About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos from I-Res donors with differences of 2-fold or more. Over 30 of the genes changed in I-Res iMyos were associated with T2D by SNPs and were functionally linked to insulin action and control of metabolism. Interestingly, we also identified more than 1,500 differences in gene expression that were dependent on the sex of the cell donor, some of which modified the insulin resistance effects. Many of these sex differences were associated with increased DNA methylation in cells from female donors and were reversed by 5-azacytidine. By contrast, the insulin sensitivity differences were not reversed and thus appear to reflect genetic or methylation-independent epigenetic effects.

中文翻译：

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胰岛素抵抗、表观遗传学和供体性别在 iPSC 衍生成肌细胞基因表达调控中的相互作用

一般人群中约 25% 的人存在胰岛素抵抗，这增加了患 2 型糖尿病 (T2D) 和代谢疾病的风险。对胰岛素抵抗 (I-Res) 与胰岛素敏感 (I-Sen) 非糖尿病个体分化为成肌细胞 (iMyos) 的诱导多能干细胞的转录组分析显示，I-Res 的 iMyos 中 306 个基因表达增加，271 个基因表达减少差异达 2 倍或以上的捐赠者。I-Res iMyos 中超过 30 个发生变化的基因通过 SNP 与 T2D 相关，并且在功能上与胰岛素作用和代谢控制相关。有趣的是，我们还发现了 1,500 多个基因表达差异，这些差异取决于细胞供体的性别，其中一些差异改变了胰岛素抵抗的影响。许多性别差异与女性供体细胞中 DNA 甲基化增加有关，并可被 5-氮杂胞苷逆转。相比之下，胰岛素敏感性差异并未逆转，因此似乎反映了遗传或甲基化无关的表观遗传效应。