期刊
DIABETES
卷 59, 期 12, 页码 3108-3116出版社
AMER DIABETES ASSOC
DOI: 10.2337/db09-1886
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资金
- Juvenile Diabetes Research Foundation (JDRF)
- JDRF
- Michael Smith Foundation for Health Research (MSFHR)
- Canadian Diabetes Association
- Stem Cell Network
- SASS Foundation for Medical Research
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. Diabetes 59: 3108-3116, 2010
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