Egr-1 transcriptionally activates protein phosphatase PTP1B to facilitate hyperinsulinemia-induced insulin resistance in the liver in type 2 diabetes
Egr-1 transcriptionally activates protein phosphatase PTP1B to facilitate hyperinsulinemia-induced insulin resistance in the liver in type 2 diabetes
复制标题
Egr-1转录激活蛋白磷酸酶PTP1B以促进2型糖尿病患者肝脏中高胰岛素血症诱导的胰岛素抵抗
DOI：
10.1002/1873-3468.13537
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发表时间：
2019
期刊：
影响因子：
3.5
通讯作者：
Li Chaojun
中科院分区：
文献类型：
--
作者：
Wu Jing;Tao Weiwei;Bu D;an;Zhao Yue;Zhang Tongyu;Chong Danyang;Xue Bin;Xing Zheng;Li Chaojun
在2型糖尿病（T2DM）的发展过程中，高胰岛素血症是最早的症状。人们认为，长期高胰岛素刺激可能会促进肝脏的胰岛素抵抗，但其潜在机制仍不清楚。在此，我们报道高胰岛素血症可以诱导肝细胞中持续的早期生长反应基因-1（Egr-1）激活，通过诱导蛋白酪氨酸磷酸酶-1B（PTP1B）的表达来提供胰岛素敏感性的负反馈抑制。肝脏中 Egr-1 的缺失显着降低了葡萄糖的产生，从而改善了全身葡萄糖耐量和胰岛素敏感性。机制分析表明Egr-1通过直接激活肝脏中的PTP1B转录来抑制胰岛素受体磷酸化。我们的结果揭示了在 T2DM 进展过程中高胰岛素血症加速肝细胞胰岛素抵抗的分子机制。
During the development of type 2 diabetes mellitus (T2DM), hyperinsulinemia is the earliest symptom. It is believed that long‐term high insulin stimulation might facilitate insulin resistance in the liver, but the underlying mechanism remains unknown. Herein, we report that hyperinsulinemia could induce persistent early growth response gene‐1 (Egr‐1) activation in hepatocytes, which provides negative feedback inhibition of insulin sensitivity by inducing the expression of protein tyrosine phosphatase‐1B (PTP1B). Deletion of Egr‐1 in the liver remarkably decreases glucose production, thus improving systemic glucose tolerance and insulin sensitivity. Mechanistic analysis indicates that Egr‐1 inhibits insulin receptor phosphorylation by directly activating PTP1B transcription in the liver. Our results reveal the molecular mechanism by which hyperinsulinemia accelerates insulin resistance in hepatocytes during the progression of T2DM.