Aldh1b1 controlled timing of pancreas specification is important for beta cell functionality and glucose homeostasis in the adult

Aims/hypothesis Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. Methods We generated an Aldh1b1-knockout mouse line (Aldh1b1tm1lacZ) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. Results Differentiation in the developing pancreas of Aldh1b1tm1lacZ null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. Conclusions/interpretation These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Islets were isolated from postnatal day one and 8 week old Aldh1b1 null and wt mice. For each P1 samples islets from three mice were combined. Each week 8 sample came from a single mouse. Three samples were analysed per genotype and time point研究目的与假说：胰腺β细胞可维持葡萄糖稳态，β细胞功能障碍是糖尿病发生的主要危险因素。因此，解析调控成熟功能β细胞形成的发育调控网络，对于阐明该疾病的遗传起源具有重要意义。乙醛脱氢酶活性与干/祖细胞存在关联，我们既往研究已证实Aldh1b1特异性表达于胰腺祖细胞群中。本研究旨在验证这一假说：Aldh1b1可调控β细胞的出现时机及其最终功能成熟状态。 研究方法：我们构建了Aldh1b1敲除小鼠品系（Aldh1b1tm1lacZ），并利用该模型探究缺失Aldh1b1功能时的胰腺发育、β细胞功能及葡萄糖稳态变化。 研究结果：Aldh1b1tm1lacZ纯合敲除小鼠的胚胎胰腺分化进程被加速。对新生及成年小鼠胰岛进行转录组分析发现，核心β细胞转录因子及调控β细胞功能的关键基因均出现表达失调。功能分析结果显示，从纯合敲除小鼠体内分离的胰岛中，葡萄糖刺激的胰岛素分泌功能受到严重损害。β细胞功能的多项核心特征均受到影响，包括氧化应激调控、葡萄糖感知、刺激-分泌耦联以及分泌颗粒生物合成。由于β细胞功能障碍，纯合敲除小鼠出现糖耐量异常，并随年龄增长发展为高血糖症。 结论与阐释：本研究结果表明，Aldh1b1可调控胰腺内分泌祖细胞向定型β细胞转化的时机；同时证实，该转化时机的异常会导致β细胞功能障碍，进而在晚年成为糖尿病的危险因素。 本研究从出生后1天及8周龄的Aldh1b1纯合敲除小鼠与野生型（wild type，wt）小鼠体内分离胰岛。对于每份出生后1天（P1）的样本，将3只小鼠的胰岛进行混合；对于8周龄样本，每份样本取自1只小鼠。每种基因型及每个时间点均分析3份样本。