ESPE Yearbook of Paediatric Endocrinology

Brief summary: This paper reviews the associations between cellular iron, ferroptosis and diabetes. It also explores the therapeutic potential of ferroptosis inhibitors in the treatment of diabetic complications.

Comment: Ferroptosis is a form of regulated cell death that is characterized by the decreased capacity of antioxidants and the accumulation of lipid reactive oxygen species (ROS).¹ This, in turn, causes oxidative damage to cell membranes and results in cell death. Ferroptosis is distinct from other forms of cell death, such as apoptosis or necrosis, and its molecular mechanisms are unique. Iron has a critical role in driving lipid peroxidation, and regulation of iron abundance in cells dictates sensitivity to ferroptosis. Increased levels of intracellular labile iron can amplify ROS production and exacerbate lipid peroxidation, promoting ferroptotic cell death. Ferroptosis has been implicated in various pathological conditions, including neurodegenerative diseases and cancer.²

This comprehensive review elucidates the regulatory mechanisms underlying ferroptosis in diabetes and diabetes complications. The authors describe the potential of ferroptosis inhibitors as therapeutic interventions for diabetic complications. They reviewed the association between iron metabolism and glucose homeostasis. A potential association was demonstrated between iron storage and T2D. You will remember that ‘bronze diabetes’ is a known manifestation of the rare iron-overload disease, hereditary hemochromatosis, caused by inherited mutations in iron regulatory genes. It is now clear that even among the general population there is an association of higher plasma serum ferritin levels with an increased risk of T2D. Reducing iron storage in vivo results in improved insulin secretion and improved peripheral tissue insulin sensitivity.

Ferroptosis is also associated with microangiopathy, as iron overload is associated with early development and an accelerated course of diabetic nephropathy. An example is in patients with thalassemia, another disorder characterised by iron overload due to repeated blood transfusions.

As ferroptosis is a cause of T2D and its complications, it is a promising therapeutic target for the treatment and prevention of T2D and its complications. It has been suggested that the effectiveness of metformin in T2D is related to its inhibition of ferroptosis. Furthermore, quercetin, a flavonoid, is a natural inhibitor of iron metabolism and is beneficial in improving conditions caused by iron overload. Quercetin treatment has been shown to have a potential beneficial effect on T2DM, by inhibiting pancreas β cell ferroptosis.

References: 1. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022 Jul 7;185(14):2401–2421. doi: 10.1016/j.cell.2022.06.003. PMID: 35803244; PMCID: PMC9273022. 2. Demuynck R, Efimova I, Catanzaro E, Krysko DV. Ferroptosis: friend or foe in cancer immunotherapy? Oncoimmunology. 2023 Feb 23;12(1):2182992. doi: 10.1080/2162402X.2023.2182992. PMID: 36875549; PMCID: PMC9980624.