Journal Article

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

Ansarullah, Guo, Zhiguang, Holstein, Martha, Lu, Yan, Rabinovitch, Alex, DeRuyter, Brittany

2013

Overview

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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids, Heterocyclic - administration & dosage / Animals / Biology / Blood Glucose - drug effects / Cell growth / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental / Dipeptidyl Peptidase 4 - metabolism / Dipeptidyl-Peptidase IV Inhibitors - administration & dosage / Drug dosages / G protein-coupled receptors / Glucagon / Glucagon-Like Peptide 1 - blood / Glucose / Glucose tolerance / Humans / Inhibitors / Insulin / Insulin-Secreting Cells - cytology / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Medical research / Medicine / Mice / Mice, Inbred C57BL / Mice, Inbred NOD - genetics / Mice, Inbred NOD - metabolism / Oxadiazoles - administration & dosage / Pancreas / Pediatrics / Pyrazines - administration & dosage / Receptors, G-Protein-Coupled - agonists / Receptors, G-Protein-Coupled - metabolism / Regeneration / Regeneration - drug effects / Replication / Rodents / Sitagliptin Phosphate / Streptozocin / Therapy / Triazoles - administration & dosage