title: Stimulating β-cell replication and improving islet graft function by AR231453, A GPR119 agonist.
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).
  
  
  CONCLUSIONS
  Our data demonstrate that AR231453, a GPR119 agonist, can stimulate β-cell replication and improve islet graft function.
authors.affiliation: Department of Surgery and Schulze Diabetes Institute, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: G
authors.initials: G
authors.lastname: Weng
authors.forename: T D
authors.initials: TD
authors.lastname: O'Brien
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D010069:Oxadiazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013997:Time Factors
chemical_list: C521085:AR 231453; C516207:Gpr119 protein, mouse; D007328:Insulin; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1