Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling
Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling
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DOI：
10.1016/j.cmet.2006.03.006
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发表时间：
2006-05-01
期刊：
影响因子：
29
通讯作者：
Chanda, Surnit K.
中科院分区：
文献类型：
--
作者：
Cho, Charles Y.;Koo, Seung-Hoi;Chanda, Surnit K.
胰岛素抵抗是2型糖尿病的主要缺陷，其特征在于外周葡萄糖摄取受损和肝脏葡萄糖输出抑制不足。胰岛素信号通过以Akt依赖性方式诱导促细胞生成转录因子FOXO 1的核排斥来抑制肝脏葡萄糖产生。通过同时应用基因组规模的功能筛选和定量图像分析，我们已经确定PTP-MEG 2作为胰岛素依赖性FOXO 1亚细胞定位的调节剂。细胞中PTP-MEG 2的异位表达抑制胰岛素诱导的胰岛素受体磷酸化，而RNAi介导的PTP-MEG 2转录水平的降低增强胰岛素作用。此外，腺病毒介导的糖尿病（db/db）小鼠肝脏中PTP-MEG 2的耗竭导致胰岛素敏化和高血糖症的正常化。这些数据暗示PTP-MEG 2通过拮抗胰岛素信号传导作为血糖稳态的介导剂，并表明PTP-MEG 2活性的调节可能是治疗2型糖尿病的有效策略。
Insulin resistance is a primary defect in type 2 diabetes characterized by impaired peripheral glucose uptake and insufficient suppression of hepatic glucose output. Insulin signaling inhibits liver glucose production by inducing nuclear exclusion of the gluconeogenic transcription factor FOXO1 in an Akt-dependent manner. Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes.