Stevenson R W, McPherson R K, Persson L M, Genereux P E, Swick A G, Spitzer J, Herbst J J, Andrews K M, Kreutter D K, Gibbs E M
Department of Metabolic Diseases, Pfizer, Inc., Groton, CT 06340, USA.
Diabetes. 1996 Jan;45(1):60-6. doi: 10.2337/diab.45.1.60.
The effects of englitazone in male Wistar rats fed a high-fat diet (59% of calories as fat) were compared with control rats fed a high-carbohydrate diet (69% of calories as carbohydrate) (5-15 animals per group). Insulin-stimulated (17 nmol/l) 2-deoxy-D-glucose (2-DG) uptake was inhibited 31% in adipocytes isolated from rats on the high-fat diet for 3 weeks, but englitazone (50 mg/kg for the last 7 days) normalized the response. There was a selective decrease in GLUT4 (54 +/- 5% of high-carbohydrate) in epididymal fat from rats on the high-fat diet for 3 weeks, but englitazone treatment did not reverse the defect in GLUT4 (43 +/- 8% of high-carbohydrate) or increase GLUT1 (81 +/- 12% of high-carbohydrate). Englitazone normalized oral glucose (1 g/kg body wt) intolerance and excessive (210% of high-carbohydrate) liver glycogen deposition (from [14C]glucose) caused by the high-fat diet. The high-fat diet tended to decrease insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3'-kinase (PI-3-kinase) expression in epididymal fat (26% decrease; P < 0.1). Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake. In summary, englitazone prevented the insulin resistance associated with a high-fat diet, but the mechanism of action does not involve changes in fat or muscle glucose transporter content and may not involve activation of the insulin signaling pathway via PI-3-kinase.
将服用高脂饮食（脂肪提供59%的热量）的雄性Wistar大鼠中恩格列净的作用，与服用高碳水化合物饮食（碳水化合物提供69%的热量）的对照大鼠进行比较（每组5 - 15只动物）。从高脂饮食喂养3周的大鼠分离的脂肪细胞中，胰岛素刺激（17 nmol/l）的2 - 脱氧 - D - 葡萄糖（2 - DG）摄取受到抑制，降低了31%，但恩格列净（在最后7天给予50 mg/kg）使反应恢复正常。高脂饮食喂养3周的大鼠附睾脂肪中，葡萄糖转运蛋白4（GLUT4，为高碳水化合物组的54±5%）有选择性减少，但恩格列净治疗并未逆转GLUT4的缺陷（为高碳水化合物组的43±8%），也未增加葡萄糖转运蛋白1（GLUT1，为高碳水化合物组的81±12%）。恩格列净使高脂饮食导致的口服葡萄糖（1 g/kg体重）不耐受和过量（为高碳水化合物组的210%）肝糖原沉积（来自[14C]葡萄糖）恢复正常。高脂饮食倾向于降低附睾脂肪中胰岛素受体底物 - 1（IRS - 1）和磷脂酰肌醇 - 3'-激酶（PI - 3 - 激酶）的表达（降低26%；P < 0.1）。恩格列净并未逆转高脂喂养大鼠脂肪中IRS - 1和PI - 3 - 激酶水平的这种降低（进一步降低25 - 30%，P < 0.05），在刺激2 - DG摄取增加六倍或增强胰岛素刺激的2 - DG摄取的条件下（孵育48小时），它也未增加3T3 - L1脂肪细胞中的PI - 3 - 激酶活性。总之，恩格列净预防了与高脂饮食相关的胰岛素抵抗，但其作用机制并不涉及脂肪或肌肉葡萄糖转运蛋白含量的变化，可能也不涉及通过PI - 3 - 激酶激活胰岛素信号通路。
