Raptor regulates functional maturation of murine beta cells.
Raptor regulates functional maturation of murine beta cells.
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Raptor 调节小鼠 β 细胞的功能成熟
DOI：
10.1038/ncomms15755
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发表时间：
2017-06-09
影响因子：
16.6
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Ni Q;Gu Y;Xie Y;Yin Q;Zhang H;Nie A;Li W;Wang Y;Ning G;Wang W;Wang Q
糖尿病与β细胞质量损失和胰岛功能障碍有关。 mTORC1 在生理和病理条件下（例如妊娠和胰腺切除术）调节 β 细胞的存活、增殖和功能。在这里，我们发现，胰岛素表达细胞中 mTORC1 的重要组成部分 Raptor 的缺失会促进低胰岛素血症和葡萄糖耐受不良。Raptor 缺陷的 β 细胞表现出葡萄糖反应性降低，并表现出类似于胎儿 β 细胞的葡萄糖代谢特征。敲除的胰岛降低了功能成熟关键因子的表达，并上调了新生儿标记物和β细胞不允许的基因，导致功能成熟度丧失。从机制上讲，Raptor 缺陷型 β 细胞表现出 DNA 甲基转移酶 3a 表达降低，并且参与抑制不允许基因的基因座的 DNA 甲基化模式发生改变。目前的研究结果强调了 mTORC1 作为控制出生后 β 细胞成熟和成年期间生理 β 细胞质量的核心机制的新作用。
Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion ofRaptor, which is an essential component of mTORC1, in insulin-expressing cells promotes hypoinsulinemia and glucose intolerance.Raptor-deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically,Raptor-deficient beta cells show reduced expression of DNA-methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood.