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

Theranostics 2020

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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. © The author(s).

Citation

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. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells. Theranostics. 2020;10(9):4233-4249