Loss of EGR-1 uncouples compensatory responses of pancreatic β cells

Sy Ying Leu, Li Hua Kuo, Wen Tsan Weng, I. Chia Lien, Ching Chun Yang, Tai Tzu Hsieh, Yi Ning Cheng, Po Hsiu Chien, Li Chun Ho, Shun Hua Chen, Yan Shen Shan, Yun Wen Chen, Pei Jane Tsai, Junne Ming Sung, Yau Sheng Tsai

研究成果: Article

摘要

Rationale: Subjects unable to sustain β-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence β-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for β-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of β-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of β-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.

原文English
頁(從 - 到)4233-4249
頁數17
期刊Theranostics
10
發行號9
DOIs
出版狀態Published - 2020

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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    Leu, S. Y., Kuo, L. H., Weng, W. T., Lien, I. C., Yang, C. C., Hsieh, T. T., Cheng, Y. N., Chien, P. H., Ho, L. C., Chen, S. H., Shan, Y. S., Chen, Y. W., Tsai, P. J., Sung, J. M., & Tsai, Y. S. (2020). Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics, 10(9), 4233-4249. https://doi.org/10.7150/thno.40664