Timothy D. O’Brien

Publications (2)5.84 Total impact

• Source

  Available from: Robert L Sorenson

  Article: Stimulating beta cell replication and improving islet graft function by GPR119 agonists

  Jie Gao, Lei Tian, Guobin Weng, Nicholas V. Bhagroo, Robert L. Sorenson, Timothy D. O’Brien, Jian Luo, Zhiguang Guo
  [show abstract] [hide abstract]
  ABSTRACT: SummaryG protein-coupled receptor 119 (GPR119) is predominantly expressed in β cells and intestinal L cells. In this study, we investigated whether oleoylethanolamide (OEA), a GPR119 endogenous ligand, and PSN632408, a GPR119 synthetic agonist, can stimulate β-cell replication in vitro and in vivo and improve islet graft function in diabetic mice. We found that OEA and PSN632408 significantly increased numbers of insulin+/5-bromo-2′-deoxyuridine (BrdU)+β cells in cultured mouse islets in a dose-dependent manner. All diabetic recipient mice, given marginal syngeneic islet transplants with OEA or PSN632408 or vehicle, achieved normoglycemia at 4 weeks after transplantation. However, normoglycemia was achieved significantly faster in OEA- or PSN632408-treated diabetic mice than in vehicle-treated diabetic mice (P < 0.05). The percentage of insulin+/BrdU+β cells in islet grafts in OEA- and PSN632408-treated mice was significantly higher than in vehicle-treated mice (P < 0.01). Our data demonstrated that OEA and PSN632408 can stimulate β-cell replication in vitro and in vivo and improve islet graft function. Targeting GPR119 is a novel therapeutic approach to increase β-cell mass and to improve islet graft function by stimulating β-cell replication.
  Transplant International 10/2011; 24(11):1124 - 1134. · 2.92 Impact Factor
• Source

  Available from: sanfordresearch.org

  Article: Comparison of exendin‐4 on beta‐cell replication in mouse and human islet grafts

  Lei Tian, Jie Gao, Guangbin Weng, Huimin Yi, Bole Tian, Timothy D. O’Brien, Zhiguang Guo
  [show abstract] [hide abstract]
  ABSTRACT: Exendin-4 can stimulate β-cell replication in mice. Whether it can stimulate β-cell replication in human islet grafts remains unknown. Therefore, we compared the effects of exendin-4 on β-cell replication in mouse and human islet grafts. Islets, isolated from mouse and human donors at different ages, were transplanted into diabetic mice and/or diabetic nude mice that were given bromodeoxyuridine (BrdU) with or without exendin-4. At 4 weeks post-transplantation, islet grafts were removed for insulin and BrdU staining and quantification of insulin+/BrdU+ cells. Although diabetes was reversed in all mice transplanting syngeneic mouse islets from young or old donors, normoglycemia was achieved significantly faster in exendin-4 treated mice. Mouse islet grafts in exendin-4 treated mice had significantly more insulin+/BrdU+β cells than in untreated mice (P < 0.01). Human islet grafts from ≤22-year-old donors had more insulin+/BrdU+β cells in exendin-4 treated mice than that in untreated mice (P < 0.01). However, human islet grafts from ≥35-year-old donors contained few insulin+/BrdU+β cells in exendin-4 treated or untreated mice. Our data demonstrated that the capacity for β-cell replication in mouse and human islet grafts is different with and without exendin-4 treatment and indicated that GLP-1 agonists can stimulate β-cell replication in human islets from young donors.
  Transplant International 07/2011; 24(8):856 - 864. · 2.92 Impact Factor