The role of phosphoinositide 3-kinase/Akt signaling in low-dose mercury-induced mouse pancreatic β-cell dysfunction in vitro and in vivo
The role of phosphoinositide 3-kinase/Akt signaling in low-dose mercury-induced mouse pancreatic β-cell dysfunction in vitro and in vivo
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DOI：
10.2337/db06-0029
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发表时间：
2006-06-01
期刊：
影响因子：
7.7
通讯作者：
Liu, Shing Hwa
中科院分区：
文献类型：
--
作者：
Chen, Ya Wen;Huang, Chun Fa;Liu, Shing Hwa
胰腺β细胞功能障碍中氧化应激与磷酸肌醇激酶（PI3K）信号传导之间的关系尚不清楚。汞是一种众所周知的有毒金属，可引起氧化应激。亚微摩尔浓度的HgCl2或甲基汞触发p细胞来源的HIT-T15细胞和离体小鼠胰岛的活性氧（ROS）产生并降低胰岛素分泌。汞增加PI3K活性及其下游效应物Akt磷酸化。抗氧化剂n -乙酰- l-半胱氨酸（NAC）抑制汞诱导的胰岛素分泌抑制和Akt磷酸化，但不增加pI3K活性。用PI3K抑制剂或通过表达显性阴性p85或Akt抑制PI3K/Akt活性可阻止汞诱导的胰岛素分泌抑制，但不能抑制ROS的产生。这些结果表明PI3K和ROS都独立调节Akt信号相关的汞诱导的胰岛素分泌抑制。我们接下来观察到，小鼠口服低剂量汞2或4周后，血浆胰岛素显著下降，血糖升高，血脂过氧化和葡萄糖耐受不良。在汞暴露小鼠胰岛中发现Akt磷酸化。NAC可有效拮抗汞诱导的反应。终止汞接触后，汞诱导的体内效应和血汞升高得到逆转。这些结果表明，低剂量汞诱导的氧化应激和PI3K激活导致Akt信号相关的胰腺β细胞功能障碍。
The relationship between oxidation stress and phosphoinositide 3-kinase (PI3K) signaling in pancreatic beta-cell dysfunction remains unclear. Mercury is a well-known toxic metal that induces oxidative stress. Submicromolar-concentration HgCl2 or methylmercury triggered reactive oxygen species (ROS) production and decreased insulin secretion in P-cell-derived HIT-T15 cells and isolated mouse islets. Mercury increased PI3K activity and its downstream effector Akt phosphorylation. Antioxidant N-acetyl-L-cysteine (NAC) prevented mercury-induced insulin secretion inhibition and Akt phosphorylation but not increased pI3K activity. Inhibition of PI3K/Akt activity with PI3K inhibitor or by expressing the dominant-negative p85 or Akt prevented mercury-induced insulin secretion inhibition but not ROS production. These results indicate that both PI3K and ROS independently regulated Akt signaling-related, mercury-induced insulin secretion inhibition. We next observed that 2- or 4-week oral exposure to low-dose mercury to mice significantly caused the decrease in plasma insulin and displayed the elevation of blood glucose and plasma lipid peroxidation and glucose intolerance. Akt phosphorylation was shown in islets isolated from mercury-exposed mice. NAC effectively antagonized mercury-induced responses. Mercury-induced in vivo effects and increased blood mercury were reversed after mercury exposure was terminated. These results demonstrate that low-dose mercury-induced oxidative stress and PI3K activation cause Akt signaling-related pancreatic beta-cell dysfunction.