Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Mol Pharm. 2010 Dec 6;7(6):2069-76. doi: 10.1021/mp100110c. Epub 2010 Nov 15.
Insulin resistance, a condition in which insulin action is impaired, is one of the characteristic features of type 2 diabetes. Excessive amounts of reactive oxygen species (ROS) interfere with the insulin signaling pathway, which leads to the progression of insulin resistance. To examine whether removal of systemic hydrogen peroxide is effective in improving insulin resistance, polyethylene glycol-conjugated catalase (PEG-catalase), a derivative with a long circulation half-life, was repeatedly injected into leptin-deficient ob/ob or high fat diet-induced obese mice for 16 or 10 consecutive weeks, respectively. Although ob/ob mice gradually gained weight with time irrespective of the treatment, repeated intraperitoneal injections of PEG-catalase significantly reduced glucose levels in the fed state. Glucose and insulin tolerance tests also showed PEG-catalase significantly improved glucose tolerance and insulin sensitivity in ob/ob mice, respectively. Similar but less marked results were obtained in the diet-induced obese mice. Treatment of 3T3-L1 adipocytes with glucose oxidase (GO) increased lipid hydroperoxide formation and reduced insulin-stimulated Akt phosphorylation. Addition of catalase or PEG-catalase significantly inhibited the GO-induced changes in adipocytes. These findings indicate that systemic removal of hydrogen peroxide by PEG-catalase activates the insulin signaling pathway and improves insulin resistance in obese mice.
胰岛素抵抗是 2 型糖尿病的特征之一，表现为胰岛素作用受损。过量的活性氧（ROS）会干扰胰岛素信号通路，导致胰岛素抵抗的进展。为了研究清除系统性过氧化氢是否能有效改善胰岛素抵抗，我们将具有长循环半衰期的聚乙二醇化过氧化氢酶（PEG-catalase）反复注射给瘦素缺乏的 ob/ob 或高脂饮食诱导肥胖的小鼠，分别连续 16 或 10 周。尽管 ob/ob 小鼠随着时间的推移逐渐增重，但重复的腹腔内注射 PEG-catalase 可显著降低进食状态下的血糖水平。葡萄糖和胰岛素耐量试验也表明，PEG-catalase 可显著改善 ob/ob 小鼠的葡萄糖耐量和胰岛素敏感性。在饮食诱导肥胖的小鼠中也得到了类似但不太明显的结果。用葡萄糖氧化酶（GO）处理 3T3-L1 脂肪细胞会增加脂质氢过氧化物的形成，并减少胰岛素刺激的 Akt 磷酸化。添加过氧化氢酶或 PEG-catalase 可显著抑制 GO 诱导的脂肪细胞变化。这些发现表明，通过 PEG-catalase 清除系统性过氧化氢可激活胰岛素信号通路，并改善肥胖小鼠的胰岛素抵抗。
