Stimulating β-cell replication and improving islet graft function by AR231453, A gpr119 agonist

J. Gao, L. Tian, G. Weng, T. D. O'Brien, J. Luo, Z. Guo

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Objective: 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. 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 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. 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+ 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). Conclusion: Our data demonstrate that AR231453, a GPR119 agonist, can stimulate β-cell replication and improve islet graft function.

Original languageEnglish (US)
Pages (from-to)3217-3220
Number of pages4
JournalTransplantation proceedings
Volume43
Issue number9
DOIs
StatePublished - Nov 1 2011

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