PDF(Pubmed)
Abstract：
Diabetes mellitus (DM), is a chronic disorder characterized by impaired glucose homeostasis that results from the loss or dysfunction of pancreatic β-cells leading to type 1 diabetes (T1DM) and type 2 diabetes (T2DM), respectively. Pancreatic β-cells rely to a great degree on their endoplasmic reticulum (ER) to overcome the increased secretary need for insulin biosynthesis and secretion in response to nutrient demand to maintain glucose homeostasis in the body. As a result, β-cells are potentially under ER stress following nutrient levels rise in the circulation for a proper pro-insulin folding mediated by the unfolded protein response (UPR), underscoring the importance of this process to maintain ER homeostasis for normal β-cell function. However, excessive or prolonged increased influx of nascent proinsulin into the ER lumen can exceed the ER capacity leading to pancreatic β-cells ER stress and subsequently to β-cell dysfunction. In mammalian cells, such as β-cells, the ER stress response is primarily regulated by three canonical ER-resident transmembrane proteins: ATF6, IRE1, and PERK/PEK. Each of these proteins generates a transcription factor (ATF4, XBP1s, and ATF6, respectively), which in turn activates the transcription of ER stress-inducible genes. An increasing number of evidence suggests that unresolved or dysregulated ER stress signaling pathways play a pivotal role in β-cell failure leading to insulin secretion defect and diabetes. In this article we first highlight and summarize recent insights on the role of ER stress and its associated signaling mechanisms on β-cell function and diabetes and second how the ER stress pathways could be targeted in vitro during direct differentiation protocols for generation of hPSC-derived pancreatic β-cells to faithfully phenocopy all features of bona fide human β-cells for diabetes therapy or drug screening.
摘要：
糖尿病(DM),是一种慢性疾病，其特征是葡萄糖稳态受损，是由胰腺β细胞丢失或功能障碍导致的，导致1型糖尿病（T1DM）和2型糖尿病（T2DM），分别。胰腺β细胞在很大程度上依赖于它们的内质网(ER)来克服响应于营养需求而增加的胰岛素生物合成和分泌的秘书需求,以维持体内葡萄糖稳态。因此,在循环中营养水平升高后，β细胞可能处于ER应激下，由未折叠的蛋白质反应（UPR）介导的适当的胰岛素原折叠，强调这一过程对维持内质网稳态对正常β细胞功能的重要性。然而,新生胰岛素原流入内质网腔的过度或长时间增加可超过内质网容量,导致胰腺β细胞内质网应激,随后导致β细胞功能障碍.在哺乳动物细胞中,如β细胞，内质网应激反应主要由三种典型的内质网驻留跨膜蛋白调节:ATF6、IRE1和PERK/PEK。这些蛋白质中的每一种都会产生一个转录因子（ATF4，XBP1s，和ATF6分别)，进而激活ER应激诱导基因的转录。越来越多的证据表明，未解决或失调的ER应激信号通路在导致胰岛素分泌缺陷和糖尿病的β细胞衰竭中起关键作用。在本文中，我们首先强调并总结了有关ER应激及其相关信号传导机制对β细胞功能和糖尿病的作用的最新见解，其次是在直接分化方案中如何在体外靶向ER应激途径以产生hPSC衍生的胰腺β细胞，以忠实地表型复制真正的人β细胞的所有特征，用于糖尿病治疗或药物筛选。
