A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes.
A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes.
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DOI：
10.1016/j.cmet.2020.08.007
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发表时间：
2020-11-03
期刊：
影响因子：
29
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Batista TM;Jayavelu AK;Wewer Albrechtsen NJ;Iovino S;Lebastchi J;Pan H;Dreyfuss JM;Krook A;Zierath JR;Mann M;Kahn CR
骨骼肌胰岛素抵抗是2型糖尿病（T2D）最早的缺陷，预示着疾病的发展。这在多大程度上反映了原发性缺陷，还是由于激素或循环代谢物的变化而继发于组织串扰，目前尚不清楚。为了解决这个问题，我们开发了一种体外疾病培养皿模型，使用从T2D患者分化成成肌细胞（iMyo）的iPS细胞。我们发现培养中的T2D iMyos表现出与人类疾病类似的多种缺陷，包括胰岛素信号传导改变、胰岛素刺激的葡萄糖摄取减少和线粒体氧化减少。更令人惊讶的是，全球磷蛋白组学分析揭示了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rho - gtpase调节、mRNA剪接/加工、囊泡运输、基因转录和染色质重塑。这些细胞自主缺陷和蛋白质磷酸化失调网络揭示了T2D基本缺陷背后的细胞机制的新维度。
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 crosstalk 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 (iMyo). We find that T2D iMyos in culture exhibit multiple defects mirroring human disease, including altered insulin signaling, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More striking, global phosphoproteomic analysis reveals a multi-dimensional network of signaling defects in T2D iMyos going beyond the canonical insulin signaling cascade and including proteins involved in regulation of Rho-GTPases, mRNA splicing/processing, vesicular trafficking, gene transcription and chromatin-remodeling. These cell-autonomous defects and dysregulated network of protein phosphorylation reveal a new dimension in the cellular mechanisms underlying the fundamental defects in T2D.
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