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DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

Academic Article
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Overview

authors

  • Riedel, M. J.
  • Gaddy, D. F.
  • Asadi, A.
  • Robbins, Paul D.
  • Kieffer, T. J.

publication date

  • February 2010

journal

  • Gene Therapy  Journal

abstract

  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

subject areas

  • Animals
  • Cell Proliferation
  • Dependovirus
  • Diabetes Mellitus, Experimental
  • Genetic Therapy
  • Genetic Vectors
  • Glucagon-Like Peptide 1
  • Injections, Intraperitoneal
  • Insulin
  • Insulin-Secreting Cells
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
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Research

keywords

  • AAV
  • GLP-1
  • adeno-associated virus
  • diabetes
  • glucagon like peptide-1
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Identity

International Standard Serial Number (ISSN)

  • 0969-7128

Digital Object Identifier (DOI)

  • 10.1038/gt.2009.143

PubMed ID

  • 19865180
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Additional Document Info

start page

  • 171

end page

  • 180

volume

  • 17

issue

  • 2

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