Metabolic Stress and Compromised Identity of Pancreatic Beta Cells.
Metabolic Stress and Compromised Identity of Pancreatic Beta Cells.
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DOI：
10.3389/fgene.2017.00021
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发表时间：
2017
影响因子：
3.7
通讯作者：
Dor Y
中科院分区：
文献类型：
--
作者：
Swisa A;Glaser B;Dor Y
β 细胞衰竭是 2 型糖尿病 (T2D) 的一个核心特征，但该过程的分子基础仍然只有部分了解。有人认为，T2D 中的 β 细胞衰竭涉及大量细胞死亡。其他研究将β细胞衰竭归因于细胞耗竭，这是由于慢性氧化或内质网应激导致细胞功能障碍。最近有人提出，T2D 中的 β 细胞可能会失去其分化特性，甚至可能获得其他胰岛细胞类型的特征。 β细胞身份的丧失似乎是由糖毒性抑制关键β细胞转录因子（包括Pdx1、Nkx6.1、MafA和Pax6）的活性引起的，从而沉默了β细胞基因并解除了替代胰岛细胞基因的抑制。血糖正常化后，β 细胞特性的丧失至少部分是可逆的，这对 T2D 的可逆性产生影响，尽管尚不清楚 β 细胞衰竭最终是否会达到不可逆转的程度。在这篇综述中，我们讨论了代谢驱动的受损 β 细胞身份的当前证据、关键知识差距以及在 T2D 治疗中的实用机会。
Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D.