Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Endocr J. 2009;56(9):1103-11. doi: 10.1507/endocrj.k09e-140. Epub 2009 Sep 29.
It is known that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo ER stress under diabetic conditions. In high fat and high sucrose diet-induced diabetic ERAI transgenic mice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. In addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. These data indicate that pioglitazone treatment suppresses ER stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance.
已知内质网（ER）应激是在糖尿病条件下引发的，可能与胰岛素抵抗的发展有关。在这项研究中，我们使用内质网应激激活指示剂（ERAI）转基因小鼠，在 ER 应激条件下表达绿色荧光蛋白，直接评估糖尿病药物吡格列酮对糖尿病状态下体内 ER 应激的影响。在高脂肪和高蔗糖饮食诱导的糖尿病 ERAI 转基因小鼠中，8 周的吡格列酮治疗减少了肝脏中脂肪滴的积累，并减轻了胰岛素抵抗的发展。在 ERAI 转基因小鼠的肝脏中，早在吡格列酮治疗 4 周后，ERAI 荧光活性就明显降低，早于胰岛素抵抗的改善。此外，吡格列酮治疗后，血清游离脂肪酸和甘油三酯水平降低，血清脂联素水平升高。这些数据表明，吡格列酮治疗可抑制肝脏中的 ER 应激，这至少可以部分解释吡格列酮降低胰岛素抵抗的药理作用。
