Gorogawa Shin ichi, Kajimoto Yoshitaka, Umayahara Yutaka, Kaneto Hideaki, Watada Hirotaka, Kuroda Akio, Kawamori Dan, Yasuda Tetsuyuki, Matsuhisa Munehide, Yamasaki Yoshimitsu, Hori Masatsugu
Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka Pref, Japan.
Diabetes Res Clin Pract. 2002 Jul;57(1):1-10. doi: 10.1016/s0168-8227(02)00005-0.
Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic beta-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of beta-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of beta-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of beta-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of beta-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280+/-82 vs. 914+/-238 pmol/l (120 min, at 16 weeks; P<0.05); glucose, 44.6+/-2.4 vs. 35.2+/-2.6 mmol/l (120 min, at 16 weeks; P<0.05). Thus, our present observations demonstrate the potential usefulness of probucol for treatment of type 2 diabetes.
在糖尿病条件下会诱导氧化应激，导致糖尿病患者出现各种形式的组织损伤。最近，胰腺β细胞已成为氧化应激诱导的组织损伤的假定靶点，这似乎部分解释了2型糖尿病中β细胞功能的渐进性恶化。作为迈向2型糖尿病抗氧化剂临床试验的一步，我们研究了普罗布考（一种广泛用作抗高脂血症药物的抗氧化剂）对糖尿病C57BL/KsJ-db/db小鼠β细胞功能保存的可能抗糖尿病作用。从6周龄到16周龄给小鼠喂食含普罗布考的饮食。对氧化应激标志物如4-羟基-2-壬烯醛（HNE）修饰蛋白和血红素加氧酶-1进行免疫染色显示，普罗布考治疗可降低糖尿病动物胰岛中的活性氧（ROS）。已知氧化应激会增强β细胞凋亡并抑制胰岛素生物合成，但普罗布考治疗可导致β细胞数量和胰岛素含量的保存。根据腹腔葡萄糖耐量试验，普罗布考治疗在10周和16周时保留了葡萄糖刺激的胰岛素分泌并改善了葡萄糖耐量：胰岛素，280±82对914±238 pmol/l（16周时120分钟；P<0.05）；葡萄糖，44.6±2.4对35.2±2.6 mmol/l（16周时120分钟；P<0.05）。因此，我们目前的观察结果证明了普罗布考治疗2型糖尿病的潜在有用性。
