Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function

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In Wfs1−/− Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2 + response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.




Ohta, Y., Taguchi, A., Matsumura, T., Nakabayashi, H., Akiyama, M., Yamamoto, K., … Tanizawa, Y. (2017). Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function. EBioMedicine, 18, 146–156.

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