Iron and the Pathophysiology of Diabetes

Harrison, Alexandria; Lorenzo, Felipe; McClain, Donald A.

doi:10.1146/annurev-physiol-022522-102832

Cited by 55 publications

(48 citation statements)

References 154 publications

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“…Deferasirox, the first orally administered iron chelator approved by FDA, showed significant reversal effect on a TWAS signature in pancreas and consistently on the DGE signature in islets. Although there are currently no reports of deferasirox being used for diabetes, high iron is a risk factor for T2D and affects most of its cardinal features 67 . Collectively, our findings correspond to a variety of drugs that exhibit therapeutic evidence for T2D, underscoring the predictive performance of TReD.…”

Section: Resultsmentioning

confidence: 99%

Integrating population-level and cell-based signatures for drug repositioning

He,

Xu,

Zhou

et al. 2023

Preprint

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Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Furthermore, drugs with genetic evidence are more likely to progress successfully through clinical trials towards FDA approval. Exploiting these developments, single gene-based drug repositioning methods have been implemented, but approaches leveraging the entire spectrum of molecular signatures are critically underexplored. Most multi-gene-based approaches rely on differential gene expression (DGE) analysis, which is prone to identify the molecular consequence of disease and renders causal inference challenging. We propose a framework TReD (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based drug-induced transcriptome response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. The robustness is ensured by evaluation in additional cell screens. For an application, we implement the framework to identify potential drugs against COVID-19. Taking transcriptome-wide association study (TWAS) results from four relevant tissues and three DGE results as disease features, we identify 37 drugs showing potential reversal roles in at least four of the seven disease signatures. Notably, over 70% (27/37) of the drugs have been linked to COVID-19 from other studies, and among them, eight drugs are supported by ongoing/completed clinical trials. For example, TReD identifies the well-studied JAK1/JAK2 inhibitor baricitinib, the first FDA-approved immunomodulatory treatment for COVID-19. Novel potential candidates, including enzastaurin, a selective inhibitor of PKC-beta which can be activated by SARS-CoV-2, are also identified. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Integrating population-level and cell-based signatures for drug repositioning

He,

Xu,

Zhou

et al. 2023

Preprint

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“…Previous evidence has linked diabetes with elevated serum ferritin levels, which is a risk factor for T2DM ( 21 ). High iron levels can have negative effects on key aspects of T2DM, such as insulin secretion, insulin resistance, and glucose production in the liver ( 42 ). This is true even when iron levels are within the normal range or in cases of excessive accumulation.…”

Section: Discussionmentioning

confidence: 99%

Quantitative susceptibility mapping for iron monitoring of multiple subcortical nuclei in type 2 diabetes mellitus: a systematic review and meta-analysis

Mohammadi,

Ghaderi,

Sayehmiri

et al. 2024

Front. Endocrinol.

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IntroductionIron accumulation in the brain has been linked to diabetes, but its role in subcortical structures involved in motor and cognitive functions remains unclear. Quantitative susceptibility mapping (QSM) allows the non-invasive quantification of iron deposition in the brain. This systematic review and meta-analysis examined magnetic susceptibility measured by QSM in the subcortical nuclei of patients with type 2 diabetes mellitus (T2DM) compared with controls.MethodsPubMed, Scopus, and Web of Science databases were systematically searched [following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines] for studies reporting QSM values in the deep gray matter (DGM) regions of patients with T2DM and controls. Pooled standardized mean differences (SMDs) for susceptibility were calculated using fixed-effects meta-analysis models, and heterogeneity was assessed using I2. Sensitivity analyses were conducted, and publication bias was evaluated using Begg’s and Egger’s tests.ResultsSix studies including 192 patients with T2DM and 245 controls were included. This study found a significant increase in iron deposition in the subcortical nuclei of patients with T2DM compared to the control group. The study found moderate increases in the putamen (SMD = 0.53, 95% CI 0.33 to 0.72, p = 0.00) and dentate nucleus (SMD = 0.56, 95% CI 0.27 to 0.85, p = 0.00) but weak associations between increased iron levels in the caudate nucleus (SMD = 0.32, 95% CI 0.13 to 0.52, p = 0.00) and red nucleus (SMD = 0.22, 95% CI 0.00 0.44, p = 0.05). No statistical significance was found for iron deposition alterations in the globus pallidus (SMD = 0.19; 95% CI −0.01 to 0.38; p = 0.06) and substantia nigra (SMD = 0.12, 95% CI −0.10, 0.34, p = 0.29). Sensitivity analysis showed that the findings remained unaffected by individual studies, and consistent increases were observed in multiple subcortical areas.DiscussionQSM revealed an increase in iron in the DGM/subcortical nuclei in T2DM patients versus controls, particularly in the motor and cognitive nuclei, including the putamen, dentate nucleus, caudate nucleus, and red nucleus. Thus, QSM may serve as a potential biomarker for iron accumulation in T2DM patients. However, further research is needed to validate these findings.

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“…High dietary iron and dysregulated iron metabolism are risk factors for type 2 diabetes mellitus (T2DM), affecting most of its features of decreased insulin secretion, insulin resistance and increased hepatic gluconeogenesis [ 29 ]. Dysregulated iron metabolism with increased serum levels of ferritin have been found in newly diagnosed type 2 diabetes but not in individuals with pre-diabetes [ 81 ].…”

Section: Iron Dysregulation Underlying Diseasementioning

confidence: 99%

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

Holbein

Lehmann

2023

Antioxidants

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Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases. Iron excess can promote proliferative diseases such as infections and cancer by supplying iron to pathogens or cancer cells. Toxicity from reactive iron plays roles in the pathogenesis of various metabolic, neurological and inflammatory diseases. Interestingly, a common underlying aspect of these conditions is availability of excess reactive iron. This underpinning aspect provides a potential new therapeutic avenue. Existing hematologically used iron chelators to take up excess iron have shown serious limitations for use but new purpose-designed chelators in development show promise for suppressing microbial pathogen and cancer cell growth, and also for relieving iron-induced toxicity in neurological and other diseases. Hepcidin and hepcidin agonists are also showing promise for relieving iron dysregulation. Harnessing iron-driven reactive oxygen species (ROS) generation with ferroptosis has shown promise for selective destruction of cancer cells. We review biological iron requirements, iron regulation and the nature of iron dysregulation in various diseases. Current results pertaining to potential new therapies are also reviewed.

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Iron and the Pathophysiology of Diabetes

Cited by 55 publications

References 154 publications

Integrating population-level and cell-based signatures for drug repositioning

Integrating population-level and cell-based signatures for drug repositioning

Quantitative susceptibility mapping for iron monitoring of multiple subcortical nuclei in type 2 diabetes mellitus: a systematic review and meta-analysis

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

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