Nuclear Factor Erythroid 2-Related Factor 2 Deletion Impairs Glucose Tolerance and Exacerbates Hyperglycemia in Type 1 Diabetic Mice
Nuclear Factor Erythroid 2-Related Factor 2 Deletion Impairs Glucose Tolerance and Exacerbates Hyperglycemia in Type 1 Diabetic Mice
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DOI：
10.1124/jpet.109.162271
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
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作者：
Aleksunes, Lauren M.;Reisman, Scott A.;Klaassen, Curtis D.
转录因子核因子红细胞2相关因子2（Nrf2）在氧化应激后诱导一系列细胞保护基因。Nrf2通过改变胰岛素信号传导来辅助肝再生;然而，Nrf2是否参与肝葡萄糖稳态尚不清楚。与野生型小鼠相比，缺乏Nrf2（Nrf2-null）的小鼠具有较低的基础血清胰岛素和对腹膜内葡萄糖挑战的长期高血糖反应。在本研究中，在雄性糖尿病野生型和Nrf2缺失小鼠中定量血糖、血清胰岛素、尿流速和葡萄糖相关基因的肝脏表达。1型糖尿病诱导与单次腹腔注射剂量（200毫克/公斤）的链脲佐菌素（STZ）。组织学和血清胰岛素水平证实了两种基因型的STZ治疗小鼠的胰腺β细胞耗竭。STZ后五天，Nrf 2缺失小鼠的血糖水平高于野生型小鼠。STZ后9天，两种基因型均出现多尿，Nrf2基因敲除小鼠的尿量（11倍）比野生型小鼠（7倍）多。此外，与野生型小鼠相比，STZ治疗的Nrf2-null小鼠在STZ后10天具有更高水平的血清β-羟基丁酸酯、甘油三酯和脂肪酸。STZ减少了两种基因型的肝糖原，在Nrf2缺失小鼠中观察到较少。STZ处理的Nrf2基因缺失小鼠的尿量和血糖增加与肝脏中增强的糖酵解（葡萄糖-6-磷酸酶和磷酸烯醇式丙酮酸羧激酶）和减少的糖酵解（丙酮酸激酶）相关mRNA表达相对应。此外，Nrf2激活剂oltipraz降低了野生型而非Nrf2缺失小鼠的血糖。总的来说，这些数据表明，在I型糖尿病小鼠中，Nrf2的缺失导致高血糖，并且Nrf2可能代表降低循环葡萄糖水平的治疗靶点。
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces a battery of cytoprotective genes after oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared with wild-type mice, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an intraperitoneal glucose challenge. In the present study, blood glucose, serum insulin, urine flow rate, and hepatic expression of glucose-related genes were quantified in male diabetic wild-type and Nrf2-null mice. Type 1 diabetes was induced with a single intraperitoneal dose (200 mg/kg) of streptozotocin (STZ). Histopathology and serum insulin levels confirmed depleted pancreatic beta-cells in STZ-treated mice of both genotypes. Five days after STZ, Nrf2-null mice had higher blood glucose levels than wild-type mice. Nine days after STZ, polyuria occurred in both genotypes with more urine output from Nrf2-null mice (11-fold) than wild-type mice (7-fold). Moreover, STZ-treated Nrf2-null mice had higher levels of serum beta-hydroxybutyrate, triglycerides, and fatty acids 10 days after STZ compared with wildtype mice. STZ reduced hepatic glycogen in both genotypes, with less observed in Nrf2-null mice. Increased urine output and blood glucose in STZ-treated Nrf2-null mice corresponded with enhanced gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase)- and reduced glycolysis (pyruvate kinase)-related mRNA expression in their livers. Furthermore, the Nrf2 activator oltipraz lowered blood glucose in wild-type but not Nrf2-null mice administered STZ. Collectively, these data indicate that the absence of Nrf2 worsens hyperglycemia in type I diabetic mice and Nrf2 may represent a therapeutic target for reducing circulating glucose levels.