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PLoS One. 2013;8(1):e53345. doi: 10.1371/journal.pone.0053345. Epub 2013 Jan 29.

Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor.

Author information

1
The Sanford Project, Children Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.

Abstract

BACKGROUND:

Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.

MATERIALS & METHODS:

Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.

RESULTS:

Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.

CONCLUSION:

Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.

PMID:
23382843
PMCID:
PMC3558424
DOI:
10.1371/journal.pone.0053345
[Indexed for MEDLINE]
Free PMC Article
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