Tsunekawa Shin, Yamamoto Naoki, Tsukamoto Katsura, Itoh Yuji, Kaneko Yukiko, Kimura Toshihide, Ariyoshi Yoh, Miura Yoshitaka, Oiso Yutaka, Niki Ichiro
Department of Endocrinology and Diabetes, School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
J Endocrinol. 2007 Apr;193(1):65-74. doi: 10.1677/JOE-06-0148.
The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic beta-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-1alpha, 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.
本研究的目的是探讨艾塞那肽-4（一种强效胰高血糖素样肽1激动剂）在体内和体外对胰腺β细胞的保护作用，防止其细胞死亡。在体内实验中，我们使用了β细胞特异性钙调蛋白过表达小鼠，其β细胞发生大量凋亡，我们研究了艾塞那肽-4长期治疗的效果。艾塞那肽-4长期皮下给药可降低高血糖。该治疗显著增加了胰腺和胰岛的胰岛素含量，并保留了胰岛素阳性区域。分散的转基因胰岛细胞存活时间很短，一些内质网（ER）应激相关分子，如免疫球蛋白结合蛋白（Bip）、肌醇需要酶-1α、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，ER应激的标志物XBP-1的剪接形式在β细胞特异性钙调蛋白过表达转基因胰岛中也增加。在定量实时PCR分析中，用艾塞那肽-4治疗的转基因小鼠胰岛中Bip和CHOP的表达水平降低。这些发现表明，转基因β细胞中发生了内质网应激，内质网应激的抑制以及由此产生的对细胞死亡的保护作用可能参与了艾塞那肽-4的抗糖尿病作用。
