Crucial roles of neuronatin in insulin secretion and high glucose-induced apoptosis in pancreatic β-cells
Crucial roles of neuronatin in insulin secretion and high glucose-induced apoptosis in pancreatic β-cells
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DOI：
10.1016/j.cellsig.2008.01.005
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发表时间：
2008-05-01
影响因子：
4.8
通讯作者：
Jung, Myeong Ho
中科院分区：
文献类型：
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作者：
Joe, Myung Kuk;Lee, Hyo Jung;Jung, Myeong Ho
Neuronatin（Nnat）最初被鉴定为新生儿脑中的选择性表达基因，但其表达也已在胰腺β细胞中被鉴定。因此，为了研究Nnat在胰腺β细胞中可能发挥的功能，使用腺病毒在鼠MIN 6 N8胰腺β细胞中表达两种Nnat同种型（α和β），并检查了Nnat对胰岛素分泌、高葡萄糖诱导的细胞凋亡和功能损害的细胞命运和作用。Nnat α和Nnat β主要定位于内质网（ER）中，并且它们的表达通过增加细胞内钙水平来增加胰岛素分泌。然而，在慢性高葡萄糖条件下，Nnat β与Nnat α的比率与暴露于高葡萄糖水平的时间成比例地逐渐增加。此外，腺病毒表达的Nnat β倾向于形成攻击体样结构，我们发现Nnat β聚集抑制蛋白酶体的功能。因此，当葡萄糖升高时，Nnat β的表达使MFN 6 N8细胞对高葡萄糖应激敏感，这进而引起ER应激。结果，Nnat β的表达增加了高血糖诱导的细胞凋亡。此外，高糖条件下Nnat β的表达降低了对β细胞功能重要的基因的表达，如葡萄糖激酶（GCK）、胰腺十二指肠同源框-1（PDX-1）和胰岛素。总的来说，Nnat可能在正常β细胞功能以及2型糖尿病的发病机制中发挥关键作用。(C)2008年爱思唯尔公司All rights reserved.
Neuronatin (Nnat) was initially identified as a selectively-expressed gene in neonatal brains, but its expression has been also identified in pancreatic beta-cells. Therefore, to investigate the possible functions that Nnat may serve in pancreatic beta-cells, two Nnat isotypes (alpha and beta) were expressed using adenoviruses in murine MIN6N8 pancreatic beta-cells, and the cellular fates and the effects of Nnat on insulin secretion, high glucose-induced apoptosis, and functional impairment were examined. Nnat alpha and Nnat beta were primarily localized in the endoplasmic reticulum (ER), and their expressions increased insulin secretion by increasing intracellular calcium levels. However, under chronic high glucose conditions, the Nnat beta to Nnat alpha ratio gradually increased in proportion to the length of exposure to high glucose levels. Moreover, adenovirally-expressed Nnat beta was inclined to form aggresome-like structures, and we found that Nnat beta aggregation inhibited the function of the proteasome. Therefore, when glucose is elevated, the expression of Nnat beta sensitizes MFN6N8 cells to high glucose stress, which in turn, causes ER stress. As a result, expression of Nnat beta increased hyperglycemia-induced apoptosis. In addition, the expression of Nnat beta under high glucose conditions decreased the expression of genes important for beta-cell function, such as glucokinase (GCK), pancreas duodenum homeobox-1 (PDX-1), and insulin. Collectively, Nnat may play a critical factor in normal beta-cell function, as well as in the pathogenesis of type 2 diabetes. (C) 2008 Elsevier Inc. All rights reserved.