NeuroD-betacellulin Gene Therapy Induces Islet Neogenesis in the Liver and Reverses Diabetes in Mice

Nat Med. 2003 May;9(5):596-603. doi: 10.1038/nm867. Epub 2003 Apr 21.

Abstract

To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Betacellulin
  • Blood Glucose / analysis
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Experimental / therapy*
  • Genetic Therapy*
  • Hepatitis / etiology
  • Homeodomain Proteins*
  • Insulin / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Islets of Langerhans / physiology
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Streptozocin
  • Trans-Activators / genetics*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Betacellulin
  • Blood Glucose
  • Btc protein, mouse
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Neurod1 protein, mouse
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Streptozocin