Pancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4–NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.

胰腺 β 细胞负责响应血糖水平的升高而产生和分泌胰岛素。β 细胞功能缺陷会导致高血糖症和糖尿病。在这里，我们发现 CNOT3，一种 CCR4–NOT 脱腺苷酶复合亚基，在糖尿病db/db小鼠的胰岛中失调，并且它对鼠 β 细胞的成熟和识别至关重要。具有 β 细胞特异性Cnot3缺失 ( Cnot3 βKO) 的小鼠表现出葡萄糖耐量降低、β 细胞量减少，并且它们逐渐发展为糖尿病。Cnot3βKO 胰岛显示 β 细胞成熟和功能的关键调节因子表达降低。此外，它们显示祖细胞标记物、β 细胞不允许的基因和与改变的 β 细胞功能相关的基因增加。Cnot3 βKO 胰岛表现出改变的去腺苷酸化和增加的 mRNA 稳定性，部分解释了这些基因的表达增加。总之，这些数据表明 CNOT3 介导的 mRNA 脱腺苷酸化和衰变构成了以前未曾怀疑的对 β 细胞身份至关重要的转录后机制。