The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas

Genes Dev. 2020 Dec 1;34(23-24):1650-1665. doi: 10.1101/gad.343137.120. Epub 2020 Nov 12.


Circadian clocks in pancreatic islets participate in the regulation of glucose homeostasis. Here we examined the role of these timekeepers in β-cell regeneration after the massive ablation of β cells by doxycycline-induced expression of diphtheria toxin A (DTA) in Insulin-rtTA/TET-DTA mice. Since we crossed reporter genes expressing α- and β-cell-specific fluorescent proteins into these mice, we could follow the fate of α- and β cells separately. As expected, DTA induction resulted in an acute hyperglycemia, which was accompanied by dramatic changes in gene expression in residual β cells. In contrast, only temporal alterations of gene expression were observed in α cells. Interestingly, β cells entered S phase preferentially during the nocturnal activity phase, indicating that the diurnal rhythm also plays a role in the orchestration of β-cell regeneration. Indeed, in arrhythmic Bmal1-deficient mice, which lack circadian clocks, no compensatory β-cell proliferation was observed, and the β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia, and fatal diabetes.

Keywords: Insulin-rtTA/TET-DTA mouse model; circadian clockwork; diabetes; glucose metabolism; pancreatic α and β cells; β-cell proliferation; β-cell regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Cell Proliferation / genetics
  • Circadian Rhythm
  • Glucagon-Secreting Cells / cytology
  • Insulin-Secreting Cells / cytology*
  • Mice
  • Pancreas / physiology*
  • Regeneration / genetics*
  • Transcriptome


  • ARNTL Transcription Factors
  • Arntl protein, mouse