Iron regulatory protein 2 deficiency may correlate with insulin resistance

Zhou, Yaru; Wu, Wenyue; Xu, Zhifang; Liu, Yan; Chang, Hengrui; Yu, Peng; Zhang, Xiaojuan; Yu, Yang; Liu, Kuanzhi; Chang, Yan‐Zhong

doi:10.1016/j.bbrc.2019.01.022

Cited by 7 publications

(5 citation statements)

References 35 publications

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“…A recent study using a distinct Irp2 −/− mouse strain reported that 18-month-old male Irp2 −/− mice displayed hyperglycemia, insulin resistance as determined by ITTs, and no change in earlyphase glucose-stimulated insulin secretion 47 , while we found that 18-month-old male Irp2 −/− mice displayed reduced pancreatic insulin content and glucose-stimulated insulin secretion compared with WT mice. An explanation for this discrepancy is not clear, but may stem from differences in strain backgrounds or different assay conditions.…”

Section: Discussioncontrasting

confidence: 54%

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

et al. 2020

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Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking ironregulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t 6 A37 in tRNA Lys UUU to ms 2 t 6 A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms 2 t 6 A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2 −/− β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.

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Section: Discussioncontrasting

confidence: 54%

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

et al. 2020

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“…However, positive correlations were detected between glucose parameters and plasmatic ferritin and iron ( Supplementary Figure S1 ) showing a possible role of iron homeostasis in insulin resistance in these subjects. Along this line, several studies evidence the association between iron overload and insulin resistance [ 24 , 25 , 26 , 27 , 28 ]. However, the molecular mechanism involved has not yet been clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Additional studies showed a correlation between adipose oxidative stress and iron metabolism and evidence of a dysregulation of iron homeostasis in T2D [ 24 , 25 , 28 ], the molecular mechanism involved in this correlation has not been elucidated yet. Thus, we focused on iron uptake via TfR, due to the relevance of TfR translocation into GLUT4 transport [ 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of Protein Carbonylation on Human Adipose Tissue Dysfunction in Obesity and Insulin Resistance

et al. 2022

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Background: Obesity is characterized by adipose tissue dysregulation and predisposes individuals to insulin resistance and type 2 diabetes. At the molecular level, adipocyte dysfunction has been linked to obesity-triggered oxidative stress and protein carbonylation, considering protein carbonylation as a link between oxidative stress and metabolic dysfunction. The identification of specific carbonylated proteins in adipose tissue could provide novel biomarkers of oxidative damage related to metabolic status (i.e prediabetes). Thus, we aimed at characterizing the subcutaneous and omental human adipose tissue carbonylome in obesity-associated insulin resistance. Methods: 2D-PAGE was used to identify carbonylated proteins, and clinical correlations studies and molecular biology approaches including intracellular trafficking, reactive oxygen species assay, and iron content were performed using in vitro models of insulin resistance. Results: The carbonylome of human adipose tissue included common (serotransferrin, vimentin, actin, and annexin A2) and depot-specific (carbonic anhydrase and α-crystallin B in the subcutaneous depot; and α-1-antitrypsin and tubulin in the omental depot) differences that point out the complexity of oxidative stress at the metabolic level, highlighting changes in carbonylated transferrin expression. Posterior studies using in vitro prediabetic model evidence alteration in transferrin receptor translocation, linked to the prediabetic environment. Finally, ligand-receptor molecular docking studies showed a reduced affinity for carbonylated transferrin binding to its receptor compared to wild-type transferrin, emphasizing the role of transferrin carbonylation in the link between oxidative stress and metabolic dysfunction. Conclusions: The adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance.

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“…The iron-regulatory proteins (IRP) IRP-1 and IRP-2 respond to cellular iron levels. Interestingly, the role of IRP is cell specific and includes regulation of proteins involved in iron regulation, tumor suppression, and insulin resistance [11][12][13]. IRP-1 s function varies depending on the concentration of iron.…”

Section: Response To Cellular Iron Levelsmentioning

confidence: 99%

Iron Therapeutics in Women’s Health: Past, Present, and Future

et al. 2020

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Iron plays a unique physiological role in the maintenance of homeostasis and the pathological outcomes of the female reproductive tract. The dual nature of elemental iron has created an evolutionary need to tightly regulate its biological concentration. The female reproductive tract is particularly unique due to the constant cycle of endometrial growth and shedding, in addition to the potential need for iron transfer to a developing fetus. Here, iron regulation is explored in a number of physiologic states including the endometrial lining and placenta. While iron dysregulation is a common characteristic in many women’s health pathologies there is currently a lack of targeted therapeutic options. Traditional iron therapies, including iron replacement and chelation, are common treatment options for gynecological diseases but pose long term negative health consequences; therefore, more targeted interventions directed towards iron regulation have been proposed. Recent findings show potential benefits in a therapeutic focus on ferritin-hepcidin regulation, modulation of reactive oxygen species (ROS), and iron mediated cell death (ferroptosis). These novel therapeutics are the direct result of previous research in iron’s complex signaling pathway and show promise for improved therapy, diagnosis, and prognosis in women’s health.

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Iron regulatory protein 2 deficiency may correlate with insulin resistance

Cited by 7 publications

References 35 publications

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

Influence of Protein Carbonylation on Human Adipose Tissue Dysfunction in Obesity and Insulin Resistance

Iron Therapeutics in Women’s Health: Past, Present, and Future

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