The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis.

Abstract

The sequential secretion of insulin and glucagon delicately maintains glucose homeostasis by inhibiting or enhancing hepatic gluconeogenesis during postprandial or fasting states, respectively. Increased glucagon/insulin ratio is believed to be a major cause of the hyperglycemia seen in type 2 diabetes. Herein, we reveal that the early growth response gene-1 (Egr-1) can be transiently activated by glucagon in hepatocytes, which mediates glucagon-regulated gluconeogenesis by increasing the expression of gluconeogenesis genes. Blockage of Egr-1 function in the liver of mice led to lower fasting blood glucose, better pyruvate tolerance, and higher hepatic glycogen content. The mechanism analysis demonstrated that Egr-1 can directly bind to the promoter of C/EBPa and regulate the expression of gluconeogenesis genes in the later phase of glucagon stimulation. The transient increase of Egr-1 by glucagon kept the glucose homeostasis after fasting for longer periods of time, whereas constitutive Egr-1 elevation found in the liver of db/db mice and high serum glucagon level overactivated the C/EBPa/gluconeogenesis pathway and resulted in hyperglycemia. Blockage of Egr-1 activation in prediabetic db/db mice was able to delay the progression of diabetes. Our results suggest that dysregulation of Egr-1/C/EBPa on glucagon stimulation may provide an alternative mechanistic explanation for type 2 diabetes.

• Authors: Ning Shen, Shan Jiang, Jia-Ming Lu, Xiao Yu, Shan-Shan Lai, Jing-Zi Zhang, Jin-Long Zhang, Wei-Wei Tao, Xiu-Xing Wang, Na Xu, Bin Xue, Chao-Jun Li
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 2 Pg. 513-23 (Feb 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25438063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, mouse
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Glucagon
• Glucose

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (metabolism)
• Diabetes Mellitus, Experimental (metabolism, pathology)
• Diabetes Mellitus, Type 2 (metabolism, pathology)
• Early Growth Response Protein 1 (metabolism)
• Glucagon (metabolism)
• Gluconeogenesis
• Glucose (metabolism)
• Liver (metabolism, pathology)
• Male
• Mice