An Early Response Transcription Factor, Egr-1, Enhances Insulin Resistance in Type 2 Diabetes with Chronic Hyperinsulinism

Fei-Yan Pan,Xiang Gao,Chao-Jun Li,Xiao Yu,Bin Xue,Ning Shen

doi:10.1074/jbc.m110.190165

Fei-Yan Pan, Xiang Gao + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m110.190165

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Abstract

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.

Highlights

If insulin resistance worsens, the glucose levels will begin to rise, both of which are major symptoms of type 2 diabetes mellitus
In Adipocytes, early growth responsive gene-1 (Egr-1) Participated in Insulin Resistance Induced by Long Term Exposure to Insulin—Before the patients are clinically diagnosed as type 2 diabetes mellitus, they are typically exposed to chronic hyperinsulinism stress, which occurs with a sustained, above normal level of insulin
To determine whether the Egr-1/geranylgeranyl diphosphate synthase (GGPPS)/Erk1/2 pathway is essential for the responses to insulin that occur during hyperinsulinism, we introduced a dnEgr-1 adenovirus (Fig. 6B), GGPPS siRNA (Fig. 6C), and U0126, a MAPK/Erk kinase inhibitor (Fig. 6D), into insulin-resistant adipocytes to block the components of this pathway

Summary

Introduction

If insulin resistance worsens, the glucose levels will begin to rise, both of which are major symptoms of type 2 diabetes mellitus. Loss of Egr-1 function in the insulin-resistant adipocytes reduced the phosphorylation of IRS-1 on Ser612, thereby restoring the activity of IRS-1, the PI3K/Akt pathway, and glucose uptake. Our results suggest that the Egr-1/GGPPS/ Erk1/2 pathway may be a promising target for the development of pharmacological inhibitors designed to prevent insulin resistance and increase insulin sensitivity in type 2 diabetes mellitus.

Results

Conclusion