In Vivo Expression of HGF/NK1 and GLP-1 From dsAAV Vectors Enhances Pancreatic β-Cell Proliferation and Improves Pathology in the db/db Mouse Model of Diabetes

Gaddy, Daniel F.
Riedel, Michael J.
Pejawar-Gaddy, Sharmila
Kieffer, Timothy J.
Robbins, Paul D.

¹ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
² Laboratory of Molecular and Cellular Medicine, Departments of Cellular & Physiological Sciences and Surgery, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Corresponding author: Paul D. Robbins, [email protected].

Received December 29, 2009

Accepted August 26, 2010

Diabetes 59(12):p 3108-3116, December 2010. | DOI: 10.2337/db09-1886

OBJECTIVE

The purpose of the current study was to determine whether double-stranded adeno-associated virus (dsAAV)-mediated in vivo expression of β-cell growth factors, glucagon-like peptide-1 (GLP-1) and the NK1 fragment of hepatocyte growth factor (HGF/NK1) in β-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 β-cells. In addition, we target both GLP-1 and HGF/NK1 to endogenous β-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 β-cell proliferation in vivo. Furthermore, both GLP-1 and HGF/NK1 expressed from dsAAV vectors enhance β-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 β-cell growth factors as a novel therapeutic strategy for the treatment of type 2 diabetes.