Theranostics 2020; 10(9):4233-4249. doi:10.7150/thno.40664 This issue Cite

Research Paper

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

Sy-Ying Leu1*, Li-Hua Kuo1,2*, Wen-Tsan Weng1*, I-Chia Lien1*, Ching-Chun Yang1, Tai-Tzu Hsieh1, Yi-Ning Cheng1, Po-Hsiu Chien3, Li-Chun Ho1,7, Shun-Hua Chen4, Yan-Shen Shan1,8,9, Yun-Wen Chen5, Pei-Jane Tsai6, Junne-Ming Sung10, Yau-Sheng Tsai1,2,3,8✉

1. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Taiwan, ROC;
2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan, ROC;
3. Department of Physiology, College of Medicine, National Cheng Kung University, Taiwan, ROC;
4. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Taiwan, ROC;
5. Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan, ROC;
6. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Taiwan, ROC;
7. School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, ROC;
8. Center for Clinical Medicine Research, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
9. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
10. Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
*Contributed equally to this work

Citation:
Leu SY, Kuo LH, Weng WT, Lien IC, Yang CC, Hsieh TT, Cheng YN, Chien PH, Ho LC, Chen SH, Shan YS, Chen YW, Tsai PJ, Sung JM, Tsai YS. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics 2020; 10(9):4233-4249. doi:10.7150/thno.40664. https://www.thno.org/v10p4233.htm
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Abstract

Graphic abstract

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.

Keywords: β-cell compensation, β-cell identity, immediate genes, islet failure, stimulus-response coupling


Citation styles

APA
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.

ACS
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. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics 2020, 10 (9), 4233-4249. DOI: 10.7150/thno.40664.

NLM
Leu SY, Kuo LH, Weng WT, Lien IC, Yang CC, Hsieh TT, Cheng YN, Chien PH, Ho LC, Chen SH, Shan YS, Chen YW, Tsai PJ, Sung JM, Tsai YS. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics 2020; 10(9):4233-4249. doi:10.7150/thno.40664. https://www.thno.org/v10p4233.htm

CSE
Leu SY, Kuo LH, Weng WT, Lien IC, Yang CC, Hsieh TT, Cheng YN, Chien PH, Ho LC, Chen SH, Shan YS, Chen YW, Tsai PJ, Sung JM, Tsai YS. 2020. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics. 10(9):4233-4249.

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