Pacifici Francesca, Arriga Roberto, Sorice Gian Pio, Capuani Barbara, Scioli Maria Giovanna, Pastore Donatella, Donadel Giulia, Bellia Alfonso, Caratelli Sara, Coppola Andrea, Ferrelli Francesca, Federici Massimo, Sconocchia Giuseppe, Tesauro Manfredi, Sbraccia Paolo, Della-Morte David, Giaccari Andrea, Orlandi Augusto, Lauro Davide
Department of System Medicine, University of Rome Tor Vergata, Rome, Italy.
Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy Diabetic Care Clinics, Associazione dei Cavalieri Italiani Sovrano Militare Ordine di Malta, Rome, Italy.
Diabetes. 2014 Oct;63(10):3210-20. doi: 10.2337/db14-0144. Epub 2014 Jun 19.
Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (-/-) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6(-/-) mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6(-/-) mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.
氧化应激增强在糖尿病及其并发症的发病机制中起作用。过氧化物酶6（PRDX6）是细胞氧化还原平衡的关键调节因子，具有中和过氧化物、过氧亚硝酸盐和磷脂氢过氧化物的独特能力。在本研究中，我们旨在使用PRDX6基因敲除（-/-）小鼠来确定PRDX6在2型糖尿病（T2D）病理生理学中的作用。通过腹腔内葡萄糖耐量试验和胰岛素耐量试验分别评估葡萄糖和胰岛素反应。通过正常血糖-高胰岛素钳夹技术分析外周胰岛素敏感性，并使用分子工具研究胰岛素信号传导。此外，还评估了炎症和脂质参数。我们证明PRDX6（-/-）小鼠表现出一种类似于早期T2D的表型，这是由葡萄糖依赖性胰岛素分泌减少和胰岛素抵抗增加共同导致的。PRDX6（-/-）小鼠存在胰岛素信号传导受损，导致肌肉葡萄糖摄取减少。在突变动物的胰岛和肝脏中观察到形态学和超微结构变化，以及血浆脂质谱和炎症参数的改变。总之，我们证明PRDX6是T2D葡萄糖代谢中明显高血糖的关键介质，为糖尿病治疗的靶向治疗策略开辟了新的前景。
