Stimulating β-Cell Replication and Improving Islet Graft Function by AR231453, A gpr119 Agonist

• Published in: Transplantation proceedings 2011-11, Vol.43 (9), p.3217-3220
• Main Authors: Gao, J., Tian, L., Weng, G., O'Brien, T.D., Luo, J., Guo, Z.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Diabetes Mellitus, Experimental - therapy; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glucagon-Like Peptide 1 - blood; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Islets of Langerhans - cytology; Islets of Langerhans Transplantation - methods; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence - methods; Oxadiazoles - pharmacology; Pyrimidines - pharmacology; Receptors, G-Protein-Coupled - agonists; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Time Factors; Tissue, organ and graft immunology
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2011.10.021

G protein-coupled receptor 119 (GPR119) is predominantly expressed in β cells and intestinal L cells. AR231453 is a selective small-molecular GPR119 agonist that enhances glucose-dependent insulin secretion and glucagon-like peptide 1 (GLP-1) release. We investigated whether AR231453 can directly stimulate β-cell replication and improve islet graft function in diabetic mice. A total of 100 syngenic C57BL/6 mouse islets were transplanted under the left kidney of each chemically induced diabetic C57BL/6 mouse. Starting from the day of transplantation, these recipients were given bromodeoxyuridine (BrdU) daily with or without AR231453 at 10 mg/kg/d. Islet graft function was monitored by measuring blood glucose levels. At 4 weeks, left nephrectomy was performed to remove the kidney bearing the islet grafts to determine β-cell replication in the islet grafts. Insulin and BrdU immunofluorescence staining was performed to detect replicated β cells. Insulin + and BrdU + β cells in islet grafts were counted using a confocal microscope. To determine whether AR231453 increases plasma GLP-1 levels, we collected plasma from AR231453 treated mice at 30 minutes after treatment and measured plasma active GLP-1 by enzyme-linked immunosorbent assay. Although all recipient mice achieved normoglycemia at 28 days with or without treatment, normoglycemia was achieved in significantly fewer days in AR231453-treated mice. The vehicle-treated mice achieved normoglycemia in 16 ± 6 days, while AR231453-treated mice only required only 8 ± 3 days ( P < .01). The percentage of insulin + and BrdU + β cells in islet grafts was significantly higher in AR231453-treated mice than in vehicle-treated mice. The mean percentage of insulin + and BrdU + β cells in islet grafts was 21.5% ± 6.9% in AR231453-treated mice and 5.6% ± 3.7% in vehicle-treated mice ( P < .01). The plasma active GLP-1 levels were also significantly higher in AR231453-treated mice than in vehicle-treated mice ( P < .05). Our data demonstrate that AR231453, a GPR119 agonist, can stimulate β-cell replication and improve islet graft function.