β-Cell-Specific Overexpression of Glutathione Peroxidase Preserves Intranuclear MafA and Reverses Diabetes in db/db Mice
β-Cell-Specific Overexpression of Glutathione Peroxidase Preserves Intranuclear MafA and Reverses Diabetes in db/db Mice
复制标题
DOI：
10.1210/en.2009-0708
复制
发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Robertson, R. Paul
中科院分区：
文献类型：
--
作者：
Harmon, Jamie S.;Bogdani, Marika;Robertson, R. Paul
慢性高血糖症引起氧化应激，这有助于各种组织和细胞（包括胰腺β细胞）的损伤。与其他组织相比，胰岛中抗氧化酶的表达水平较低，使得β细胞更容易受到高血糖症引起的损伤。本研究的目的是调查是否增加内源性谷胱甘肽过氧化物酶-1（GPx-1）的水平，特别是在β细胞中，可以保护他们免受慢性高血糖症的不良影响，并评估可能涉及的机制。产生了仅在胰腺β细胞中过表达抗氧化酶GPx-1的C57 BLKS/J小鼠。当转基因小鼠的β细胞受到链脲佐菌素保护时，记录了过表达GPx-1转基因的生物学有效性。然后将转基因渗入db/db小鼠的β细胞中。在不使用降血糖剂的情况下，db/db-GPx（+）小鼠的高血糖最初比db/db-GPx（-）动物有所改善，然后在20周龄时基本上逆转。与db/db-GPx（-）动物相比，db/db-GPx（+）动物的β细胞体积和胰岛素颗粒以及免疫染色更大。重要的是，在非转基因db/db小鼠中观察到的核内肌肉腱膜纤维肉瘤癌基因同源物A（MafA）的丢失被GPx-1过表达所阻止，使其成为改善血糖控制的可能机制。这些研究表明，β细胞内在抗氧化防御的增强可保护其在高血糖期间免受恶化。（内分泌学150：4855-4862，2009）
Chronic hyperglycemia causes oxidative stress, which contributes to damage in various tissues and cells, including pancreatic beta-cells. The expression levels of antioxidant enzymes in the islet are low compared with other tissues, rendering the beta-cell more susceptible to damage caused by hyperglycemia. The aim of this study was to investigate whether increasing levels of endogenous glutathione peroxidase-1 (GPx-1), specifically in beta-cells, can protect them against the adverse effects of chronic hyperglycemia and assess mechanisms that may be involved. C57BLKS/J mice overexpressing the antioxidant enzyme GPx-1 only in pancreatic beta-cells were generated. The biological effectiveness of the overexpressed GPx-1 transgene was documented when beta-cells of transgenic mice were protected from streptozotocin. The transgene was then introgressed into the beta-cells of db/db mice. Without use of hypoglycemic agents, hyperglycemia in db/db-GPx(+) mice was initially ameliorated compared with db/db-GPx(-) animals and then substantially reversed by 20 wk of age. beta-Cell volume and insulin granulation and immunostaining were greater in db/db-GPx(+) animals compared with db/db-GPx(-) animals. Importantly, the loss of intranuclear musculoaponeurotic fibrosarcoma oncogene homolog A(MafA) that was observed in nontransgenic db/db mice was prevented by GPx-1 overexpression, making this a likely mechanism for the improved glycemic control. These studies demonstrate that enhancement of intrinsic antioxidant defenses of the beta-cell protects it against deterioration during hyperglycemia. (Endocrinology 150: 4855-4862, 2009)