Wang Xinhui, Fang Xuexian, Wang Fudi
Department of Nutrition, Research Center for Nutrition and Health, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China.
Rev Endocr Metab Disord. 2015 Mar;16(1):15-23. doi: 10.1007/s11154-014-9303-y.
As an essential element, iron plays a central role in many physiological processes, including redox balance, inflammation, energy metabolism, and environment sensing. Perturbations in iron homeostasis are associated with several conditions, including hyperglycemia and diabetes, both of which have been studied in patients and animal models. To clarify the pleiotropic role of iron homeostasis in diabetes development, the early studies on diseases with iron-overload, studies on clinical iron depletion therapies, associations between iron-related genetic polymorphisms and diabetes, and etiological mechanisms underlying iron perturbations-impaired insulin secretion and insulin sensitivity were carefully reviewed and discussed. Hereditary hemochromatosis, transfusion-dependent thalassemia, and excess heme iron intake can increase the risk of developing diabetes. Genetically modified mice and mice fed a high-iron diet present with discrepant phenotypes due to differences in tissue iron distribution. Moreover, several genetic polymorphisms related to iron homeostasis have been associated with the risk of developing diabetes. Tightly controlled iron metabolism is essential for insulin secretion and insulin sensitivity, and iron overload in pancreatic islets alters reactive oxygen species (ROS) generation, as well as hypoxia-inducible factor-1α (HIF-1α) stability and adenosine triphosphate (ATP) synthesis, thereby impairing the function and viability of β-cells. Decreased levels of adiponectin, macrophage-mediated inflammation, and ROS-mediated liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) activation can contribute to iron overload-induced insulin resistance, whereas iron deficiency could also participate in obesity-related inflammation, hypoxia, and insulin resistance. Because iron homeostasis is closely correlated with many metabolic processes, future studies are needed in order to elucidate the finely tuned network among iron homeostasis, carbohydrate and lipid metabolism, inflammation, and hypoxia.
作为一种必需元素，铁在许多生理过程中发挥着核心作用，包括氧化还原平衡、炎症、能量代谢和环境感知。铁稳态的紊乱与多种病症相关，包括高血糖和糖尿病，这两种病症均已在患者和动物模型中进行了研究。为了阐明铁稳态在糖尿病发展中的多效性作用，我们仔细回顾并讨论了关于铁过载疾病的早期研究、临床铁耗竭疗法的研究、铁相关基因多态性与糖尿病之间的关联，以及铁紊乱损害胰岛素分泌和胰岛素敏感性的病因机制。遗传性血色素沉着症、输血依赖型地中海贫血和过量的血红素铁摄入会增加患糖尿病的风险。由于组织铁分布的差异，基因改造小鼠和喂食高铁饮食的小鼠呈现出不同的表型。此外，几种与铁稳态相关的基因多态性与患糖尿病的风险有关。严格控制铁代谢对于胰岛素分泌和胰岛素敏感性至关重要，胰岛中的铁过载会改变活性氧（ROS）的生成，以及缺氧诱导因子-1α（HIF-1α）的稳定性和三磷酸腺苷（ATP）的合成，从而损害β细胞的功能和活力。脂联素水平降低、巨噬细胞介导的炎症以及ROS介导的肝激酶B1（LKB1）/单磷酸腺苷激活蛋白激酶（AMPK）激活可导致铁过载诱导的胰岛素抵抗，而铁缺乏也可能参与肥胖相关的炎症、缺氧和胰岛素抵抗。由于铁稳态与许多代谢过程密切相关，因此需要进一步的研究来阐明铁稳态、碳水化合物和脂质代谢、炎症以及缺氧之间精细调节的网络。
