Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus
Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus
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DOI：
10.1177/153537020322801018
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发表时间：
2003-11-01
影响因子：
3.2
通讯作者：
Mori, M
中科院分区：
文献类型：
--
作者：
Araki, E;Oyadomari, S;Mori, M
糖尿病是由胰腺β细胞中胰岛素分泌受损和外周胰岛素抵抗引起的。胰腺β细胞的超负荷导致β细胞衰竭，最终导致糖尿病的发展。在2型糖尿病中，β-细胞质量减少是明显的，并且细胞凋亡与该过程有关。β-细胞的一个特征性特征是由于大量参与胰岛素分泌而高度发达的内质网（ER）。ER具有几种重要的功能，包括翻译后修饰、折叠和新合成的分泌蛋白的组装，其适当的功能对细胞存活至关重要。各种条件可以干扰ER功能，这些条件称为ER应激。最近，我们发现一氧化氮（NO）诱导的β细胞凋亡是通过ER应激途径介导的。NO引起内质网应激，并通过诱导内质网应激相关凋亡因子CHOP而导致细胞凋亡。在胰岛素2基因中具有错义突变（Cys 96 Tyr）的秋田小鼠具有高血糖症和减少的β细胞质量。该突变破坏了胰岛素A和B链之间的二硫键，并可能诱导其构象变化。在秋田小鼠糖尿病的发展中，ER伴侣Bip和CHOP的mRNA在胰腺中被诱导。突变胰岛素在小鼠MIN 6 β细胞中的过表达诱导CHOP表达并导致细胞凋亡。CHOP基因的靶向破坏并没有延迟纯合子秋田小鼠糖尿病的发病，但它保护胰岛细胞免于凋亡，并延迟了杂合子秋田小鼠糖尿病的发病。我们的结论是，ER超载β细胞引起ER应激，并导致细胞凋亡，通过CHOP诱导。这些结果强调了慢性ER应激在2型糖尿病β细胞凋亡中的重要性，并提出了治疗该疾病的新靶点。
Diabetes is caused by impaired insulin secretion in pancreatic beta-cells and peripheral insulin resistance. Overload of pancreatic beta-cells leads to beta-cell exhaustion and finally to the development of diabetes. Reduced beta-cell mass is evident in type 2 diabetes, and apoptosis is implicated in this process. One characteristic feature of beta-cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important functions, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various conditions can interfere with ER function and these conditions are called ER stress. Recently, we found that nitric oxide (NO)-induced apoptosis in beta-cells is mediated by the ER-stress pathway. NO causes ER stress and leads to apoptosis through induction of ER stress-associated apoptosis factor CHOP. The Akita mouse with a missense mutation (Cys96Tyr) in the insulin 2 gene has hyperglycemia and a reduced beta-cell mass. This mutation disrupts a disulfide bond between A and B chains of insulin and may induce its conformational change. In the development of diabetes in Akita mice, mRNAs for an ER chaperone Bip and CHOP were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 beta-cells induced CHOP expression and led to apoptosis. Targeted disruption of the CHOP gene did not delay the onset of diabetes in the homozygous Akita mice, but it protected islet cells from apoptosis and delayed the onset of diabetes in the heterozygous Akita mice. We conclude that ER overload in beta-cells causes ER stress and leads to apoptosis via CHOP induction. These results highlight the importance of chronic ER stress in beta-cell apoptosis in type 2 diabetes, and suggest a new target to the management of the disease.