Stimulating beta cell replication and improving islet graft function by GPR119 agonists
Stimulating beta cell replication and improving islet graft function by GPR119 agonists
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DOI：
10.1111/j.1432-2277.2011.01332.x
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发表时间：
2011-11-01
影响因子：
3.1
通讯作者：
Guo, Zhiguang
中科院分区：
文献类型：
--
作者：
Gao, Jie;Tian, Lei;Guo, Zhiguang
G蛋白偶联受体119（GPR 119）主要在β细胞和肠L细胞中表达。在这项研究中，我们研究了GPR 119内源性配体油酰乙醇胺（OEA）和GPR 119合成激动剂PSN 632408是否可以在体外和体内刺激β细胞复制并改善糖尿病小鼠的胰岛移植功能。我们发现OEA和PSN 632408以剂量依赖性方式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。所有糖尿病受体小鼠，给予边缘同系胰岛移植OEA或PSN 632408或媒介物，在移植后4周达到正常血糖。然而，在OEA或PSN 632408治疗的糖尿病小鼠中比在媒介物治疗的糖尿病小鼠中显著更快地达到正常血糖（P < 0.05）。OEA和PSN 632408处理的小鼠中胰岛移植物中胰岛素（+）/BrdU（+）β细胞的百分比显著高于溶剂处理的小鼠（P < 0.01）。我们的数据表明，OEA和PSN 632408可以在体外和体内刺激β细胞复制，并改善胰岛移植物功能。靶向GPR 119是一种通过刺激β细胞复制来增加β细胞质量和改善胰岛移植物功能的新治疗方法。
G protein-coupled receptor 119 (GPR119) is predominantly expressed in beta 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 beta-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)(+) beta 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(+) beta 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 beta-cell replication in vitro and in vivo and improve islet graft function. Targeting GPR119 is a novel therapeutic approach to increase beta-cell mass and to improve islet graft function by stimulating beta-cell replication.