Egr-1 transcriptionally activates protein phosphatase PTP1B to facilitate hyperinsulinemia-induced insulin resistance in the liver in type 2 diabetes

FEBS Letters

article

Jing Wu¹  Weiwei Tao¹  Dandan Bu¹  Yue Zhao¹  Tongyu Zhang¹  Danyang Chong¹  Bin Xue³  Zheng Xing¹  Chaojun Li¹ 

[1] Medical School of Nanjing University;Model Animal Research Center, Nanjing University;Core Laboratory, Sir Run Run Hospital, Nanjing Medical University

关键词: Egr-1;    hyperinsulinemia;    insulin resistance;    insulin signaling;    liver;    PTP1B;   

DOI  :  10.1002/1873-3468.13537

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown