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

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