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.

中文翻译：

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核心时钟转录因子BMAL1在内分泌胰腺的代偿性再生过程中驱动昼夜节律性β细胞增殖

胰岛的生物钟参与葡萄糖稳态的调节。在这里，我们检查了这些计时器在胰岛素-rtTA / TET-DTA小鼠中强力霉素诱导的白喉毒素A（DTA）表达引起的β细胞大量消融后在β细胞再生中的作用。由于我们将表达α-和β-细胞特异性荧光蛋白的报告基因转入这些小鼠，因此我们可以分别追踪α-和β-细胞的命运。不出所料，DTA诱导导致急性高血糖症，并伴有残留β细胞中基因表达的急剧变化。相反，在α细胞中仅观察到基因表达的时间变化。有趣的是，β细胞在夜间活动阶段优先进入S期，这表明昼夜节律在协调β细胞再生中也起作用。确实，在心律不齐中缺乏昼夜节律的Bmal1缺陷小鼠，未观察到代偿性β细胞增殖，β细胞消融导致高血糖，高血糖素血症和致命性糖尿病加重。