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. One 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 up-regulation of p53-responsive genes in islets, including a mediator of cell cycle arrest p21 (Waf1/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 the global β-cell defects in STZ-treated islets. 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 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, up-regulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given that the pro-β-cell-survival effects of Cxcl12 (Sdf-1) in inducing GLP-1 production in β-cells, pancreatic GLP-1-mediated Cxcl13 induction may also play a critical role in maintaining the integrity of β-cells in damaged islets.
- Received March 30, 2013.
- Accepted July 1, 2013.
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