Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. To what extent this reflects a primary defect or is secondary to tissue cross talk due to changes in hormones or circulating metabolites is unknown. To address this question, we have developed an in vitro disease-in-a-dish model using iPS cells from T2D patients differentiated into myoblasts (iMyos). We find that T2D iMyos in culture exhibit multiple defects mirroring human disease, including an altered insulin signaling, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More strikingly, global phosphoproteomic analysis reveals a multidimensional network of signaling defects in T2D iMyos going beyond the canonical insulin-signaling cascade, including proteins involved in regulation of Rho GTPases, mRNA splicing and/or processing, vesicular trafficking, gene transcription, and chromatin remodeling. These cell-autonomous defects and the dysregulated network of protein phosphorylation reveal a new dimension in the cellular mechanisms underlying the fundamental defects in T2D.

骨骼肌胰岛素抵抗是 2 型糖尿病 (T2D) 中最早的缺陷，是疾病发展的先兆和预测因素。由于激素或循环代谢物的变化，这在多大程度上反映了原发性缺陷或继发于组织串扰，尚不清楚。为了解决这个问题，我们开发了一种体外使用来自 T2D 患者的 iPS 细胞分化为成肌细胞 (iMyos) 的疾病盘中模型。我们发现培养中的 T2D iMyos 表现出反映人类疾病的多种缺陷，包括改变的胰岛素信号传导、减少胰岛素刺激的葡萄糖摄取和减少线粒体氧化。更引人注目的是，全球磷酸化蛋白质组学分析揭示了 T2D iMyos 中信号缺陷的多维网络，超出了典型的胰岛素信号级联，包括参与 Rho GTPases 调节、mRNA 剪接和/或加工、囊泡运输、基因转录和染色质重塑的蛋白质. 这些细胞自主缺陷和失调的蛋白质磷酸化网络揭示了 T2D 基本缺陷背后的细胞机制的新维度。