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