Department of Surgery and Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, USA.
Transpl Int. 2011 Nov;24(11):1124-34. doi: 10.1111/j.1432-2277.2011.01332.x. Epub 2011 Sep 8.
G 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.
G 蛋白偶联受体 119（GPR119）主要表达于β细胞和肠 L 细胞。在本研究中，我们探讨了内源性 GPR119 配体油酰乙醇胺（OEA）和 GPR119 合成激动剂 PSN632408 是否能在体外和体内刺激β细胞增殖，并改善糖尿病小鼠胰岛移植物的功能。我们发现 OEA 和 PSN632408 能呈浓度依赖性地显著增加培养的小鼠胰岛中胰岛素（+）/5-溴-2'-脱氧尿苷（BrdU）（+）β细胞的数量。所有接受边缘同种异体胰岛移植的糖尿病受体小鼠，在移植后 4 周时均实现了血糖正常。然而，与给予 OEA 或 PSN632408 或载体的糖尿病小鼠相比，给予 OEA 或 PSN632408 的糖尿病小鼠更快地实现了血糖正常（P<0.05）。在 OEA 和 PSN632408 处理的小鼠中，胰岛移植物内胰岛素（+）/BrdU（+）β细胞的比例显著高于给予载体的小鼠（P<0.01）。我们的数据表明，OEA 和 PSN632408 能在体外和体内刺激β细胞增殖，并改善胰岛移植物的功能。靶向 GPR119 是一种通过刺激β细胞增殖来增加β细胞数量和改善胰岛移植物功能的新的治疗方法。
