Iron overload is related to elevated blood glucose levels in obese children and aggravates high glucose-induced endothelial cell dysfunction in vitro

Abstract

IntroductionThis study was performed to investigate the role of iron overload in the early stage of hyperglycemia-induced vascular functional impairment.Research design and methodsA total of 196 obese children were enrolled, and data regarding ferritin levels, blood glucose levels, intima-media thickness of carotid arteries, liver function and fibrosis index, hemoglobin, blood pressure, blood lipids, and inflammation indicators were collected. Ferritin levels were compared with a control group, which consisted of 148 healthy non-obese children who were age-matched and gender-matched. Endothelial cells were cultured in high glucose medium and supplemented with ferric citrate with or without iron remover (deferoxamine), a reducing agent (N-acetyl-cysteine), or a nuclear factor-κB (NF-κB) inhibitor (BAY 11-7082). Apoptosis, oxidative stress, nitric oxide levels, and endothelin content were evaluated. DNA microarray analysis was performed to analyze the expression of genes in the NF-κB signaling pathway.ResultsObese children have significantly higher ferritin levels compared with the control group. Ferritin level was positively correlated with hemoglobin and was related to metabolic disorders, including impaired glucose tolerance, higher blood pressure, dyslipidemia, and impaired hepatic function. Endothelial cells treated with ferric citrate showed a significantly higher rate of apoptosis, higher levels of oxidative stress, and impaired vasomotor function under high glucose conditions. The above effects were rescued by treatment with an iron remover, reducing agent, or NF-κB inhibitor. Further, detection of phosphorylated-p65 distribution in cells confirmed activation of the NF-κB pathway. DNA microarrays and subsequent gene oncology enrichment analyses revealed the main processes activated in cells.ConclusionIncreased ferritin levels are related to impaired glucose tolerance and other metabolic disorders in obese children. At the cellular level, iron overload aggravated the endothelial cell dysfunction caused by high glucose.

Effects of Hyperferritinemia on Functional Outcome in Acute Ischemic Stroke Patients with Admission Hyperglycemia

“…Experimental studies have provided some insight into the cooperative effects of hyperglycemia and increased iron. Ferritin could aggravate cell damage and dysfunction in cells cultured with high glucose by nuclear factor-κB activation, inflammatory response, lipopolysaccharide-mediated signaling pathway, protein kinase B signaling, and regulation of nitric oxide biosynthesis [19]. Excessive iron increased markers of ferroptosis and lipid reactive oxygen species in brain microvascular endothelial cells from diabetic animals [20].…”

“…Some studies reported elevated serum ferritin is related to poorer prognosis of ischemic stroke [14-17], whereas other study found higher serum ferritin could not predict functional disability at 3 months [18]. Besides, high iron status may have a cooperative effect on the process of cell damage and dysfunction induced by hyperglycemic status [19, 20]. Our previous study reported acute iron overload affects mortality and neurologic deficits at 24 h after transient focal ischemia in rats with hyperglycemia [21].…”

Oxidative Stress and Lipid Peroxidation: Prospective Associations Between Ferroptosis and Delayed Wound Healing in Diabetic Ulcers

“…One of the main sources of endothelial oxidative stress and inflammation is hyperglycemia, and iron overload aggravates endothelial dysfunction caused by hyperglycemia (Wu et al, 2020). Iron overload enhances oxidative stress and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome signaling, triggering the evolution of several inflammatory mediators, resulting in a cascade of inflammatory responses and renal dysfunction in ironoverloaded rats (Chaudhary et al, 2018).…”

Ferroptosis and metabolic dysfunction‐associated fatty liver disease: Is there a link?

“…4,49 Epidemiological studies have also shown that elevated serum ferritin or iron overload are associated with higher levels of plasma glucose, diastolic blood pressure, uric acid and IR. 50,51 Thus, as schematically summarized in Figure 1, it is reasonable to hypothesize that ferroptosis is closely related to obesity, T2DM or other coexisting metabolic disorders that occur with MAFLD.…”