Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress;: in vivo and in vitro studies
Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress;: in vivo and in vitro studies
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DOI：
10.1677/joe-06-0148
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发表时间：
2007-04-01
影响因子：
4
通讯作者：
Niki, Ichiro
中科院分区：
文献类型：
--
作者：
Tsunekawa, Shin;Yamamoto, Naoki;Niki, Ichiro
本研究的目的是调查exendin-4，一种有效的胰高血糖素样肽I激动剂，对胰腺P细胞的保护作用，防止其细胞死亡的体内和体外效应。在体内实验中，我们使用了β细胞特异性钙调素过表达小鼠，在这些小鼠的β细胞中发生了大量凋亡，我们检查了用exendin-4长期治疗的效果。慢性和皮下施用毒蜥外泌肽-4降低了高血糖症。治疗引起胰腺和胰岛的胰岛素含量显著增加，并保留胰岛素阳性区域。分散的转基因胰岛细胞仅存活很短时间，并且几种内质网（ER）应激相关分子如免疫球蛋白结合蛋白（Bip）、肌醇需要酶-1 α、X盒结合蛋白-1（XBP-1）、RNA激活蛋白激酶样内质网激酶、激活转录因子-4和C/EBP同源蛋白（CHOP）在转基因胰岛中表达更多。我们还发现，XBP-1的剪接形式，ER应激的标志物，也增加了β细胞特异性钙调素过表达转基因胰岛。在定量实时PCR分析中，Bip和CHOP的表达水平在用exendin-4处理的转基因小鼠的胰岛中降低。这些发现表明，过量的ER应激发生在转基因β-细胞中，并且ER应激的抑制和由此产生的针对细胞死亡的保护可能涉及exendin-4的抗糖尿病作用。
The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide I agonist, on the protection of the pancreatic P-cells against their cell death. In in vivo experiments, we used beta-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their beta-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1 alpha, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in beta-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic beta-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.