NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice.
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.
Kojima
Hideto
H
Section of Diabetes, Endocrinology & Metabolism, Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Fujimiya
Mineko
M
Matsumura
Kazuhiro
K
Younan
Patrick
P
Imaeda
Hirotsugu
H
Maeda
Makiko
M
Chan
Lawrence
L
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D066259:Betacellulin; D001786:Blood Glucose / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D015316:Genetic Therapy; D006505:Hepatitis / Q000209:etiology; D018398:Homeodomain Proteins; D007328:Insulin / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007515:Islets of Langerhans / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013311:Streptozocin; D015534:Trans-Activators / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D066259:Betacellulin; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D013311:Streptozocin; D015534:Trans-Activators; C587852:Btc protein, mouse; C501008:Neurod1 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein