Shu Tingting, Lv Zhigang, Xie Yuchun, Tang Junming, Mao Xuhua
Department of Central Laboratory, Jiangsu Province Official Hospital, Nanjing, Jiangsu, China.
Department of Clinical Laboratory, Yixing People Hospital, Affiliated Jiangsu University, Yixing, Wuxi, Jiangsu, China.
Endocr Connect. 2019 Mar 1;8(3):150-161. doi: 10.1530/EC-18-0516.
It has been well established that glucotoxicity induces pancreatic β-cells dysfunction; however, the precise mechanism remains unclear. Our previous studies demonstrated that high glucose concentrations are associated with decreased hepcidin expression, which inhibits insulin synthesis. In this study, we focused on the role of low hepcidin level-induced increased iron deposition in β-cells and the relationship between abnormal iron metabolism and β-cell dysfunction. Decreased hepcidin expression increased iron absorption by upregulating transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) expression, resulting in iron accumulation within cells. Prussia blue stain and calcein-AM assays revealed greater iron accumulation in the cytoplasm of pancreatic tissue isolated from db/db mice, cultured islets and Min6 cells in response to high glucose stimulation. Increased cytosolic iron deposition was associated with greater Fe2+ influx into the mitochondria, which depolarized the mitochondria membrane potential, inhibited ATP synthesis, generated excessive ROS and induced oxidative stress. The toxic effect of excessive iron on mitochondrial function eventually resulted in impaired insulin secretion. The restricted iron content in db/db mice via reduced iron intake or accelerated iron clearance improved blood glucose levels with decreased fasting blood glucose (FBG), fasting blood insulin (FIns), HbA1c level, as well as improved intraperitoneal glucose tolerance test (IPGTT) results. Thus, our study may reveal the mechanism involved in the role of hepcidin in the glucotoxcity impaired pancreatic β cell function pathway.
葡萄糖毒性诱导胰腺β细胞功能障碍已得到充分证实；然而，确切机制仍不清楚。我们之前的研究表明，高葡萄糖浓度与铁调素表达降低有关，而铁调素会抑制胰岛素合成。在本研究中，我们重点关注低铁调素水平诱导β细胞中铁沉积增加的作用，以及铁代谢异常与β细胞功能障碍之间的关系。铁调素表达降低通过上调转铁蛋白受体1（TfR1）和二价金属转运蛋白1（DMT1）的表达增加铁吸收，导致细胞内铁蓄积。普鲁士蓝染色和钙黄绿素-AM检测显示，在高葡萄糖刺激下，从db/db小鼠分离的胰腺组织、培养的胰岛和Min6细胞的细胞质中铁蓄积更多。细胞溶质中铁沉积增加与更多的Fe2+流入线粒体有关，这使线粒体膜电位去极化，抑制ATP合成，产生过量的活性氧并诱导氧化应激。过量铁对线粒体功能的毒性作用最终导致胰岛素分泌受损。通过减少铁摄入或加速铁清除来限制db/db小鼠体内的铁含量，可改善血糖水平，降低空腹血糖（FBG）、空腹血胰岛素（FIns）、糖化血红蛋白（HbA1c）水平，并改善腹腔内葡萄糖耐量试验（IPGTT）结果。因此，我们的研究可能揭示了铁调素在葡萄糖毒性损害胰腺β细胞功能途径中的作用机制。
