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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.

Gaddy DF, Riedel MJ, Pejawar-Gaddy S, Kieffer TJ, Robbins PD - Diabetes (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

ABSTRACT

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.

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Related in: MedlinePlus

dsAAV-mediated expression of GLP-1 and HGF/NK1 does not affect the weight of obese db/db mice. The weights of female db/db mice treated with dsAAV–eGFP (black squares; n = 10), dsAAV–GLP1 (open triangles; n = 10), and dsAAV–NK1 (open circles; n = 10) were monitored weekly. A significant difference in weights of dsAAV–GLP1 and dsAAV–NK1 infected mice was observed at 6 weeks of age but at no other time points. *P < 0.05.
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Figure 7: dsAAV-mediated expression of GLP-1 and HGF/NK1 does not affect the weight of obese db/db mice. The weights of female db/db mice treated with dsAAV–eGFP (black squares; n = 10), dsAAV–GLP1 (open triangles; n = 10), and dsAAV–NK1 (open circles; n = 10) were monitored weekly. A significant difference in weights of dsAAV–GLP1 and dsAAV–NK1 infected mice was observed at 6 weeks of age but at no other time points. *P < 0.05.

Mentions: GLP-1 inhibits gastric emptying and gastric acid secretion in humans and rodent models, leading to decreased food intake and reduced body weight (18,20). To assess the effects of dsAAV-expressed GLP-1 and HGF/NK1 on body weight, the weights of db/db mice treated at 4 weeks of age were monitored weekly (Fig. 7). At 6 weeks of age, there was a modest, but statistically significant, difference in body weights, with dsAAV–GLP1- and dsAAV–NK1-infected mice weighing ∼7–10 g less than mice treated with dsAAV–eGFP. However, there was no difference in body weight at any other time point.


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.

Gaddy DF, Riedel MJ, Pejawar-Gaddy S, Kieffer TJ, Robbins PD - Diabetes (2010)

dsAAV-mediated expression of GLP-1 and HGF/NK1 does not affect the weight of obese db/db mice. The weights of female db/db mice treated with dsAAV–eGFP (black squares; n = 10), dsAAV–GLP1 (open triangles; n = 10), and dsAAV–NK1 (open circles; n = 10) were monitored weekly. A significant difference in weights of dsAAV–GLP1 and dsAAV–NK1 infected mice was observed at 6 weeks of age but at no other time points. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992772&req=5

Figure 7: dsAAV-mediated expression of GLP-1 and HGF/NK1 does not affect the weight of obese db/db mice. The weights of female db/db mice treated with dsAAV–eGFP (black squares; n = 10), dsAAV–GLP1 (open triangles; n = 10), and dsAAV–NK1 (open circles; n = 10) were monitored weekly. A significant difference in weights of dsAAV–GLP1 and dsAAV–NK1 infected mice was observed at 6 weeks of age but at no other time points. *P < 0.05.
Mentions: GLP-1 inhibits gastric emptying and gastric acid secretion in humans and rodent models, leading to decreased food intake and reduced body weight (18,20). To assess the effects of dsAAV-expressed GLP-1 and HGF/NK1 on body weight, the weights of db/db mice treated at 4 weeks of age were monitored weekly (Fig. 7). At 6 weeks of age, there was a modest, but statistically significant, difference in body weights, with dsAAV–GLP1- and dsAAV–NK1-infected mice weighing ∼7–10 g less than mice treated with dsAAV–eGFP. However, there was no difference in body weight at any other time point.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus