Transplant Proc. 2011 Nov;43(9):3217-20.
Stimulating ß-Cell Replication and Improving Islet Graft Function by AR231453, A gpr119 Agonist.
Gao J, Tian L, Weng G, O'Brien TD, Luo J, Guo Z.
Department of Surgery and Schulze Diabetes Institute, University of Minnesota, Minneapolis, Minnesota, USA; Department of Hepatobiliary Surgery, People's Hospital, Peking University, Beijing, China.
OBJECTIVE:
G protein-coupled receptor 119 (GPR119) is predominantly expressed in ß 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 ß-cell replication and improve islet graft function in diabetic mice.
METHODS:
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 ß-cell replication in the islet grafts. Insulin and BrdU immunofluorescence staining was performed to detect replicated ß cells. Insulin(+) and BrdU(+) ß 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.
RESULTS:
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(+) ß cells in islet grafts was significantly higher in AR231453-treated mice than in vehicle-treated mice. The mean percentage of insulin(+) and BrdU(+) ß 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).
CONCLUSION:
Our data demonstrate that AR231453, a GPR119 agonist, can stimulate ß-cell replication and improve islet graft function. |
