O'Malley Yunxia, Coleman Mitchell C, Sun Xingshen, Lei Junying, Yao Jianrong, Pulliam Casey F, Kluz Paige, McCormick Michael L, Yi Yaling, Imai Yumi, Engelhardt John F, Norris Andrew W, Spitz Douglas R, Uc Aliye
Stead Family Department of Pediatrics, The University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242, USA.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA.
Adv Redox Res. 2022 Jul;5. doi: 10.1016/j.arres.2022.100040. Epub 2022 Jun 9.
Cystic fibrosis-related diabetes (CFRD) is one the most common comorbidities in cystic fibrosis (CF). Pancreatic oxidative stress has been postulated in the pathogenesis of CFRD, but no studies have been done to show an association. The main obstacle is the lack of suitable animal models and no immediate availability of pancreas tissue in humans. In the CF porcine model, we found increased pancreatic total glutathione (GSH), glutathione disulfide (GSSG), 3-nitrotyrosine- and 4-hydroxynonenal-modified proteins, and decreased copper zinc superoxide dismutase (CuZnSOD) activity, all indicative of oxidative stress. CF pig pancreas demonstrated increased DHE oxidation (as a surrogate marker of superoxide) compared to non-CF and this was inhibited by a SOD-mimetic (GC4401). Catalase and glutathione peroxidase activities were not different between CF and non-CF pancreas. Isolated CF pig islets had significantly increased DHE oxidation, peroxide production, reduced insulin secretion in response to high glucose and diminished secretory index compared to non-CF islets. Acute treatment with apocynin or an SOD mimetic failed to restore insulin secretion. These results are consistent with the hypothesis that CF pig pancreas is under significant oxidative stress as a result of increased O and peroxides combined with reduced antioxidant defenses against reactive oxygen species (ROS). We speculate that insulin secretory defects in CF may be due to oxidative stress.
囊性纤维化相关糖尿病（CFRD）是囊性纤维化（CF）最常见的合并症之一。胰腺氧化应激被认为与CFRD的发病机制有关，但尚未有研究证实两者之间的关联。主要障碍在于缺乏合适的动物模型，且无法直接获取人体胰腺组织。在CF猪模型中，我们发现胰腺总谷胱甘肽（GSH）、谷胱甘肽二硫化物（GSSG）、3-硝基酪氨酸和4-羟基壬烯醛修饰蛋白增加，铜锌超氧化物歧化酶（CuZnSOD）活性降低，所有这些都表明存在氧化应激。与非CF猪相比，CF猪胰腺的脱氢表雄酮（DHE）氧化增加（作为超氧化物的替代标志物），且这种增加被超氧化物歧化酶模拟物（GC4401）抑制。CF和非CF胰腺之间的过氧化氢酶和谷胱甘肽过氧化物酶活性没有差异。与非CF胰岛相比，分离的CF猪胰岛的DHE氧化、过氧化物生成显著增加，对高糖的胰岛素分泌减少，分泌指数降低。用载脂蛋白或超氧化物歧化酶模拟物进行急性治疗未能恢复胰岛素分泌。这些结果与以下假设一致：由于O和过氧化物增加，同时对抗活性氧（ROS）的抗氧化防御能力降低，CF猪胰腺处于显著的氧化应激状态。我们推测CF中的胰岛素分泌缺陷可能是由于氧化应激所致。
