Abstract
SUMMARYStreptozotocin (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.
Highlights
Streptozotocin (STZ) is a monofunctional nitrosourea derivative that was first derived from Streptomyces achromogenes
The authors analyzed the effects of STZ-induced diabetes and GLP-1mediated β-cell protection in STZ-treated mice on the genome-wide expression patterns in pancreatic islets
They report that STZ administration induces p53-responsive genes in affected islets, including p21, which encodes a mediator of cell cycle arrest
Summary
Streptozotocin (STZ) is a monofunctional nitrosourea derivative that was first derived from Streptomyces achromogenes. STZ is a potent alkylating agent, known as an alkylnitrosourea, that directly methylates DNA (Randerath et al, 1981). STZ-induced DNA damage is characterized by N7-methylguanine (N7-MeG): more than 70% of DNA methylation occurs at the N7 position of guanine (Capucci et al, 1995). In addition to covalent adducts (N7-MeG), STZ induces DNA strand breaks in rat β-cells (LeDoux et al, 1986). Because of its selective toxic effects on pancreatic β-cells, STZ is frequently used to induce diabetes mellitus in experimental animals. To induce insulin-dependent diabetes, STZ is typically given through a single intravenous administration or through multiple low-dose intraperitoneal administrations (Deeds et al, 2011). Despite its extensive use in diabetes research, the Received 30 March 2013; Accepted 1 July 2013
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