DC260126: a small-molecule antagonist of GPR40 that protects against pancreatic β-Cells dysfunction in db/db mice.
DC260126: a small-molecule antagonist of GPR40 that protects against pancreatic β-Cells dysfunction in db/db mice.
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DOI：
10.1371/journal.pone.0066744
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Sun P;Wang T;Zhou Y;Liu H;Jiang H;Zhu W;Wang H
G蛋白偶联受体40（GPR 40）介导游离脂肪酸（FFA）对胰岛素分泌的急性和慢性作用。然而，抑制GPR 40是否有利于预防2型糖尿病仍存在争议。本研究旨在评价对肥胖糖尿病db/db小鼠给予10 mg/kg剂量的DC 260126（一种GPR 40的小分子拮抗剂）后DC 260126对β细胞功能的潜在影响。采用口服葡萄糖耐量试验、葡萄糖刺激胰岛素分泌试验和胰岛素耐量试验观察DC 260126对db/db小鼠的药理作用。同时进行免疫组化和血清生化分析。虽然在DC 260126处理的小鼠中未发现血糖水平的显著变化，但DC 260126在db/db小鼠中给药3周后显著抑制葡萄糖刺激的胰岛素分泌，降低血胰岛素水平并改善胰岛素敏感性。此外，与溶剂处理的小鼠相比，DC 260126显著降低DC 260126处理的db/db小鼠中胰岛素原/胰岛素比率和胰腺β细胞的凋亡率（p<0.05，n = 8）。 结果表明，虽然DC 260126不能提供改善高血糖的益处，但它可以通过减少β细胞的过载来保护胰腺β细胞功能障碍，并且可能通过减轻db/db小鼠的高胰岛素血症来增加胰岛素敏感性。
G protein-coupled receptor 40 (GPR40) mediates both acute and chronic effects of free fatty acids (FFAs) on insulin secretion. However, it remains controversial whether inhibition of GPR40 would be beneficial in prevention of type 2 diabetes. This study is designed to evaluate the potential effects of DC260126, a small molecule antagonist of GPR40, on β-cell function following administration of 10 mg/kg dose of DC260126 to obese diabetic db/db mice. Oral glucose tolerance test, glucose stimulated insulin secretion and insulin tolerance test were used to investigate the pharmacological effects of DC260126 on db/db mice after 21-days treatment. Immunohistochemistry and serum biochemical analysis were also performed in this study. Although no significant change of blood glucose levels was found in DC260126-treated mice, DC260126 significantly inhibited glucose stimulated insulin secretion, reduced blood insulin level and improved insulin sensitivity after 3 weeks administration in db/db mice. Moreover, DC260126 reduced the proinsulin/insulin ratio and the apoptotic rate of pancreatic β-cells remarkably in DC260126-treated db/db mice compared to vehicle-treated mice (p<0.05, n = 8). The results suggest that although DC260126 could not provide benefit for improving hyperglycemia, it could protect against pancreatic β-cells dysfunction through reducing overload of β-cells, and it increases insulin sensitivity possibly via alleviation of hyperinsulinemia in db/db mice.
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影响因子：
4.1
作者：
Remizov, O;Jakubov, R;Schöfl, C
通讯作者：
Schöfl, C
DOI：
10.1083/jcb.119.3.493
发表时间：
1992-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gavrieli Y;Sherman Y;Ben-Sasson SA
通讯作者：
Ben-Sasson SA
影响因子：
8
作者：
Abaraviciene, S. Meidute;Lundquist, I.;Salehi, A.
通讯作者：
Salehi, A.
影响因子：
7.7
作者：
Han, Myoung Sook;Chung, Kun Wook;Cheon, Hyae Gyeong;Dal Rhee, Sang;Yoon, Chang-Hwan;Lee, Moon-Kyu;Kim, Kwang-Won;Lee, Myung-Shik
通讯作者：
Lee, Myung-Shik
影响因子：
8.2
作者：
MATTHEWS, DR;HOSKER, JP;TURNER, RC
通讯作者：
TURNER, RC