Cho Charles Y, Koo Seung-Hoi, Wang Yan, Callaway Scott, Hedrick Susan, Mak Puiying A, Orth Anthony P, Peters Eric C, Saez Enrique, Montminy Marc, Schultz Peter G, Chanda Sumit K
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Cell Metab. 2006 May;3(5):367-78. doi: 10.1016/j.cmet.2006.03.006.
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.
胰岛素抵抗是2型糖尿病的主要缺陷，其特征为外周葡萄糖摄取受损和肝脏葡萄糖输出抑制不足。胰岛素信号传导通过以Akt依赖的方式诱导糖异生转录因子FOXO1的核排除来抑制肝脏葡萄糖生成。通过同时应用基因组规模的功能筛选和定量图像分析，我们已确定PTP-MEG2为胰岛素依赖的FOXO1亚细胞定位的调节剂。PTP-MEG2在细胞中的异位表达抑制了胰岛素诱导的胰岛素受体磷酸化，而RNA干扰介导的PTP-MEG2转录水平降低增强了胰岛素作用。此外，腺病毒介导的糖尿病（db/db）小鼠肝脏中PTP-MEG2的缺失导致胰岛素敏感性增加和高血糖正常化。这些数据表明PTP-MEG2通过拮抗胰岛素信号传导作为血糖稳态的介质，并表明调节PTP-MEG2活性可能是治疗2型糖尿病的有效策略。
