| First Author | Gaddy DF | Year | 2010 |
| Journal | Diabetes | Volume | 59 |
| Issue | 12 | Pages | 3108-16 |
| PubMed ID | 20841608 | Mgi Jnum | J:170210 |
| Mgi Id | MGI:4944145 | Doi | 10.2337/db09-1886 |
| Citation | Gaddy DF, et al. (2010) In vivo expression of HGF/NK1 and GLP-1 From dsAAV vectors enhances pancreatic ss-cell proliferation and improves pathology in the db/db mouse model of diabetes. Diabetes 59(12):3108-16 |
| abstractText | OBJECTIVE: The purpose of the current study was to determine whether double-stranded adeno-associated virus (dsAAV)-mediated in vivo expression of beta-cell growth factors, glucagon-like peptide-1 (GLP-1) and the NK1 fragment of hepatocyte growth factor (HGF/NK1) in beta-cells, improves pathology in the db/db mouse model of type 2 diabetes. RESEARCH DESIGN AND METHODS; The glucoregulatory actions of GLP-1 and full-length HGF are well characterized. Here, we test the ability of HGF/NK1 to induce proliferation of exogenous islets and MIN6 beta-cells. In addition, we target both GLP-1 and HGF/NK1 to endogenous beta-cells using dsAAV vectors containing the mouse insulin-II promoter. We compare the abilities of these gene products to induce islet proliferation in vitro and in vivo and characterize their abilities to regulate diabetes after AAV-mediated delivery to endogenous islets of db/db mice. RESULTS: Recombinant HGF/NK1 induces proliferation of isolated islets, and dsAAV-mediated expression of both GLP-1 and HGF/NK1 induces significant beta-cell proliferation in vivo. Furthermore, both GLP-1 and HGF/NK1 expressed from dsAAV vectors enhance beta-cell mass and insulin secretion in vivo and significantly delay the onset of hyperglycemia in db/db mice. CONCLUSIONS: A single treatment with dsAAV vectors expressing GLP-1 or HGF/NK1 enhances islet growth and significantly improves pathology in a mouse model of type 2 diabetes. This represents the first example of a successful use of HGF/NK1 for diabetes therapy, providing support for direct AAV-mediated in vivo delivery of beta-cell growth factors as a novel therapeutic strategy for the treatment of type 2 diabetes. |
