Regulation of Insulin Degrading Enzyme Activity by Obesity-Associated Factors and Pioglitazone in Liver of Diet-Induced Obese Mice
Regulation of Insulin Degrading Enzyme Activity by Obesity-Associated Factors and Pioglitazone in Liver of Diet-Induced Obese Mice
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DOI：
10.1371/journal.pone.0095399
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发表时间：
2014-04-16
期刊：
影响因子：
3.7
通讯作者：
Ye, Jianping
中科院分区：
文献类型：
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作者：
Wei, Xiuqing;Ke, Bilun;Ye, Jianping
胰岛素降解酶（IDE）是治疗2型糖尿病（T2D）的潜在药物靶点。 IDE 通过多种组织中降解依赖性清除机制控制循环胰岛素。然而，关于肥胖中 IDE 调节的信息还不够。在这项研究中，我们测试了肥胖相关因素和吡格列酮对饮食诱导肥胖 (DIO) C57BL/6 小鼠 IDE 的调节作用。 DIO小鼠肝脏中IDE的酶活性和蛋白质水平增加。吡格列酮（10 mg/kg/天）给药 2 个月显着增强了 DIO 小鼠中 IDE 的酶活性（75%）、蛋白质（180%）和 mRNA（100%）。吡格列酮引起的变化伴随着空腹胰岛素下降 50% 和空腹血糖下降 20%。在小鼠肝癌细胞系（Hepa 1c1c7 细胞）中研究了肝脏中 IDE 调节的机制，其中吡格列酮（5 μM）在 8 小时的研究中以时间依赖性方式增加了 IDE 蛋白和 mRNA。游离脂肪酸（棕榈酸酯 300 mM）诱导 IDE 蛋白，但减少 mRNA。胰高血糖素诱导，TNF-α 降低 IDE 蛋白。胰岛素在相同条件下没有表现出任何活性。总之，吡格列酮、FFA和胰高血糖素直接增加，但TNF-α降低肝细胞中的IDE活性。结果表明，肥胖症中肝脏中的 IDE 活性受到多种因素的调节，吡格列酮可能诱导 IDE 活性来控制 T2D。
Insulin degrading enzyme (IDE) is a potential drug target in the treatment of type 2 diabetes (T2D). IDE controls circulating insulin through a degradation-dependent clearance mechanism in multiple tissues. However, there is not sufficient information about IDE regulation in obesity. In this study, we test obesity-associated factors and pioglitazone in the regulation of IDE in diet-induced obese (DIO) C57BL/6 mice. The enzyme activity and protein level of IDE were increased in the liver of DIO mice. Pioglitazone (10 mg/kg/day) administration for 2 months significantly enhanced the enzyme activity (75%), protein (180%) and mRNA (100%) of IDE in DIO mice. The pioglitazone-induced changes were coupled with 50% reduction in fasting insulin and 20% reduction in fasting blood glucose. The mechanism of IDE regulation in liver was investigated in the mouse hepatoma cell line (Hepa 1c1c7 cells), in which pioglitazone (5 mu M) increased IDE protein and mRNA in a time-dependent manner in an 8 h study. Free fatty acid (palmitate 300 mM) induced IDE protein, but reduced the mRNA. Glucagon induced, and TNF-alpha decreased IDE protein. Insulin did not exhibit any activity in the same condition. In summary, pioglitazone, FFA and glucagon directly increased, but TNF-alpha decreased the IDE activity in hepatocytes. The results suggest that IDE activity is regulated in liver by multiple factors in obesity and pioglitazone may induce IDE activity in the control of T2D.