RNA-seq analysis in residual pancreatic β-cells of Bmal1KO/DTA mice following massive ablation

We aimed to fill the gap in understanding functional roles of the islet cellular oscillators under diabetic conditions following massive β-cell ablation, and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and transcriptional landscape in separated α- and residual β-cells -utilizing rtTA/TET-DTA mouse model that bears α- and β-cell specific labeling. Acute hyperglycemia and loss of β-cell mass perturbed absolute expression levels and temporal transcriptome profiles in residual β-cells, whereas in neighboring α-cells only changes in temporal profiles were observed. Strikingly, compensatory regeneration of β-cells exhibited circadian rhythmicity. In arrhythmic BMAL1 knockout mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal non-compensated diabetes. No activation of β-cell regeneration via entry into cell-cycle was observed in arrhythmic mice, suggesting essential role of functional circadian clocks in this process. mRNA from FACS-sorted residual β-cells from Bmal1KO/DTA and Bmal1+/-DTA mice following massive β-cell ablation induced by 10-day Doxycycline administration