Tan Carina P, Feng Yue, Zhou Yun-Ping, Eiermann George J, Petrov Aleksandr, Zhou Changyou, Lin Songnian, Salituro Gino, Meinke Peter, Mosley Ralph, Akiyama Taro E, Einstein Monica, Kumar Sanjeev, Berger Joel P, Mills Sander G, Thornberry Nancy A, Yang Lihu, Howard Andrew D
Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey, USA.
Diabetes. 2008 Aug;57(8):2211-9. doi: 10.2337/db08-0130. Epub 2008 May 13.
Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40.
We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)).
Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically.
GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
游离脂肪酸（FFA）或合成G蛋白偶联受体40（GPR40）激动剂对GPR40的急性激活可增强胰岛素分泌。然而，GPR40的激活对2型糖尿病治疗是否有益仍存在争议，因为长期暴露于FFA会损害胰岛功能。我们试图使用特异性激活GPR40的化合物来评估GPR40在胰岛中的具体作用及其作为治疗靶点的潜力。
我们开发了一系列GPR40选择性小分子激动剂，并研究了它们对分离胰岛中葡萄糖依赖性胰岛素分泌（GDIS）的急性和慢性影响，以及对野生型和GPR40基因敲除小鼠（GPR40(-/-)）腹腔内葡萄糖耐量试验期间血糖水平的影响。
小分子GPR40激动剂显著增强了分离胰岛中的GDIS，并改善了野生型小鼠的葡萄糖耐量，但对GPR40(-/-)小鼠无效。虽然在组织培养中72小时暴露于FFA会显著损害野生型和GPR40(-/-)小鼠胰岛中的GDIS，但类似暴露于GPR40激动剂不会损害野生型小鼠胰岛中的GDIS。此外，GPR40激动剂增强了新生链脲佐菌素诱导的糖尿病大鼠灌注胰腺中的胰岛素分泌，并急性和慢性改善了高脂饮食诱导肥胖小鼠的血糖水平。
GPR40不介导FFA对胰岛功能的慢性毒性作用。GPR40的药理激活可能增强人类的GDIS，并有利于2型糖尿病患者的整体血糖控制。
