Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass.
Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass.
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DOI：
10.1007/s00125-018-4743-7
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发表时间：
2019-01
期刊：
影响因子：
8.2
通讯作者：
Biden TJ
中科院分区：
文献类型：
--
作者：
Cantley J;Davenport A;Vetterli L;Nemes NJ;Whitworth PT;Boslem E;Thai LM;Mellett N;Meikle PJ;Hoehn KL;James DE;Biden TJ
胰腺β细胞分泌胰岛素以维持葡萄糖稳态，β细胞衰竭是2型糖尿病的标志。葡萄糖通过氧化线粒体途径触发β细胞中的胰岛素分泌。然而，它也提供线粒体回补途径，通过乙酰辅酶A羧化酶1（ACC 1）驱动柠檬酸盐输出和细胞溶质丙二酰辅酶A生产。该途径已被提出作为替代葡萄糖敏感机制，主要由体外数据支持。在这里，我们试图解决β细胞ACC 1偶联途径在体内胰岛素分泌和葡萄糖稳态中的作用。使用Cre/loxP系统在小鼠的β细胞中缺失编码ACC 1（胰岛中的主要ACC同种型）的Acaca。Acaca floxed小鼠与Ins 2cre小鼠（β ACC 1 KO;终身β细胞基因缺失）或Pdx 1creER小鼠（tmx-β ACC 1 KO;成年β细胞中的诱导型基因缺失）杂交。使用体内代谢生理学和离体胰岛实验评估β细胞功能。使用组织学技术分析β细胞质量。β ACC 1 KO和tmx-β ACC 1 KO小鼠是葡萄糖不耐受的，并且在体内具有胰岛素分泌缺陷。分离的胰岛研究确定β细胞的胰岛素分泌受损，与先前作为扩增信号的中性脂质丰度的变化无关。胰腺形态测定意外地显示β ACC 1 KO小鼠中β细胞大小减小，但在tmx-β ACC 1 KO小鼠中没有，与雷帕霉素激酶（mTOR）依赖性蛋白翻译途径的机制靶点相关的蛋白水平降低，支持了这种效应。我们的研究表明，β细胞ACC 1偶联途径是至关重要的胰岛素分泌在体内和体外，它是必不可少的葡萄糖稳态。我们进一步揭示了ACC 1在成年前控制β细胞生长中的作用。本文的在线版本（10.1007/s 00125 -018-4743-7）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. βACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood. The online version of this article (10.1007/s00125-018-4743-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
4.8
作者：
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通讯作者：
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