Section for Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Physiology, University of Toronto, Toronto, ON, Canada.
Acta Physiol (Oxf). 2014 Apr;210(4):717-32. doi: 10.1111/apha.12256.
The interest in the role of ferrous iron in diabetes pathophysiology has been revived by recent evidence of iron as an important determinant of pancreatic islet inflammation and as a biomarker of diabetes risk and mortality. The iron metabolism in the β-cell is complex. Excess free iron is toxic, but at the same time, iron is required for normal β-cell function and thereby glucose homeostasis. In the pathogenesis of diabetes, iron generates reactive oxygen species (ROS) by participating in the Fenton chemistry, which can induce oxidative damage and apoptosis. The aim of this review is to present and discuss recent evidence, suggesting that iron is a key pathogenic factor in both type 1 and type 2 diabetes with a focus on inflammatory pathways. Pro-inflammatory cytokine-induced β-cell death is not fully understood, but may include iron-induced ROS formation resulting in dedifferentiation by activation of transcription factors, activation of the mitochondrial apoptotic machinery or of other cell death mechanisms. The pro-inflammatory cytokine IL-1β facilitates divalent metal transporter 1 (DMT1)-induced β-cell iron uptake and consequently ROS formation and apoptosis, and we propose that this mechanism provides the relay between inflammation and oxidative β-cell damage. Iron chelation may be a potential therapeutic approach to reduce disease severity and mortality among diabetes patients. However, the therapeutic effect and safety of iron reduction need to be tested in clinical trials before dietary interventions or the use of iron chelation therapy titrated to avoid anaemia.
铁在糖尿病发病机制中的作用引起了人们的兴趣，最近的证据表明，铁是胰岛炎症的重要决定因素，也是糖尿病风险和死亡率的生物标志物。β细胞中的铁代谢很复杂。过量的游离铁是有毒的，但同时，铁是β细胞正常功能所必需的，从而维持血糖平衡。在糖尿病的发病机制中，铁通过参与芬顿化学参与生成活性氧（ROS），这会导致氧化损伤和细胞凋亡。本综述的目的是介绍和讨论最近的证据，表明铁是 1 型和 2 型糖尿病的关键致病因素，重点是炎症途径。促炎细胞因子诱导的β细胞死亡尚未完全阐明，但可能包括铁诱导的 ROS 形成，通过激活转录因子、激活线粒体凋亡机制或其他细胞死亡机制导致去分化。促炎细胞因子 IL-1β促进二价金属转运蛋白 1（DMT1）诱导的β细胞铁摄取，进而导致 ROS 形成和细胞凋亡，我们提出，这种机制提供了炎症和氧化β细胞损伤之间的联系。铁螯合可能是一种潜在的治疗方法，可以降低糖尿病患者的疾病严重程度和死亡率。然而，在进行饮食干预或使用铁螯合疗法来避免贫血之前，需要在临床试验中测试铁减少的治疗效果和安全性。
