Stimulating b-Cell Regeneration by Combining a GPR119 Agonist with a DPP-IV Inhibitor

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 b-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, b-cell mass along with a- and b-cell replication, and b-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 a- and b-cell replication, and augmented b-cell mass. Furthermore, treatment with combination therapy induced b-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 therapeuti