Ding Yin-Yi, Li Zhu-Qing, Cheng Xiang-Rong, Ran Yu-Mei, Wu Sha-Ji, Shi Yonghui, Le Guowei
Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China.
The State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Lihu Avenue 1800, Wuxi, 214122, China.
Amino Acids. 2017 Aug;49(8):1401-1414. doi: 10.1007/s00726-017-2442-1. Epub 2017 Jun 17.
Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in insulin synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co-activator factors (RXRα, Src-1), together with the decreased protein level of thyroid hormone receptor β1 (TRβ1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in insulin synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated insulin secretion by upregulating mRNA levels of insulin synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRβ1. These data suggest that Dityr suppress T3-regulated insulin synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder.
氧化酪氨酸产物常见于高蛋白含量的食物中，并且在我们之前的研究中已被证明会导致肝脏和肾脏损伤。二酪氨酸（Dityr）是一种典型的氧化酪氨酸产物。由于其与甲状腺激素T3的结构同源性，我们推测最有可能与其被Dityr破坏相关的内分泌系统之一可能是T3作用。T3在胰岛素合成中起重要作用，并且甲状腺激素抵抗（RTH）与葡萄糖代谢受损有关。因此，本研究确定了Dityr暴露是否会损害胰腺中的T3功能，从而导致葡萄糖代谢紊乱。用Dityr灌胃10周后，小鼠表现出葡萄糖耐量受损和能量代谢紊乱。血浆中游离甲状腺激素（THs）含量升高、甲状腺中THs合成特异性基因表达上调以及甲状腺滤泡组织学形态和面积增加表明Dityr增强了甲状腺中的THs合成。此外，Dityr诱导的RTH表现为在未抑制的促甲状腺激素存在下血浆游离THs升高。胰腺中T3膜转运体（MCT8）和共激活因子（RXRα、Src-1）的mRNA下调，以及甲状腺激素受体β1（TRβ1）蛋白水平降低，说明Dityr抑制了T3对胰岛素合成相关下游基因的激活能力。在MIN-6细胞实验中，T3通过上调胰岛素合成相关基因（Ins2、MafA、Pdx1）和T3作用相关基因的mRNA水平，以及增加TRβ1蛋白水平来改善葡萄糖刺激的胰岛素分泌。这些数据表明，Dityr通过间接降低胰腺对T3的敏感性来抑制葡萄糖刺激的T3调节的胰岛素合成。所有这些发现表明，Dityr可破坏胰腺中的THs功能，导致葡萄糖代谢紊乱。
