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

EBioMedicine. 2017 Apr;18:146-156. doi: 10.1016/j.ebiom.2017.03.040. Epub 2017 Mar 30.


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.

Keywords: Clock out-put gene; Diabetes mellitus; Endoplasmic reticulum stress; Insulin secretion; Pancreatic islet β-cell.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • CLOCK Proteins / genetics*
  • CLOCK Proteins / metabolism
  • Calcium / analysis
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress*
  • Glucose Tolerance Test
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Promoter Regions, Genetic
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Basic-Leucine Zipper Transcription Factors
  • DBP protein, human
  • DNA-Binding Proteins
  • Ins1 protein, mouse
  • Insulin
  • Membrane Proteins
  • NFIL3 protein, human
  • Transcription Factors
  • wolframin protein
  • CLOCK Proteins
  • CLOCK protein, human
  • Calcium