Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy

Dis Model Mech. 2013 Sep;6(5):1236-45. doi: 10.1242/dmm.012591. Epub 2013 Jul 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / genetics
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / prevention & control
  • Diabetes Mellitus, Experimental / therapy*
  • Gene Expression Profiling*
  • Gene Expression Regulation
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Glucagon-Like Peptide 1 / genetics*
  • Glucagon-Like Peptide 1 / therapeutic use*
  • HEK293 Cells
  • Humans
  • Hyperglycemia / complications
  • Hyperglycemia / genetics
  • Hyperglycemia / prevention & control
  • Hyperglycemia / therapy
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Pancreatitis-Associated Proteins
  • Proteins / metabolism
  • Streptozocin
  • Transcriptome / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Insulin
  • Pancreatitis-Associated Proteins
  • Proteins
  • Reg3b protein, mouse
  • Tumor Suppressor Protein p53
  • Streptozocin
  • Glucagon-Like Peptide 1