title: Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Tonne
authors.forename: Toshie
authors.initials: T
authors.lastname: Sakuma
authors.forename: Michael C
authors.initials: MC
authors.lastname: Deeds
authors.forename: Miguel
authors.initials: M
authors.lastname: Munoz-Gomez
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics / Q000517:prevention & control / Q000628:therapy; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism; D013311:Streptozocin; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007328:Insulin; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490253:Reg3b protein, mouse; D016159:Tumor Suppressor Protein p53; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1