Xu Jinxia, Zhang Wei, Lu Zhongbing, Zhang Fang, Ding Wenjun
Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Sino-Danish College, University of Chinese Academy of Sciences, No. 3 Zhongguancun South 1st Alley, Beijing 100190, China.
Int J Environ Res Public Health. 2017 Jul 14;14(7):787. doi: 10.3390/ijerph14070787.
Animal and epidemiological studies have suggested that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM) is associated with the risk of developing type 2 diabetes. However, the mechanism underlying this risk is poorly understood. In the present study, we investigated the effects of PM exposure on glucose homeostasis and related signaling pathways in mice. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2) C57BL/6 male mice were exposed to either ambient concentrated PM or filtered air (FA) for 12 weeks through a whole-body PM exposure system. At the end of the exposure, we assessed liver damage, and performed metabolic studies, gene expressions, as well as molecular signal transductions to determine the signaling pathways involving oxidative responses, insulin signaling, and glucose metabolism. Our results indicated that PM exposure for 12 weeks caused significant liver damage as evidenced by elevated levels of aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, PM exposure induced impaired glucose tolerance and inhibited glycogen synthesis, leading to hepatic insulin resistance indicated by higher glucose levels, higher area under the curve (AUC), and homeostasis model assessment of insulin resistance (HOMA-IR) values. We further found that PM exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes. Moreover, PM exposure activated the c-Jun N-terminal kinase (JNK) signaling pathway and increased insulin receptor substrate-1 (IRS-1) phosphorylation at Ser, but reduced protein kinase B phosphorylation at Ser. Taken together, our study demonstrated PM exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic insulin resistance.
动物和流行病学研究表明，暴露于空气动力学直径小于2.5μm的空气颗粒物（PM）与2型糖尿病的发病风险相关。然而，这种风险背后的机制尚不清楚。在本研究中，我们调查了PM暴露对小鼠葡萄糖稳态及相关信号通路的影响。通过全身PM暴露系统，将野生型和核因子红细胞2相关因子2（Nrf2）基因敲除（Nrf2-/-）的C57BL/6雄性小鼠暴露于环境浓缩PM或过滤空气（FA）中12周。在暴露结束时，我们评估了肝脏损伤，并进行了代谢研究、基因表达以及分子信号转导分析，以确定涉及氧化反应、胰岛素信号传导和葡萄糖代谢的信号通路。我们的结果表明，12周的PM暴露导致了显著的肝脏损伤，这可通过转氨酶（AST）和丙氨酸转氨酶（ALT）水平升高得到证明。此外，PM暴露导致葡萄糖耐量受损并抑制糖原合成，导致肝脏胰岛素抵抗，表现为血糖水平升高、曲线下面积（AUC）增加以及胰岛素抵抗的稳态模型评估（HOMA-IR）值升高。我们进一步发现，PM暴露显著增加了Nrf2和Nrf2调节的抗氧化基因的表达。此外，PM暴露激活了c-Jun氨基末端激酶（JNK）信号通路，增加了胰岛素受体底物1（IRS-1）丝氨酸位点的磷酸化，但降低了蛋白激酶B丝氨酸位点的磷酸化。综上所述，我们的研究表明，PM暴露引发了Nrf2介导的氧化反应并激活了JNK介导的抑制性信号通路，从而导致肝脏胰岛素抵抗。
