An Early Response Transcription Factor, Egr-1, Enhances Insulin Resistance in Type 2 Diabetes with Chronic Hyperinsulinism
An Early Response Transcription Factor, Egr-1, Enhances Insulin Resistance in Type 2 Diabetes with Chronic Hyperinsulinism
复制标题
早期反应转录因子 Egr-1 可增强伴有慢性高胰岛素血症的 2 型糖尿病患者的胰岛素抵抗
DOI：
10.1074/jbc.m110.190165
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发表时间：
2011-04-22
影响因子：
4.8
通讯作者：
Li, Chao-Jun
中科院分区：
文献类型：
--
作者：
Shen, Ning;Yu, Xiao;Li, Chao-Jun
2型糖尿病最重要的特征之一是胰岛素抵抗，在此期间，患者通常经历高胰岛素应激，这将改变胰岛素靶组织中的胰岛素信号转导。我们以前发现，早期生长反应基因-1（Egr-1），一种锌指转录因子，在db/db小鼠和2型糖尿病个体的脂肪组织中高度表达。在这份报告中，我们发现，长期暴露于高胰岛素血症引起脂肪细胞中持续的Erk/MAPK活性，并以Egr-1依赖的方式增强胰岛素抵抗。Egr-1的升高通过香叶基香叶基二磷酸合酶（GGPPS）增强Erk 1/2的激活。Egr-1促进的GGPPS转录增加Ras异戊烯化并引起Erk 1/2激活。Erk 1/2的持续激活导致胰岛素受体底物-1在丝氨酸612处的磷酸化。该位点的磷酸化损害了脂肪细胞中的胰岛素信号传导并降低了葡萄糖摄取。胰岛素抵抗脂肪细胞中Egr-1功能的丧失、GGPPS的敲低或Erk 1/2活性的抑制恢复了胰岛素受体底物-1酪氨酸磷酸化并增加了胰岛素敏感性。我们的研究结果表明，Egr-1/GGPPS/Erk 1/2途径是负责高胰岛素血症期间的胰岛素抵抗的新机制。该途径为增加胰岛素敏感性提供了新的治疗靶点：抑制Egr-1的功能。
One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.