The First Affiliated Hospital, Jinan University, Guangzhou, China.
Developmental Biology/Signal Transduction Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Diabetes. 2018 Dec;67(12):2615-2625. doi: 10.2337/db17-1330. Epub 2018 Sep 26.
Baseline β-cell mass is established during the early postnatal period when β-cells expand. In this study, we show that heterozygous ablation of decreases baseline β-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an background, glucose intolerance was more severe in mice compared with mice, although no further decrease in the β-cell mass was detected. In islets of early postnatal mice, the cell cycle was prolonged in β-cells due to downregulation of the cell cycle gene Although Insm1 had a low affinity for the promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the promoter after downregulation of expression. Furthermore, downregulation of resulted in a prolonged cell cycle, and overexpression of Ccnd1 rescued cell cycle abnormalities observed in Insm1-deficient β-cells. We conclude that decreases in Insm1 interfere with β-cell specification during the early postnatal period and impair glucose homeostasis during metabolic stress in adults. Insm1 levels are therefore a factor that can influence the development of diabetes.
基础β细胞质量是在β细胞扩增的新生儿后期建立的。在这项研究中，我们表明，杂合子缺失 会降低基础β细胞质量，随后损害葡萄糖耐量。与 相比，在高脂肪饮食或 背景下， 小鼠的葡萄糖耐量更差，尽管未检测到β细胞质量的进一步下降。在早期新生 小鼠的胰岛中，由于细胞周期基因 的下调，β细胞的细胞周期延长。尽管与其他结合位点相比，Insm1 对 启动子的亲和力较低，但结合亲和力强烈依赖于 Insm1 水平。我们观察到，在下调 的表达后，Insm1 与 启动子的结合明显减少。此外，下调 导致细胞周期延长，并且 Ccnd1 的过表达挽救了在 Insm1 缺陷型β细胞中观察到的细胞周期异常。我们得出结论，Insm1 的减少会干扰新生儿后期的β细胞特化，并在成年代谢应激期间损害葡萄糖稳态。因此，Insm1 水平是影响糖尿病发展的一个因素。
