Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes.
Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes.
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DOI：
10.1186/gm130
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发表时间：
2010-02-01
期刊：
影响因子：
12.3
通讯作者：
Timmons JA
中科院分区：
文献类型：
--
作者：
Gallagher IJ;Scheele C;Keller P;Nielsen AR;Remenyi J;Fischer CP;Roder K;Babraj J;Wahlestedt C;Hutvagner G;Pedersen BK;Timmons JA
骨骼肌胰岛素抵抗（IR）被认为是II型糖尿病的重要组成部分，但迄今为止，IR在人类中的全球基因表达水平上一直没有得到表征。microRNA（miRNAs）被认为是蛋白质编码基因产物丰度的精细尺度变阻器。miRNAs在人类复杂疾病中的相对重要性和作用模式仍有待充分阐明。我们制作了人类肌肉IR中编码和非编码RNA的全球图谱，目的是鉴定新的疾病生物标志物。我们使用基因芯片和118名受试者（n = 71名患者与n = 47名对照）分析了> 47，000个mRNA序列和>500个人类miRNA。开发了一种组织特异性基因排序系统，用于对数千个miRNA靶基因进行分层，去除假阳性，产生加权抑制剂评分，该评分综合了上调和下调miRNA的净影响。信息学和蛋白质检测验证均用于验证体内变化的预测。肌肉mRNA转录组相对于胰岛素或葡萄糖稳态是不变的。相比之下，在肌肉中检测到的三分之一的miRNAs在疾病中发生了改变（n = 62），许多在临床糖尿病发作之前发生了变化。新的排名指标确定了六个典型的途径，证明与代谢疾病的联系，而对照数据表明没有富集。Benjamini-Hochberg校正后的基因本体图谱显示，最高等级的靶点是代谢（P < 7.4 × 10-8）、翻译后修饰（P < 9.7 × 10-5）和发育（P < 1.3 × 10-6）过程。六个发育相关基因的蛋白质谱验证了预测。脑源性神经营养因子蛋白仅在肌肉卫星细胞中检测到，并且与对照组相比，糖尿病患者中的脑源性神经营养因子蛋白增加，这与观察结果一致，即总体miRNA变化与肌源性分化期间发现的变化相反。我们提供的证据表明，人类的IR可能与多种microRNA的协调变化有关，这些microRNA作用于靶向相关信号通路。似乎miRNA可以通过以组合方式工作而在体内产生靶蛋白丰度的显著变化。因此，miRNA检测代表了胰岛素抵抗的一种新的分子生物标志物策略，其中需要微克的患者材料来监测药物或生活方式干预期间的疗效。
Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
DOI：
10.1098/rstb.1980.0061
发表时间：
1980-01-01
期刊：
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BROWN, TR
通讯作者：
BROWN, TR
DOI：
10.1073/pnas.0601752103
发表时间：
2006-04-25
影响因子：
11.1
作者：
Gesta, S;Blüher, M;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko