitro and in vivo and the available data indicate that they all affect insulin signaling and action as well as insulin secretion. They also affect insulin-mediated regulation of endothelial cell function. In addition, several reports indicate that the effects of all three polymorphisms on the risk of T2DM and cardiovascular diseases related to insulin resistance depend on the clinical features of the individual, including their body weight and age at disease onset. Thus, these polymorphisms might be used to demonstrate how difficult it is to ascertain the contribution of relatively infrequent genetic variants with heterogeneous effects on disease susceptibility. Unraveling the role of such variants might be facilitated by improving disease definition and focusing on specific subsets of patients.
2 型糖尿病（T2DM）是一种复杂的疾病，具有异质的遗传和环境背景。在这篇综述中，我们讨论了调节胰岛素信号的基因中相对罕见的多态性在 T2DM 及其他与胰岛素抵抗相关疾病中的作用，这些基因包括调节胰岛素信号的基因（包括 ENPP1 的 K121Q 多态性、IRS1 的 G972R 多态性和 TRIB3 的 Q84R 多态性）。这三种多态性在体外和体内的生物学相关性都得到了非常彻底的描述，现有数据表明它们都影响胰岛素信号和作用以及胰岛素分泌。它们还影响胰岛素介导的内皮细胞功能的调节。此外，有几项报告表明，这三种多态性对 T2DM 和与胰岛素抵抗相关的心血管疾病风险的影响取决于个体的临床特征，包括其发病时的体重和年龄。因此，这些多态性可能被用来证明确定对疾病易感性具有异质影响的相对罕见遗传变异的贡献是多么困难。通过改善疾病定义并关注特定的患者亚组，可能会促进对这些变异作用的研究。
