Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Dis Model Mech. 2013 Sep;6(5):1236-45. doi: 10.1242/dmm.012591. Epub 2013 Jul 4.
Streptozotocin (STZ), a glucosamine-nitrosourea compound, has potent genotoxic effects on pancreatic β-cells and is frequently used to induce diabetes in experimental animals. Glucagon-like peptide-1 (GLP-1) has β-cell protective effects and is known to preserve β-cells from STZ treatment. In this study, we analyzed the mechanisms of STZ-induced diabetes and GLP-1-mediated β-cell protection in STZ-treated mice. At 1 week after multiple low-dose STZ administrations, pancreatic β-cells showed impaired insulin expression, while maintaining expression of nuclear Nkx6.1. This was accompanied by significant upregulation of p53-responsive genes in islets, including a mediator of cell cycle arrest, p21 (also known as Waf1 and Cip1). STZ treatment also suppressed expression of a wide range of genes linked with key β-cell functions or diabetes development, such as G6pc2, Slc2a2 (Glut2), Slc30a8, Neurod1, Ucn3, Gad1, Isl1, Foxa2, Vdr, Pdx1, Fkbp1b and Abcc8, suggesting global β-cell defects in STZ-treated islets. The Tmem229B, Prss53 and Ttc28 genes were highly expressed in untreated islets and strongly suppressed by STZ, suggesting their potential roles in β-cell function. When a pancreas-targeted adeno-associated virus (AAV) vector was employed for long-term Glp-1 gene delivery, pancreatic GLP-1 expression protected mice from STZ-induced diabetes through preservation of the β-cell mass. Despite its potent β-cell protective effects, however, pancreatic GLP-1 overexpression showed limited effects on the global gene expression profiles in the islets. Network analysis identified the programmed-cell-death-associated pathways as the most relevant network in Glp-1 gene therapy. Upon pancreatic GLP-1 expression, upregulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given the pro-β-cell-survival effects of Cxcl12 (Sdf-1) in inducing GLP-1 production in α-cells, pancreatic GLP-1-mediated Cxcl13 induction might also play a crucial role in maintaining the integrity of β-cells in damaged islets.
链脲佐菌素（STZ）是一种氨基葡萄糖-亚硝脲化合物，对胰腺β细胞具有很强的遗传毒性作用，常用于诱导实验动物糖尿病。胰高血糖素样肽-1（GLP-1）具有β细胞保护作用，已知可防止β细胞受到 STZ 处理的影响。在这项研究中，我们分析了 STZ 诱导的糖尿病的机制和 GLP-1 介导的 STZ 处理的β细胞保护作用。在多次低剂量 STZ 给药后 1 周，胰腺β细胞表现出胰岛素表达受损，同时维持核 Nkx6.1 的表达。这伴随着胰岛中 p53 反应基因的显著上调，包括细胞周期停滞的介体 p21（也称为 Waf1 和 Cip1）。STZ 处理还抑制了与关键β细胞功能或糖尿病发展相关的广泛基因的表达，例如 G6pc2、Slc2a2（Glut2）、Slc30a8、Neurod1、Ucn3、Gad1、Isl1、Foxa2、Vdr、Pdx1、Fkbp1b 和 Abcc8，表明 STZ 处理的胰岛中存在整体β细胞缺陷。Tmem229B、Prss53 和 Ttc28 基因在未处理的胰岛中高表达，并被 STZ 强烈抑制，提示它们在β细胞功能中的潜在作用。当使用胰腺靶向腺相关病毒（AAV）载体进行长期 GLP-1 基因传递时，胰腺 GLP-1 表达通过保护β细胞质量使小鼠免受 STZ 诱导的糖尿病。然而，尽管其具有很强的β细胞保护作用，但胰腺 GLP-1 过表达对胰岛中的整体基因表达谱的影响有限。网络分析确定程序化细胞死亡相关途径是 GLP-1 基因治疗中最相关的网络。在胰腺 GLP-1 表达后，在 STZ 损伤的胰岛中观察到 Cxcl13 和 Nptx2 的上调，但在未处理的正常胰岛中没有观察到。鉴于 Cxcl12（Sdf-1）在诱导α细胞中 GLP-1 产生方面对β细胞生存的促进作用，胰腺 GLP-1 介导的 Cxcl13 诱导也可能在维持受损胰岛中β细胞的完整性方面发挥关键作用。
