High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress-mediated β-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes
High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress-mediated β-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes
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DOI：
10.2337/db07-0197
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发表时间：
2007-08-01
期刊：
影响因子：
7.7
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Huang, Chang-jiang;Lin, Chia-yu;Butler, Peter C.
目的：内质网（ER）应激诱导的细胞凋亡可能是淀粉样蛋白错误折叠和寡聚化为特征的疾病中细胞损耗的常见原因。2型糖尿病胰岛的特点是胰岛淀粉样蛋白来源于胰岛淀粉样蛋白多肽（IAPP）和β细胞凋亡增加。我们质疑：1)iapp诱导的β细胞凋亡是否由内质网应激介导；2)2型糖尿病β细胞是否以内质网应激为特征。研究设计与方法研究iapp诱导INS-1细胞和人IPP （HIP）转基因大鼠细胞凋亡的机制。通过解剖获得的7例瘦型非糖尿病患者、12例肥胖型非糖尿病患者和14例肥胖型2型糖尿病患者胰腺的β细胞C/EBP同源蛋白（CHOP）表达，研究了人内质网应激。为了确保2型糖尿病的特异性，我们还检查了8例1型糖尿病患者的胰腺。结果：iapp通过内质网应激诱导INS-1细胞和HIP大鼠β细胞凋亡。核周CHOP在瘦型非糖尿病患者中少见（2.6 +/- 2.0%），而在肥胖型非糖尿病患者（14.6 +/- 3.0%）和肥胖型糖尿病患者（18.5 +/- 3.6%）胰腺中更为常见。核CHOP在瘦型非糖尿病患者中未检出，在肥胖型非糖尿病患者中少见（0.08 +/- 0.04%），但在肥胖型糖尿病患者中发生率高6倍（P < 0.01）（0.49 +/- 0.17%）。1型糖尿病胰腺，核周CHOP罕见（2.5% +/- 2.3%），核周CHOP未检出。结论内质网应激是IAPP诱导β细胞凋亡的机制之一，是2型糖尿病患者β细胞的特征，而非1型糖尿病患者。这些发现与蛋白质错误折叠在2型糖尿病β细胞凋亡中的作用一致。
Objective-Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased beta-cell apoptosis. We questioned the following: 1) whether IAPP-induced beta-cell apoptosis is mediated by ER stress and 2) whether beta-cells in type 2 diabetes are characterized by ER stress.Research design and methods-The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IPP (HIP) transgenic rats. ER stress in humans was investigated by beta-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.Results-IAPP induces beta-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 +/- 2.0%) and more frequent in obese nondiabetic (14.6 +/- 3.0%) and obese diabetic (18.5 +/- 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 +/- 0.04%) but six times higher (P < 0.01) in obese diabetic (0.49 +/- 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 +/- 2.3%) and nuclear CHOP not detected.Conclusions-ER stress is a mechanism by which IAPP induces beta-cell apoptosis and is characteristic of beta-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in beta-cell apoptosis in type 2 diabetes.