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Xulu N, Nkosi A, Khathi A, Sibiya NH, Ngubane PS. Changes to the Haematological Parameters of Rat Offspring Born From High Fat High Carbohydrate (HFHC) Diet-Induced Prediabetic and Preeclamptic Sprague Dawley Rats: Assessing the Effects on Selected Haematological Markers. Diabetes Metab Syndr Obes 2025; 18:831-845. [PMID: 40134831 PMCID: PMC11934874 DOI: 10.2147/dmso.s436001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/21/2023] [Indexed: 03/27/2025] Open
Abstract
Introduction Infants delivered from preeclamptic pregnancies frequently exhibit developmental programming which leads to foetal growth restriction and foetal haematological abnormalities. Diabetes is recognised as a predisposing factor for preeclampsia (PE). Hyperglycaemia, a characteristic feature of pregestational type 2 diabetes, has been associated with the pathogenesis of intrauterine growth restriction (IUGR), a condition associated with disrupted foetal haematological pathways. Prediabetes pre-empts the onset of type 2 diabetes and is characterised by moderately elevated blood glucose levels, which have been shown in prediabetic models to induce erythrocyte dysfunction. However, the precise relationship between prediabetes and the development of preeclampsia or associated foetal complications remains to be fully elucidated. Accordingly, this study aims to investigate prediabetes as a risk factor for preeclampsia and its effects on selected haematological markers in Sprague Dawley rat pups. Methods and Materials Male and female pups born from normal, L-NAME preeclamptic and HFHC diet-induced prediabetic dams were immediately collected and weighed. The pups were then carefully returned to the dams for further development. On day 21, the pups were weaned and separated into males and females. Thereafter, the pups were sacrificed using a guillotine and blood and plasma was collected for haematological and biochemical analysis. Results Pups born from prediabetic and preeclamptic dams exhibited significantly lower birth weights than those born from normal pregnancies. Moreover, pups born from prediabetic and preeclamptic dams exhibited dysregulation of red blood cell (RBC) count, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO) levels, glutathione peroxidase (GPx) and malondialdehyde (MDA) concentrations compared to those delivered from normal dams. Conclusion These findings suggest prediabetes caused dysregulation of haematological parameters in offspring and may be a predisposing factor for the development of preeclampsia in pregnancy. Therefore, strict monitoring of prediabetes during pregnancy may reduce the risk of preeclampsia and resultant foetal morbidity and mortality.
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Affiliation(s)
- Nombuso Xulu
- Schools of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Ayanda Nkosi
- Schools of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Khathi
- Schools of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Ntethelelo H Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda, South Africa
| | - Phikelelani S Ngubane
- Schools of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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Kumar R, Kulshreshtha D, Aggarwal A, Asthana S, Dinda A, Mukhopadhyay CK. Glucose induced regulation of iron transporters implicates kidney iron accumulation. Biochim Biophys Acta Gen Subj 2024; 1868:130713. [PMID: 39278370 DOI: 10.1016/j.bbagen.2024.130713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/06/2024] [Accepted: 09/11/2024] [Indexed: 09/18/2024]
Abstract
Increased iron level is detected in rat kidney and human urine in diabetic condition and implicated in associated nephropathy. However, the biological cue and mechanism of the iron accumulation remain unclear. Here we reveal that glucose increases iron uptake by promoting transferrin receptor 1 (TFRC) in kidney cells by a translational mechanism but does not alter expression of endosomal iron transporter DMT1. Glucose decreases iron exporter ferroportin (FPN) by a protein degradation mechanism. Hepcidin is known to bind at Cys-326 residue in promoting degradation of human ferroportin. When Cys-326 was mutated to Ser in human-FPN-FLAG and expressed in kidney cells, glucose still could degrade FPN-FLAG implicating involvement of hepcidin independent mechanism in glucose induced ferroportin degradation. Chronic hyperglycemia was generated in rats by administering streptozotocin (STZ) with periodic insulin injection to determine the level of iron homeostasis components. Increased TFRC and decreased ferroportin levels were detected in hyperglycemic rat kidney by Western blot and immunohistochemistry analyses. Hepcidin mRNA was not significantly altered in kidney but was marginally decreased in liver. Perls' staining and non-heme iron estimation showed an elevated iron level in hyperglycemic rat kidney. These results suggest that high glucose dysregulates iron transport components resulting iron accumulation in diabetic kidney.
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Affiliation(s)
- Rajiv Kumar
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India
| | - Diksha Kulshreshtha
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ayushi Aggarwal
- All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India
| | - Somya Asthana
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Amit Dinda
- All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India.
| | - Chinmay K Mukhopadhyay
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
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Maiti S, Pal S, Chatterjee D, Dasgupta A, Podder A. Serum Uric Acid and Iron Status: Exploring a Complex Interaction in Metabolic Syndrome Patients of Eastern India. Cureus 2024; 16:e70803. [PMID: 39493039 PMCID: PMC11531647 DOI: 10.7759/cureus.70803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Metabolic syndrome, a cluster of illnesses including insulin resistance, hyperlipidemia, hypertension, and central obesity, is affecting roughly a quarter of the world population. Dysregulation of iron homeostasis may be associated with insulin resistance, leading to metabolic syndrome. Uric acid is an antioxidant currently studied in relation to several metabolic disorders. It may also be interlinked with iron metabolism. Yet, data regarding the interplay between serum iron, ferritin, and uric acid in metabolic syndrome are scarce. Hence, this study aimed to identify any alteration of serum iron, ferritin, and uric acid levels in metabolic syndrome patients of Eastern India and to explore any inter-relationship between these parameters. Methodology: A cross-sectional observational study including 103 patients suffering from metabolic syndrome and 107 age- and sex-matched healthy individuals was conducted. Subjects were evaluated for serum iron, ferritin, and uric acid levels, besides the diagnostic parameters of metabolic syndrome. RESULTS Metabolic syndrome cases had higher serum iron, ferritin, and uric acid levels as compared to the controls. Serum uric acid was positively correlated with both iron and ferritin. CONCLUSION Metabolic syndrome is associated with elevated serum levels of iron, ferritin, and uric acid. Iron overload, reflected in elevated serum ferritin, can cause oxidative stress and endothelial damage, thereby predisposing to metabolic and vascular complications. Uric acid, an antioxidant, can rise in an attempt to counter oxidative stress. Metabolic syndrome patients should be periodically assessed for iron profile and uric acid to design suitable treatment protocols for better management of disease progression and alleviation of complications.
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Affiliation(s)
- Saumyajit Maiti
- Biochemistry, North Bengal Medical College and Hospital, Siliguri, IND
| | - Sudipa Pal
- Biochemistry, Institute of Post Graduate Medical Education and Research, Kolkata, IND
| | - Debabrata Chatterjee
- Biochemistry, Tamralipto Government Medical College and Hospital, Midnapore, IND
| | - Arkajit Dasgupta
- Biochemistry, Teerthanker Mahaveer Medical College and Research Centre, Moradabad, IND
| | - Amrit Podder
- Physiology, Teerthanker Mahaveer Medical College and Research Centre, Moradabad, IND
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Chen Y, Zhao W, Hu A, Lin S, Chen P, Yang B, Fan Z, Qi J, Zhang W, Gao H, Yu X, Chen H, Chen L, Wang H. Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis. J Transl Med 2024; 22:409. [PMID: 38693581 PMCID: PMC11064363 DOI: 10.1186/s12967-024-05191-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024] Open
Abstract
With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.
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Affiliation(s)
- Yili Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen Zhao
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - An Hu
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Shi Lin
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Ping Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bing Yang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhirong Fan
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ji Qi
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wenhui Zhang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huanhuan Gao
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiubing Yu
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Haiyun Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Luyuan Chen
- Stomatology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 510086, China.
| | - Haizhou Wang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Ahern J, Boyle ME, Thompson WK, Fan CC, Loughnan R. Dietary and Lifestyle Factors of Brain Iron Accumulation and Parkinson's Disease Risk. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.13.24304253. [PMID: 38559115 PMCID: PMC10980125 DOI: 10.1101/2024.03.13.24304253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Purpose Iron is an essential nutrient which can only be absorbed through an individual's diet. Excess iron accumulates in organs throughout the body including the brain. Iron dysregulation in the brain is commonly associated with neurodegenerative diseases like Alzheimer's disease and Parkinson's Disease (PD). Our previous research has shown that a pattern of iron accumulation in motor regions of the brain related to a genetic iron-storage disorder called hemochromatosis is associated with an increased risk of PD. To understand how diet and lifestyle factors relate to this brain endophenotype and risk of PD we analyzed the relationship between these measures, estimates of nutrient intake, and diet and lifestyle preference using data from UK Biobank. Methods Using distinct imaging and non-imaging samples (20,477 to 28,388 and 132,023 to 150,603 participants, respectively), we performed linear and logistic regression analyses using estimated dietary nutrient intake and food preferences to predict a) brain iron accumulation score (derived from T2-Weighted Magnetic Resonance Imaging) and b) PD risk. In addition, we performed a factor analysis of diet and lifestyle preferences to investigate if latent lifestyle factors explained significant associations. Finally, we performed an instrumental variable regression of our results related to iron accumulation and PD risk to identify if there were common dietary and lifestyle factors that were jointly associated with differences in brain iron accumulation and PD risk. Results We found multiple highly significant associations with measures of brain iron accumulation and preferences for alcohol (factor 7: t=4.02, pFDR=0.0003), exercise (factor 11: t=-4.31, pFDR=0.0001), and high-sugar foods (factor 2: t=-3.73, pFDR=0.0007). Preference for alcohol (factor 7: t=-5.83, pFDR<1×10-8), exercise (factor 11: t=-7.66, pFDR<1×10-13), and high sugar foods (factor 2: t=6.03, pFDR<1×10-8) were also associated with PD risk. Instrumental variable regression of individual preferences revealed a significant relationship in which dietary preferences associated with higher brain iron levels also appeared to be linked to a lower risk for PD (p=0.004). A similar relationship was observed for estimates of nutrient intake (p=0.0006). Voxel-wise analysis of i) high-sugar and ii) alcohol factors confirmed T2-weighted signal differences consistent with iron accumulation patterns in motor regions of the brain including the cerebellum and basal ganglia. Conclusion Dietary and lifestyle factors and preferences, especially those related to carbohydrates, alcohol, and exercise, are related to detectable differences in brain iron accumulation and alterations in risk of PD, suggesting a potential avenue for lifestyle interventions that could influence risk.
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Affiliation(s)
- Jonathan Ahern
- Department of Cognitive Science, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
- Center for Human Development, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92161, USA
| | - Mary Et Boyle
- Department of Cognitive Science, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Wesley K Thompson
- Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK 74103, USA
| | - Chun Chieh Fan
- Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK 74103, USA
- Department of Radiology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92037, USA
| | - Robert Loughnan
- Department of Cognitive Science, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
- Center for Human Development, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92161, USA
- Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK 74103, USA
- Center for Multimodal Imaging and Genetics, University of California, San Diego School of Medicine, 9444 Medical Center Dr, La Jolla, CA 92037, USA
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Zhang QW, Wang Y, Tong ZY, Li CP, He LP. Vitamin D May Play a Vital Role in Alleviating Type 2 Diabetes Mellitus by Modulating the Ferroptosis Signaling Pathway. Horm Metab Res 2024; 56:193-196. [PMID: 37402397 DOI: 10.1055/a-2122-5701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/06/2023]
Abstract
Ferroptosis is an iron-dependent death mode mediated by the aggregation of lipid peroxides and lipid-reactive oxygen species. It is characterized by iron-dependent lipid peroxide accumulation accompanied by oxidoreductase deficiency. Pancreatic beta cell dysfunction and insulin resistance are two major causes of type 2 diabetes mellitus (T2DM). Iron accumulation and metabolism may play a role in the development of T2DM. The molecular mechanism of β cell apoptosis and iron death in T2DM were reviewed. In addition, we discuss recent insights on the relationship between the trace element iron and apoptosis of β cells in T2DM.
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Affiliation(s)
| | - Yan Wang
- School of Medicine, Taizhou University, Jiaojiang, China
| | - Zi-Ying Tong
- School of Medicine, Taizhou University, Jiaojiang, China
| | - Cui-Ping Li
- School of Medicine, Taizhou University, Jiaojiang, China
| | - Lian-Ping He
- School of Medicine, Taizhou University, Jiaojiang, China
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Ahmadi Badi S, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathog Dis 2024; 82:ftae005. [PMID: 38555503 PMCID: PMC10990161 DOI: 10.1093/femspd/ftae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024] Open
Abstract
INTRODUCTION There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis. AREA COVERED This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis. EXPERT OPINION One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.
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Affiliation(s)
- Sara Ahmadi Badi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX 76203, USA
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran,1963737611, Iran
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Vinokur V, Berenshtein E, Chevion M, Chevion D. A New Concept in Antidiabetic Therapeutics: A Concerted Removal of Labile Iron and Intracellular Deposition of Zinc. Diabetes Metab J 2024; 48:59-71. [PMID: 38173374 PMCID: PMC10850271 DOI: 10.4093/dmj.2022.0292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 04/10/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGRUOUND The inflammatory process is known to be an integral part of the pathophysiology of type 2 diabetes mellitus (T2DM). The "labile," redox-active iron, serving as a catalyst in Fenton reaction, producing the deleterious reactive oxygen species, triggering and maintaining inflammation, is hypothesized to play a causative role in this process. Concenter Biopharma continued the development of a new platform of iron chelators (Zygosids), first initiated at the Hebrew University of Jerusalem, Israel (HUJI), acting via the novel mechanism, based on a sequestration of the labile redox-active iron and its substitution by zinc or gallium. The mode of action of Zygosids is based on the higher affinity of the metal-binding moiety of the complex to Fe3+ in comparison to already bound ion, leading to rapid release of the ion of another metal and chelation of Fe3+. Concomitantly, zinc ion, released by the complex, is known for its antidiabetic and anti-inflammatory role. METHODS The therapeutic effect of zinc-desferrioxamine (Zygosid-50) and gallium-desferrioxamine, was tested on fat sand rat (Psammomys obesus) model of diet-induced T2DM and on Leprdb transgenic diabetic mice. RESULTS Zygosids demonstrated an ability to noticeably reduce blood glucose and insulin levels and improve the lipid profile. Moreover, an ability to mitigate insulin resistance by >90% was shown on the sand rat model. In addition, a potent anti-inflammatory effect, expressed as a diminishment of the proinflammatory cytokines in tissue levels, was demonstrated. CONCLUSION Zygosids demonstrated robust therapeutic efficacy in treatment of T2DM. Importantly, no adverse effects were detected, in all the experiments, indicating high safety profile.
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Affiliation(s)
- Vladimir Vinokur
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
- Concenter Biopharma, Jerusalem, Israel
| | - Eduard Berenshtein
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
| | - Mordechai Chevion
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
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Liang Y, Luo S, Wong THT, He B, Schooling CM, Au Yeung SL. Association of iron homeostasis biomarkers in type 2 diabetes and glycaemic traits: a bidirectional two-sample Mendelian randomization study. Int J Epidemiol 2023; 52:1914-1925. [PMID: 37400992 DOI: 10.1093/ije/dyad093] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 06/14/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Mendelian randomization (MR) studies show iron positively associated with type 2 diabetes (T2D) but included potentially biasing hereditary haemochromatosis variants and did not assess reverse causality. METHODS We assessed the relation of iron homeostasis with T2D and glycaemic traits bidirectionally, using genome-wide association studies (GWAS) of iron homeostasis biomarkers [ferritin, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT) (n ≤ 246 139)], T2D (DIAMANTE n = 933 970 and FinnGen n = 300 483), and glycaemic traits [fasting glucose (FG), 2-h glucose, glycated haemoglobin (HbA1c) and fasting insulin (FI) (n ≤ 209 605)]. Inverse variance weighting (IVW) was the main analysis, supplemented with sensitivity analyses and assessment of mediation by hepcidin. RESULTS Iron homeostasis biomarkers were largely unrelated to T2D, although serum iron was potentially associated with higher T2D [odds ratio: 1.07 per standard deviation; 95% confidence interval (CI): 0.99 to 1.16; P-value: 0.078) in DIAMANTE only. Higher ferritin, serum iron, TSAT and lower TIBC likely decreased HbA1c, but were not associated with other glycaemic traits. Liability to T2D likely increased TIBC (0.03 per log odds; 95% CI: 0.01 to 0.05; P-value: 0.005), FI likely increased ferritin (0.29 per log pmol/L; 95% CI: 0.12 to 0.47; P-value: 8.72 x 10-4). FG likely increased serum iron (0.06 per mmol/L; 95% CI: 0.001 to 0.12; P-value: 0.046). Hepcidin did not mediate these associations. CONCLUSION It is unlikely that ferritin, TSAT and TIBC cause T2D although an association for serum iron could not be excluded. Glycaemic traits and liability to T2D may affect iron homeostasis, but mediation by hepcidin is unlikely. Corresponding mechanistic studies are warranted.
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Affiliation(s)
- Ying Liang
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Shan Luo
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Tommy Hon Ting Wong
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Baoting He
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - C Mary Schooling
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
- School of Public Health and Health Policy, City University of New York, New York, NY, USA
| | - Shiu Lun Au Yeung
- School of Public Health, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
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Hilton C, Sabaratnam R, Drakesmith H, Karpe F. Iron, glucose and fat metabolism and obesity: an intertwined relationship. Int J Obes (Lond) 2023; 47:554-563. [PMID: 37029208 PMCID: PMC10299911 DOI: 10.1038/s41366-023-01299-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 03/08/2023] [Accepted: 03/16/2023] [Indexed: 04/09/2023]
Abstract
A bidirectional relationship exists between adipose tissue metabolism and iron regulation. Total body fat, fat distribution and exercise influence iron status and components of the iron-regulatory pathway, including hepcidin and erythroferrone. Conversely, whole body and tissue iron stores associate with fat mass and distribution and glucose and lipid metabolism in adipose tissue, liver, and muscle. Manipulation of the iron-regulatory proteins erythroferrone and erythropoietin affects glucose and lipid metabolism. Several lines of evidence suggest that iron accumulation and metabolism may play a role in the development of metabolic diseases including obesity, type 2 diabetes, hyperlipidaemia and non-alcoholic fatty liver disease. In this review we summarise the current understanding of the relationship between iron homoeostasis and metabolic disease.
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Affiliation(s)
- Catriona Hilton
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
| | - Rugivan Sabaratnam
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Zheng H, Yang F, Deng K, Wei J, Liu Z, Zheng YC, Xu H. Relationship between iron overload caused by abnormal hepcidin expression and liver disease: A review. Medicine (Baltimore) 2023; 102:e33225. [PMID: 36930080 PMCID: PMC10019217 DOI: 10.1097/md.0000000000033225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/16/2023] [Indexed: 03/18/2023] Open
Abstract
Iron is essential to organisms, the liver plays a vital role in its storage. Under pathological conditions, iron uptake by the intestine or hepatocytes increases, allowing excess iron to accumulate in liver cells. When the expression of hepcidin is abnormal, iron homeostasis in humans cannot be regulated, and resulting in iron overload. Hepcidin also regulates the release of iron from siderophores, thereby regulating the concentration of iron in plasma. Important factors related to hepcidin and systemic iron homeostasis include plasma iron concentration, body iron storage, infection, inflammation, and erythropoietin. This review summarizes the mechanism and regulation of iron overload caused by hepcidin, as well as related liver diseases caused by iron overload and treatment.
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Affiliation(s)
- Haoran Zheng
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Fan Yang
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Kaige Deng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jiaxin Wei
- Department of Emergency, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhenting Liu
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-Chang Zheng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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12
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Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell Death Dis 2023; 14:186. [PMID: 36882414 PMCID: PMC9992652 DOI: 10.1038/s41419-023-05708-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/09/2023]
Abstract
The maintenance of iron homeostasis is essential for proper endocrine function. A growing body of evidence suggests that iron imbalance is a key factor in the development of several endocrine diseases. Nowadays, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process to mediate the pathogenesis and progression of type 2 diabetes mellitus (T2DM). It has been shown that ferroptosis in pancreas β cells leads to decreased insulin secretion; and ferroptosis in the liver, fat, and muscle induces insulin resistance. Understanding the mechanisms concerning the regulation of iron metabolism and ferroptosis in T2DM may lead to improved disease management. In this review, we summarized the connection between the metabolic pathways and molecular mechanisms of iron metabolism and ferroptosis in T2DM. Additionally, we discuss the potential targets and pathways concerning ferroptosis in treating T2DM and analysis the current limitations and future directions concerning these novel T2DM treatment targets.
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Elumalai S, Karunakaran U, Moon JS, Won KC. Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting. Int J Mol Sci 2022; 23:13679. [PMID: 36430158 PMCID: PMC9690757 DOI: 10.3390/ijms232213679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/02/2022] [Accepted: 11/05/2022] [Indexed: 11/10/2022] Open
Abstract
Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure.
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Affiliation(s)
- Suma Elumalai
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
| | - Udayakumar Karunakaran
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
| | - Jun-Sung Moon
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea
| | - Kyu-Chang Won
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea
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14
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Park WR, Choi B, Kim YJ, Kim YH, Park MJ, Kim DI, Choi HS, Kim DK. Melatonin Regulates Iron Homeostasis by Inducing Hepcidin Expression in Hepatocytes. Int J Mol Sci 2022; 23:ijms23073593. [PMID: 35408955 PMCID: PMC8998539 DOI: 10.3390/ijms23073593] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/10/2022] Open
Abstract
The pineal hormone, melatonin, plays important roles in circadian rhythms and energy metabolism. The hepatic peptide hormone, hepcidin, regulates iron homeostasis by triggering the degradation of ferroportin (FPN), the protein that transfers cellular iron to the blood. However, the role of melatonin in the transcriptional regulation of hepcidin is largely unknown. Here, we showed that melatonin upregulates hepcidin gene expression by enhancing the melatonin receptor 1 (MT1)-mediated c-Jun N-terminal kinase (JNK) activation in hepatocytes. Interestingly, hepcidin gene expression was increased during the dark cycle in the liver of mice, whereas serum iron levels decreased following hepcidin expression. In addition, melatonin significantly induced hepcidin gene expression and secretion, as well as the subsequent FPN degradation in hepatocytes, which resulted in cellular iron accumulation. Melatonin-induced hepcidin expression was significantly decreased by the melatonin receptor antagonist, luzindole, and by the knockdown of MT1. Moreover, melatonin activated JNK signaling and upregulated hepcidin expression, both of which were significantly decreased by SP600125, a specific JNK inhibitor. Chromatin immunoprecipitation analysis showed that luzindole significantly blocked melatonin-induced c-Jun binding to the hepcidin promoter. Finally, melatonin induced hepcidin expression and secretion by activating the JNK-c-Jun pathway in mice, which were reversed by the luzindole treatment. These findings reveal a previously unrecognized role of melatonin in the circadian regulation of hepcidin expression and iron homeostasis.
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Affiliation(s)
- Woo-Ram Park
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (W.-R.P.); (B.C.); (Y.-J.K.)
| | - Byungyoon Choi
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (W.-R.P.); (B.C.); (Y.-J.K.)
| | - Yu-Ji Kim
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (W.-R.P.); (B.C.); (Y.-J.K.)
| | - Yong-Hoon Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Min-Jung Park
- Department of Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea; (M.-J.P.); (D.-I.K.)
| | - Dong-Il Kim
- Department of Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea; (M.-J.P.); (D.-I.K.)
| | - Hueng-Sik Choi
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea;
| | - Don-Kyu Kim
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (W.-R.P.); (B.C.); (Y.-J.K.)
- Correspondence: ; Tel.: +82-62-530-2166; Fax: +82-62-530-2160
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15
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Matta RA, AbdElftah ME, Essawy MG, Saedii AA. Interplay of serum hepcidin with female sex hormones, metabolic syndrome, and abdominal fat distribution among premenopausal and postmenopausal women. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2022. [DOI: 10.1186/s43162-022-00098-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background and purpose
Hepcidin is the central regulatory molecule of systemic iron homeostasis. Serum ferritin, insulin resistance (IR) and metabolic syndrome (MetS), female sex hormones, and abdominal fat distribution are related to each other and all are linked to menopausal state. Our study was the first to assess the impact of these parameters on hepcidin level among premenopausal women (group I) during the early follicular phase (group I-F) and mid-luteal-phase (group I-L) of the same reproductive cycle and among postmenopausal women (group II). Serum iron parameters, estrogen, progesterone and hepcidin, and plasma insulin were assessed. Abdominal subcutaneous fat (SCF) and peritoneal visceral fat (PVF) thickness were measured by unenhanced- CT. Group I and group II were divided into MetS and non-MetS subgroups.
Results
The entire group II and MetS-stratified subgroups had significant higher hepcidin level than corresponding group I-F and group I-L. Group I-L had significant higher hepcidin than group I-F. Among group I-F, group I-L, and group II, MetS subgroups had higher hepcidin but not hepcidin/ ferritin ratio (H/F) than corresponding non-MetS; and hepcidin had positive correlations with ferritin, insulin, IR, and SCF. In group I-F and group II, hepcidin had positive correlations with estrogen and progesterone; hepcidin levels increase significantly and linearly with increasing number of MetS features; and cut off values of hepcidin for prediction of MetS were 5.8 ≥ and ≥ 10.3 ng/ml respectively. Main contributors to hepcidin were iron and ferritin in all groups, SCF and progesterone in group I-F, and insulin, progesterone, and MetS in group II. H/F ratio was higher in group II.
Conclusion
Postmenopausal state (postMS), MetS, and luteal phase are independently associated with high hepcidin level. Serum iron parameters (iron and ferritin) as main regulators of hepcidin are preserved regardless of menopausal state. Its regulation differs based on menopausal state: IR, MetS, and progesterone in postMS meanwhile abdominal SCF and progesterone in premenopausal states. Despite positive associations of estrogen and progesterone with hepcidin, they do not explain its higher level in postMS. Hepcidin levels linearly increase with number of Mets feature and it had high sensitivity for diagnosis of MetS.
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16
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Marku A, Galli A, Marciani P, Dule N, Perego C, Castagna M. Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction. Cells 2021; 10:2841. [PMID: 34831062 PMCID: PMC8616520 DOI: 10.3390/cells10112841] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/26/2022] Open
Abstract
Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.
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Affiliation(s)
| | | | | | | | - Carla Perego
- Department of Excellence Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste, 22134 Milano, Italy; (A.M.); (A.G.); (P.M.); (N.D.)
| | - Michela Castagna
- Department of Excellence Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste, 22134 Milano, Italy; (A.M.); (A.G.); (P.M.); (N.D.)
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17
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Tiglis M, Cobilinschi C, Elena Mirea L, Emil Băetu A, Peride I, Paul Neagu T, Niculae A, Alexandru Checherită I, Marina Grintescu I. The Importance of Iron Administration in Correcting Anaemia After Major Surgery. J Crit Care Med (Targu Mures) 2021; 7:184-191. [PMID: 34722921 PMCID: PMC8519388 DOI: 10.2478/jccm-2021-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/21/2021] [Indexed: 11/20/2022] Open
Abstract
INTRODUCTION Postoperative anaemia can affect more than 90% of patients undergoing major surgeries. Patients develop an absolute iron deficiency in the face of significant blood loss or preoperative anaemia and major surgery. Studies have shown the negative impact of these factors on transfusion requirements, infections, increased hospitalisation and long-term morbidities. AIM OF THE STUDY The research was performed to determine the correlation between intravenous iron administration in the postoperative period and improved haemoglobin correction trend. MATERIAL AND METHODS A prospective study was conducted to screen and treat iron deficiency in patients undergoing major surgery associated with significant bleeding. For iron deficiency anaemia screening, in the postoperative period, the following bioumoral parameters were assessed: haemoglobin, serum iron, transferrin saturation (TSAT), and ferritin, direct serum total iron-binding capacity (dTIBC), mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH). In addition, serum glucose, fibrinogen, urea, creatinine and lactate values were also collected. RESULTS Twenty-one patients undergoing major surgeries (52,38% were emergency and 47,61% elective interventions) were included in the study. Iron deficiency, as defined by ferritin 100-300 μg/L along with transferrin saturation (TSAT) < 20 %, mean corpuscular volume (MVC) < 92 fL, mean corpuscular haemoglobin (MCH) < 33 g/dL, serum iron < 10 μmol/L and direct serum total iron-binding capacity (dTIBC) > 36 μmol/L, was identified in all cases. To correct the deficit and optimise the haematological status, all patients received intravenous ferric carboxymaltose (500-1000 mg, single dose). Using Quadratic statistical analysis, the trend of haemoglobin correction was found to be a favourable one. CONCLUSION The administration of intravenous ferric carboxymaltose in the postoperative period showed the beneficial effect of this type of intervention on the haemoglobin correction trend in these groups of patients.
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Affiliation(s)
- Mirela Tiglis
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Emergency Clinical Hospital of Bucharest, BucharestRomania
| | - Cristian Cobilinschi
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Emergency Clinical Hospital of Bucharest, BucharestRomania
| | - Liliana Elena Mirea
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Emergency Clinical Hospital of Bucharest, BucharestRomania
| | - Alexandru Emil Băetu
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Emergency Clinical Hospital of Bucharest, BucharestRomania
| | - Ileana Peride
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | | | - Andrei Niculae
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | | | - Ioana Marina Grintescu
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Emergency Clinical Hospital of Bucharest, BucharestRomania
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18
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Jo JR, Lee SE, An S, Nedumaran B, Ghosh S, Park KG, Kim YD. Gluconeogenic signals regulate hepcidin gene expression via a CRBN-KLF15 axis. BMB Rep 2021. [PMID: 33795032 PMCID: PMC8093939 DOI: 10.5483/bmbrep.2021.54.4.215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Hepcidin (HAMP) is synthesized in the liver. It is a key iron-regulatory hormone that controls systemic iron homeostasis. Cereblon (CRBN) and Kruppel-like factor 15 (KLF15) are known to regulate diverse physiological functions. In this study, we investigated the role of CRBN on hepatic hepcidin gene expression and production under gluconeogenic stimuli. Fasted mice as well as forskolin (FSK)- and glucagon (GLU)-treated mice had reduced serum iron levels but increased expression levels of hepatic Crbn and Klf15 and hepcidin secretion. MicroRNA (miRNA) expression analysis of fasted and Ad-Crbn-infected mice revealed significant reduction of microRNA-639 (miR-639). Hepatic overexpression of Crbn elevated hepcidin expression and production along with Klf15 gene expression, whereas knockdown of Crbn and Klf15 markedly decreased FSK- and fasting-mediated induction of hepcidin gene expression and its biosynthesis in mouse livers and primary hepatocytes. Moreover, expression of KLF15 significantly increased the activity of hepcidin reporter gene. It was exclusively dependent on the KLF15-binding site identified within the hepcidin gene promoter. Overall, this study demonstrates that CRBN and KLF15 are novel mediators of gluconeogenic signal-induced hepcidin gene expression and production. Thus, CRBN and KLF15 might be novel potential therapeutic targets to intervene metabolic dysfunction.
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Affiliation(s)
- Jeong-Rang Jo
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Sung-Eun Lee
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea
| | - Seungwon An
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA
| | - Balachandar Nedumaran
- Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Swati Ghosh
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Keun-Gyu Park
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Yong Deuk Kim
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea
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19
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Zeinivand M, Nahavandi A, Baluchnejadmojarad T, Roghani M, Golab F. Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation. Basic Clin Neurosci 2020; 11:795-804. [PMID: 33850616 PMCID: PMC8019852 DOI: 10.32598/bcn.11.6.1775.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 04/25/2019] [Accepted: 06/25/2019] [Indexed: 11/20/2022] Open
Abstract
Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models. Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200–250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6. Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline. Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.
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Affiliation(s)
- Motahareh Zeinivand
- Department of Physiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Nahavandi
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Iran, Iran
| | | | - Mehrdad Roghani
- Department of Physiology, School of Medicine, Shahed University, Tehran, Iran
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
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20
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Fillebeen C, Lam NH, Chow S, Botta A, Sweeney G, Pantopoulos K. Regulatory Connections between Iron and Glucose Metabolism. Int J Mol Sci 2020; 21:ijms21207773. [PMID: 33096618 PMCID: PMC7589414 DOI: 10.3390/ijms21207773] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/07/2020] [Accepted: 10/16/2020] [Indexed: 02/06/2023] Open
Abstract
Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.
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Affiliation(s)
- Carine Fillebeen
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
| | - Nhat Hung Lam
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Samantha Chow
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Amy Botta
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
- Correspondence: ; Tel.: +1-514-340-8260 (ext. 25293)
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21
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Bek SG, Üstüner B, Eren N, Sentürk Z, Gönüllü BK. The effect of hepcidin on components of metabolic syndrome in chronic kidney disease: a cross-sectional study. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2020; 66:1100-1107. [PMID: 32935805 DOI: 10.1590/1806-9282.66.8.1100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepcidin is an important regulator of iron homeostasis. OBJECTIVES This cross-sectional study was conducted to evaluate the association between hepcidin and components of metabolic syndrome in patients with chronic kidney disease (CKD). DESIGN AND SETTING 103 CKD patients and 59 healthy volunteers were included in the study from the University Hospital. METHODS Serum hepcidin levels were measured by enyzme-linked immunosorbent assay (ELISA) test. As for the study parameters, age, sex, body mass index, renal diseases, serum biochemistry, complete blood count, iron and total iron-binding capacity, ferritin, high-sensitive C-reactive protein (hsCRP), C- reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated. RESULTS The mean age of the patients was 58.63 ± 11.8 years. Hepcidin level was significantly associated with hypertension and higher uric acid levels (P < 0.05). There was a positive correlation between hepcidin and urea, uric acid, creatinine, ferritin, CRP, ESR, phosphorus, triglyceride, low-density lipoprotein (LDL), proteinuria and albuminuria in 24-hour urine collection. A negative correlation was found between hepcidin and estimated glomerular filtration rate (eGFR), hemoglobin, hematocrit, calcium, 25 OH vitamin D, pH, and bicarbonate levels. CONCLUSION Hepcidin, a well-known hormone regulator of iron metabolism, may play an important role in the pathogenesis of metabolic syndrome in patients with CKD, and further studies might delineate in-depth its potential as a promising early marker in these patients.
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Affiliation(s)
- Sibel Gökçay Bek
- . Assistant Professor, Nephrology Department, Kocaeli University Hospital, Internal Medicine, İzmit/Kocaeli, Turkey
| | - Berna Üstüner
- . Resident in Internal Medicine, Kocaeli University Hospital, Internal Medicine, İzmit/Kocaeli, Turkey
| | - Necmi Eren
- . Assistant Professor, Nephrology Department, Kocaeli University Hospital, Internal Medicine, İzmit/Kocaeli, Turkey
| | - Zeynep Sentürk
- . Resident in Internal Medicine, Kocaeli University Hospital, Internal Medicine, İzmit/Kocaeli, Turkey
| | - Betül Kalender Gönüllü
- . Assistant Professor, Nephrology Department, Kocaeli University Hospital, Internal Medicine, İzmit/Kocaeli, Turkey
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22
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Saraf SL, Gordeuk VR. Iron. ESSENTIAL AND TOXIC TRACE ELEMENTS AND VITAMINS IN HUMAN HEALTH 2020:83-102. [DOI: 10.1016/b978-0-12-805378-2.00006-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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23
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Shu T, Lv Z, Xie Y, Tang J, Mao X. Hepcidin as a key iron regulator mediates glucotoxicity-induced pancreatic β-cell dysfunction. Endocr Connect 2019; 8:150-161. [PMID: 30776286 PMCID: PMC6391907 DOI: 10.1530/ec-18-0516] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
Abstract
It has been well established that glucotoxicity induces pancreatic β-cells dysfunction; however, the precise mechanism remains unclear. Our previous studies demonstrated that high glucose concentrations are associated with decreased hepcidin expression, which inhibits insulin synthesis. In this study, we focused on the role of low hepcidin level-induced increased iron deposition in β-cells and the relationship between abnormal iron metabolism and β-cell dysfunction. Decreased hepcidin expression increased iron absorption by upregulating transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) expression, resulting in iron accumulation within cells. Prussia blue stain and calcein-AM assays revealed greater iron accumulation in the cytoplasm of pancreatic tissue isolated from db/db mice, cultured islets and Min6 cells in response to high glucose stimulation. Increased cytosolic iron deposition was associated with greater Fe2+ influx into the mitochondria, which depolarized the mitochondria membrane potential, inhibited ATP synthesis, generated excessive ROS and induced oxidative stress. The toxic effect of excessive iron on mitochondrial function eventually resulted in impaired insulin secretion. The restricted iron content in db/db mice via reduced iron intake or accelerated iron clearance improved blood glucose levels with decreased fasting blood glucose (FBG), fasting blood insulin (FIns), HbA1c level, as well as improved intraperitoneal glucose tolerance test (IPGTT) results. Thus, our study may reveal the mechanism involved in the role of hepcidin in the glucotoxcity impaired pancreatic β cell function pathway.
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Affiliation(s)
- Tingting Shu
- Department of Central Laboratory, Jiangsu Province Official Hospital, Nanjing, Jiangsu, China
| | - Zhigang Lv
- Department of Central Laboratory, Jiangsu Province Official Hospital, Nanjing, Jiangsu, China
| | - Yuchun Xie
- Department of Central Laboratory, Jiangsu Province Official Hospital, Nanjing, Jiangsu, China
| | - Junming Tang
- Department of Clinical Laboratory, Yixing People Hospital, Affiliated Jiangsu University, Yixing, Wuxi, Jiangsu, China
| | - Xuhua Mao
- Department of Clinical Laboratory, Yixing People Hospital, Affiliated Jiangsu University, Yixing, Wuxi, Jiangsu, China
- Correspondence should be addressed to X Mao:
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24
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Carlos AR, Weis S, Soares MP. Cross-Talk Between Iron and Glucose Metabolism in the Establishment of Disease Tolerance. Front Immunol 2018; 9:2498. [PMID: 30425714 PMCID: PMC6218924 DOI: 10.3389/fimmu.2018.02498] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 10/10/2018] [Indexed: 12/13/2022] Open
Abstract
Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection.
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Affiliation(s)
| | - Sebastian Weis
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.,Institute for Infectious Disease and Infection Control, Jena University Hospital, Jena, Germany.,Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
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25
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Chand SK, Singh RG, Pendharkar SA, Petrov MS. Iron: a Strong Element in the Pathogenesis of Chronic Hyperglycaemia After Acute Pancreatitis. Biol Trace Elem Res 2018; 183:71-79. [PMID: 28836100 DOI: 10.1007/s12011-017-1131-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 08/11/2017] [Indexed: 12/12/2022]
Abstract
Evidence shows an association between markers of iron metabolism and glucose metabolism in type 2 diabetes mellitus. Acute pancreatitis is the largest contributor to diabetes of the exocrine pancreas. However, the pathogenesis of new-onset pre-diabetes or diabetes after pancreatitis remains unclear. This study aimed to investigate associations between markers of iron metabolism and glucose metabolism following acute pancreatitis. Fasting blood samples were collected to analyse markers of glucose metabolism (haemoglobin A1c) and iron metabolism (hepcidin, ferritin, and soluble transferrin receptor). Participants were categorised into two groups: normoglycaemia after acute pancreatitis and chronic hyperglycaemia after acute pancreatitis. Binary logistic and linear regression analyses were conducted, and potential confounders were adjusted for in multivariable analyses. A total of 83 individuals following an episode of acute pancreatitis were included, of whom 19 developed chronic hyperglycaemia. Hepcidin was significantly increased in individuals with chronic hyperglycaemia after acute pancreatitis in two adjusted models (p = 0.045 and p = 0.048). Ferritin was significantly decreased in individuals with chronic hyperglycaemia after acute pancreatitis in three adjusted models (p = 0.016, p = 0.009, and p = 0.011). Soluble transferrin receptor was not significantly associated with chronic hyperglycaemia after acute pancreatitis. These findings suggest that iron metabolism is significantly altered in individuals with chronic hyperglycaemia after acute pancreatitis and may provide better insights into the pathogenesis of new-onset diabetes after pancreatitis.
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Affiliation(s)
- Shayal K Chand
- Department of Surgery, University of Auckland, Room 12.085A, Level 12, Auckland City Hospital, Private Bag 92019, Victoria Street West, Auckland, 1142, New Zealand
| | - Ruma G Singh
- Department of Surgery, University of Auckland, Room 12.085A, Level 12, Auckland City Hospital, Private Bag 92019, Victoria Street West, Auckland, 1142, New Zealand
| | - Sayali A Pendharkar
- Department of Surgery, University of Auckland, Room 12.085A, Level 12, Auckland City Hospital, Private Bag 92019, Victoria Street West, Auckland, 1142, New Zealand
| | - Maxim S Petrov
- Department of Surgery, University of Auckland, Room 12.085A, Level 12, Auckland City Hospital, Private Bag 92019, Victoria Street West, Auckland, 1142, New Zealand.
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26
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Vela D, Sopi RB, Mladenov M. Low Hepcidin in Type 2 Diabetes Mellitus: Examining the Molecular Links and Their Clinical Implications. Can J Diabetes 2018; 42:179-187. [DOI: 10.1016/j.jcjd.2017.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 04/18/2017] [Accepted: 04/21/2017] [Indexed: 01/14/2023]
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27
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Zacharski LR, Shamayeva G, Chow BK. Iron reduction response and demographic differences between diabetics and non-diabetics with cardiovascular disease entered into a controlled clinical trial. Metallomics 2018; 10:264-277. [DOI: 10.1039/c7mt00282c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Filings of elemental iron separated magnetically from a homogenate of breakfast cereal implicated in the risk of cardiovascular disease and diabetes.
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Affiliation(s)
- Leo R. Zacharski
- Veterans Affairs New England Health Care System
- Research Service (151)
- VA Medical Center
- White River Jct
- USA
| | - Galina Shamayeva
- Veterans Affairs Cooperative Studies Program Coordinating Center
- Veterans Affairs Palo Alto Health Care System
- Palo Alto
- USA
| | - Bruce K. Chow
- Veterans Affairs Cooperative Studies Program Coordinating Center
- Veterans Affairs Palo Alto Health Care System
- Palo Alto
- USA
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28
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Deugnier Y, Bardou-Jacquet É, Lainé F. Dysmetabolic iron overload syndrome (DIOS). Presse Med 2017; 46:e306-e311. [PMID: 29169710 DOI: 10.1016/j.lpm.2017.05.036] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/18/2017] [Indexed: 02/08/2023] Open
Abstract
Dysmetabolic iron overload syndrome (DIOS) corresponds to mild increase in both liver and body iron stores associated with various components of metabolic syndrome in the absence of any identifiable cause of iron excess. It is characterized by hyperferritinemia with normal or moderately increased transferrin saturation, one or several metabolic abnormalities (increased body mass index with android distribution of fat, elevated blood pressure, dyslipidaemia, abnormal glucose metabolism, steatohepatitis), and mild hepatic iron excess at magnetic resonance imaging or liver biopsy. Alteration of iron metabolism in DIOS likely results from a multifactorial and dynamic process triggered by an excessively rich diet, facilitated by environmental and genetic cofactors and implying a cross-talk between the liver and visceral adipose tissue. Phlebotomy therapy cannot be currently considered as a valuable option in DIOS patients. Sustained modification of diet and life-style habits remains the first therapeutic intervention in these patients together with drug control of increased blood pressure, abnormal blood glucose and dyslipidaemia when necessary.
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Affiliation(s)
- Yves Deugnier
- CHU de Rennes, hôpital Pontchaillou, centre de référence des surcharges génétiques en fer, service des maladies du foie, 2, rue Henri-Le-Guilloux, 35033 Rennes, France; University of Rennes 1, faculté de médecine, 35034 Rennes, France; Hôpital Pontchaillou, Inserm, CIC1414, 35033 Rennes, France.
| | - Édouard Bardou-Jacquet
- CHU de Rennes, hôpital Pontchaillou, centre de référence des surcharges génétiques en fer, service des maladies du foie, 2, rue Henri-Le-Guilloux, 35033 Rennes, France; University of Rennes 1, faculté de médecine, 35034 Rennes, France; Hôpital Pontchaillou, Inserm, CIC1414, 35033 Rennes, France
| | - Fabrice Lainé
- CHU de Rennes, hôpital Pontchaillou, centre de référence des surcharges génétiques en fer, service des maladies du foie, 2, rue Henri-Le-Guilloux, 35033 Rennes, France; Hôpital Pontchaillou, Inserm, CIC1414, 35033 Rennes, France
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29
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Liu J, Qian L, Guo L, Feng Y. Studying hepcidin and related pathways in osteoblasts using a mouse model with insulin receptor substrate 1‑loss of function. Mol Med Rep 2017; 17:350-357. [PMID: 29115497 DOI: 10.3892/mmr.2017.7876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 07/11/2017] [Indexed: 11/05/2022] Open
Abstract
Hepcidin is one of the most important proteins in iron metabolism. In the present study, its role in iron metabolism and the associated signaling pathways involved was investigated in a mouse model with insulin receptor substrate 1‑loss of function (IRS‑/‑), and osteoblasts in the iron overload condition. Protein expression levels of hepcidin, interleukin 6 (IL‑6), bone morphogenetic protein receptor 1α and ferritin demonstrated a significant increase in the liver of the IRS‑/‑ mice compared with the IRS+/‑ and IRS+/+ mice. Hepcidin levels in the jaw bone were also increased in the IRS‑/‑ mice (although not significantly). Furthermore, mRNA expression levels of bone morphogenetic protein 6 (BMP6) and ferroportin (FPN) were significantly increased in the liver of the IRS‑/‑ mice compared with the other two models, but no significant differences were observed in the transferrin receptor mRNA expression levels. Additionally, the mRNA expression of hepcidin, FPN and IL‑6 was upregulated in osteoblasts after ferric ammonium citrate exposure, while the mRNA expression of BMP6 was inhibited. Collectively, the results of the present study indicated that hepcidin is involved in iron metabolism in IRS‑1‑/‑ mice via the signaling pathways involving BMP6 and IL‑6. Furthermore, hepcidin is also involved in iron metabolism in osteoblasts under iron overload conditions. Therefore, hepcidin and its associated signaling pathway proteins may represent potential targets for the treatment of conditions associated with iron overload.
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Affiliation(s)
- Jia Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Ling Qian
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Linna Guo
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yunzhi Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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30
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Søgaard KL, Ellervik C, Svensson J, Thorsen SU. The Role of Iron in Type 1 Diabetes Etiology: A Systematic Review of New Evidence on a Long-Standing Mystery. Rev Diabet Stud 2017; 14:269-278. [PMID: 29145537 PMCID: PMC6115007 DOI: 10.1900/rds.2017.14.269] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/13/2017] [Accepted: 08/24/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The incidence of type 1 diabetes (T1D) is rising, which might be due to the influence of environmental factors. Biological and epidemiological evidence has shown that excess iron is associated with beta-cell damage and impaired insulin secretion. AIM In this review, our aim was to assess the association between iron and the risk of T1D. METHODS A systematic literature search was performed in PubMed and EMBASE in July 2016. Studies investigating the effect of iron status/intake on the risk of developing T1D later were included, and study quality was evaluated. The results have been summarized in narrative form. RESULTS From a total of 931 studies screened, we included 4 observational studies evaluating iron intake from drinking water or food during early life and the risk of T1D. The quality of the studies was moderate to high assessed via the nine-star Newcastle Ottawa Scale. One out of the four studies included in this review found estimates of dietary iron intake to be associated with risk of T1D development, whereas three studies found no such relationship for estimates of iron in drinking water. CONCLUSIONS The limited number of studies included found dietary iron, but not iron in drinking water, to be associated with risk of T1D. Further studies are needed to clarify the association between iron and risk of T1D, especially studies including measurements of body iron status.
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Affiliation(s)
- Karen L. Søgaard
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Christina Ellervik
- Department of Production, Research, and Innovation; Region Zealand, Alleen 15, 4180 Sorø, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
- Department of Laboratory Medicine, Boston Children`s Hospital, 300 Longwood Avenue, 02115, Boston, MA, USA
- Harvard Medical School, 25 Shattuck St, 02115, Boston, MA, USA
| | - Jannet Svensson
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Steffen U. Thorsen
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark
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31
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Chand SK, Singh RG, Pendharkar SA, Bharmal SH, Petrov MS. Interplay between innate immunity and iron metabolism after acute pancreatitis. Cytokine 2017; 103:90-98. [PMID: 28982582 DOI: 10.1016/j.cyto.2017.09.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/21/2017] [Accepted: 09/12/2017] [Indexed: 12/12/2022]
Abstract
Emerging evidence shows that chronic low-grade inflammation and changes in markers of innate immunity are implicated in a range of metabolic abnormalities following an episode of acute pancreatitis. Also, deranged iron metabolism has been linked to type 2 diabetes mellitus, gestational diabetes, and new-onset diabetes after pancreatitis - the conditions characterized by high haemoglobin glycation index (HGI). This study aimed to investigate the associations between markers of innate immunity and iron metabolism in individuals after acute pancreatitis. Fasting blood samples were collected to analyse lipopolysaccharide binding protein (LBP), interleukin (IL)-6, tumor necrosis factor-α, hepcidin, ferritin, soluble transferrin receptor, HbA1c, and glucose. Participants were categorized into two groups: low HGI and high HGI. Linear regression analyses were conducted, and potential confounders (age, sex, ethnicity, body mass index, diabetes mellitus status, smoking status, aetiology of pancreatitis, duration, recurrence, and severity of pancreatitis) were adjusted for in 5 statistical models. A total of 93 patients following an episode of acute pancreatitis were included, of who 40 (43%) had high HGI. In the overall cohort, LBP was significantly associated with hepcidin and ferritin, and IL-6 was significantly associated with hepcidin, consistently in all the models. Further, LBP contributed to 7.7% and 9.5% of variance in hepcidin and ferritin levels, respectively, whereas IL-6 contributed to 5.3% of hepcidin variance. Upon subgroup analysis, the observed LBP associations were maintained in the high HGI subgroup only and the IL-6 association in the low HGI subgroup only. No consistently significant associations were found between any of the other markers. The interplay between LBP, IL-6, hepcidin, and ferritin characterizes metabolic derangements after acute pancreatitis and may play a role in the pathogenesis of new-onset diabetes after pancreatitis.
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Affiliation(s)
- Shayal K Chand
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Ruma G Singh
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | | | - Sakina H Bharmal
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Maxim S Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand.
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32
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Lainé F, Laviolle B, Bardou-Jacquet E, Fatih N, Jezequel C, Collet N, Ropert M, Morcet J, Hamon C, Reymann JM, Loréal O. Curcuma decreases serum hepcidin levels in healthy volunteers: a placebo-controlled, randomized, double-blind, cross-over study. Fundam Clin Pharmacol 2017; 31:567-573. [DOI: 10.1111/fcp.12288] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 01/23/2017] [Accepted: 03/20/2017] [Indexed: 01/24/2023]
Affiliation(s)
- Fabrice Lainé
- Inserm; Centre d'investigation Clinique 1414; CHU Rennes; F-35033 Rennes France
- Inserm; UMR 991; CHU Rennes; F-35033 Rennes France
| | - Bruno Laviolle
- Inserm; Centre d'investigation Clinique 1414; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
| | - Edouard Bardou-Jacquet
- Inserm; UMR 991; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
| | - Nadia Fatih
- Inserm; UMR 991; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
| | - Caroline Jezequel
- Inserm; Centre d'investigation Clinique 1414; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
| | - Nicolas Collet
- Laboratoire de Biochimie; CHU Rennes; F-35033 Rennes France
| | - Martine Ropert
- Inserm; UMR 991; CHU Rennes; F-35033 Rennes France
- Laboratoire de Biochimie; CHU Rennes; F-35033 Rennes France
| | - Jeff Morcet
- Inserm; Centre d'investigation Clinique 1414; CHU Rennes; F-35033 Rennes France
| | - Catherine Hamon
- Pôle Pharmaceutique; Secteur PCBU/essais cliniques; CHU Rennes; F-35033 Rennes France
| | - Jean-Michel Reymann
- Inserm; Centre d'investigation Clinique 1414; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
| | - Olivier Loréal
- Inserm; UMR 991; CHU Rennes; F-35033 Rennes France
- Universite de Rennes 1; F-35033 Rennes France
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Sternberg Z, Hu Z, Sternberg D, Waseh S, Quinn JF, Wild K, Jeffrey K, Zhao L, Garrick M. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer's Disease. Aging Dis 2017; 8:215-227. [PMID: 28400987 PMCID: PMC5362180 DOI: 10.14336/ad.2016.0811] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 08/11/2016] [Indexed: 01/06/2023] Open
Abstract
This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer's disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aβ), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aβ40, Aβ42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients' existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aβ40, Aβ42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aβ peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion and improving iron homeostasis could have a beneficial impact on AD progression.
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Affiliation(s)
- Zohara Sternberg
- Department of Neurology, Stroke Center, Buffalo Medical Center, Buffalo, NY, USA.
| | - Zihua Hu
- Center for Computational Research, New York State Center for Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Daniel Sternberg
- Department of Neurology, Stroke Center, Buffalo Medical Center, Buffalo, NY, USA.
| | - Shayan Waseh
- Department of Biology, State University of New York at Buffalo, Buffalo, NY 14260 USA.
| | - Joseph F. Quinn
- Layton Aging & Alzheimer's Research Center, Oregon Health and Science University, Portland, Oregon, USA.
| | - Katharine Wild
- Layton Aging & Alzheimer's Research Center, Oregon Health and Science University, Portland, Oregon, USA.
| | - Kaye Jeffrey
- Layton Aging & Alzheimer's Research Center, Oregon Health and Science University, Portland, Oregon, USA.
| | - Lin Zhao
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214 USA.
| | - Michael Garrick
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214 USA.
- Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY 14214 USA.
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Mao X, Chen H, Tang J, Wang L, Shu T. Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression. Endocr Connect 2017; 6:121-128. [PMID: 28179377 PMCID: PMC5424768 DOI: 10.1530/ec-16-0115] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/08/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. DESIGN We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. METHODS MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. RESULTS Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. CONCLUSIONS Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.
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Affiliation(s)
- Xuhua Mao
- Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China
| | - Hucheng Chen
- Department of Nuclear MedicineNanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junmin Tang
- Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China
| | - Liangliang Wang
- Department of NeurologyYixing People's Hospital Affiliated to Jiangsu University, Yixing, Wuxi, Jiangsu, China
| | - Tingting Shu
- Department of Central LaboratoryJiangsu Province Official Hospital, Nanjing, Jiangsu, China
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35
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Cikomola JC, Flórez MR, Costas-Rodríguez M, Anoshkina Y, Vandepoele K, Katchunga PB, Kishabongo AS, Speeckaert MM, Vanhaecke F, Delanghe JR. Whole blood Fe isotopic signature in a sub-Saharan African population. Metallomics 2017; 9:1142-1149. [DOI: 10.1039/c7mt00170c] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The Fe isotopic composition of an individual's whole blood has recently been shown to be an interesting clinical indicator of Fe status.
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Affiliation(s)
- Justin C. Cikomola
- Department of Internal Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | - María R. Flórez
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | | | - Yulia Anoshkina
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | - Karl Vandepoele
- Laboratory of Molecular Diagnostics and Hematology
- Ghent University Hospital
- Ghent
- Belgium
| | - Philippe B. Katchunga
- Department of Internal Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | - Antoine S. Kishabongo
- Department of Laboratory Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | | | - Frank Vanhaecke
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | - Joris R. Delanghe
- Department of Clinical Chemistry
- Ghent University Hospital
- De Pintelaan 185 B-9000 Ghent
- Belgium
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Sikorska K, Bernat A, Wroblewska A. Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis. Hepatobiliary Pancreat Dis Int 2016; 15:461-479. [PMID: 27733315 DOI: 10.1016/s1499-3872(16)60135-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.
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Affiliation(s)
- Katarzyna Sikorska
- Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Powstania Styczniowego 9b, 81-519 Gdynia, Poland.
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Backe MB, Moen IW, Ellervik C, Hansen JB, Mandrup-Poulsen T. Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress. Annu Rev Nutr 2016; 36:241-73. [PMID: 27146016 DOI: 10.1146/annurev-nutr-071715-050939] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Dietary advice is the cornerstone in first-line treatment of metabolic diseases. Nutritional interventions directed at these clinical conditions mainly aim to (a) improve insulin resistance by reducing energy-dense macronutrient intake to obtain weight loss and (b) reduce fluctuations in insulin secretion through avoidance of rapidly absorbable carbohydrates. However, even in the majority of motivated patients selected for clinical trials, massive efforts using this approach have failed to achieve lasting efficacy. Less attention has been given to the role of micronutrients in metabolic diseases. Here, we review the evidence that highlights (a) the importance of iron in pancreatic beta-cell function and dysfunction in diabetes and (b) the integrative pathophysiological effects of tissue iron levels in the interactions among the beta cell, gut microbiome, hypothalamus, innate and adaptive immune systems, and insulin-sensitive tissues. We propose that clinical trials are warranted to clarify the impact of dietary or pharmacological iron reduction on the development of metabolic disorders.
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Affiliation(s)
- Marie Balslev Backe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
| | - Ingrid Wahl Moen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
| | - Christina Ellervik
- Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts 02115
| | - Jakob Bondo Hansen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
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Buratti P, Gammella E, Rybinska I, Cairo G, Recalcati S. Recent Advances in Iron Metabolism: Relevance for Health, Exercise, and Performance. Med Sci Sports Exerc 2016; 47:1596-604. [PMID: 25494391 DOI: 10.1249/mss.0000000000000593] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Iron is necessary for physiological processes essential for athletic performance, such as oxygen transport, energy production, and cell division. However, an excess of "free" iron is toxic because it produces reactive hydroxyl radicals that damage biological molecules, thus leading to cell and tissue injury. Therefore, iron homeostasis is strictly regulated; and in recent years, there have been important advancements in our knowledge of the underlying processes. Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of the iron exporter ferroportin on the cell membrane. Hepcidin binding induces ferroportin degradation, thus leading to cellular iron retention and decreased levels of circulating iron. As iron is required for hemoglobin synthesis, the tight link between erythropoiesis and iron metabolism is particularly relevant to sports physiology. The iron needed for hemoglobin synthesis is ensured by inhibiting hepcidin to increase ferroportin activity and iron availability and hence to make certain that efficient blood oxygen transport occurs for aerobic exercise. However, hepcidin expression is also affected by exercise-associated conditions, such as iron deficiency, anemia or hypoxia, and, particularly, inflammation, which can play a role in the pathogenesis of sports anemia. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. Low body iron levels can cause anemia and thus limit the delivery of oxygen to exercising muscle, but tissue iron deficiency may also affect performance by, for example, hampering muscle oxidative metabolism. Accordingly, a hemoglobin-independent effect of iron on exercise capacity has been demonstrated in animal models and humans. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance.
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Affiliation(s)
- Paolo Buratti
- Department of Biomedical Sciences for Health, University of Milan, Milan, ITALY
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Pechlaner R, Weiss G, Bansal S, Mayr M, Santer P, Pallhuber B, Notdurfter M, Bonora E, Willeit J, Kiechl S. Inadequate hepcidin serum concentrations predict incident type 2 diabetes mellitus. Diabetes Metab Res Rev 2016; 32:187-92. [PMID: 26378394 DOI: 10.1002/dmrr.2711] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 06/15/2015] [Accepted: 08/17/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is closely associated with elevated body iron stores. The hormone hepcidin is the key regulator of iron homeostasis. Inadequately low hepcidin levels were recently reported in subjects with manifest T2DM. We investigated whether alterations of hepcidin levels precede the manifestation of T2DM and predict T2DM development independently of established risk conditions. METHODS This prospective population-based study included 675 subjects aged 50-89 years, 51.9% of whom were female. Hepcidin levels were measured by gold standard tandem mass spectrometry. Diabetes was diagnosed according to American Diabetes Association criteria, and incident diabetes was recorded between baseline in 2000 and 2010. RESULTS The baseline hepcidin-to-ferritin ratio in subjects that subsequently developed diabetes during follow-up was reduced on average by 29.8% as compared with subjects with normal glucose tolerance (95% confidence interval, -50.7% to -0.2%; p = 0.049). After adjustment for age, sex, and serum ferritin, higher hepcidin levels were associated with reduced risk of incident diabetes (hazard ratio per 1-unit higher log2 hepcidin, 0.80; 95% confidence interval, 0.64-0.98; p = 0.035; 33 events). Additional adjustment for established diabetes risk factors and determinants of hepcidin concentration did not appreciably change these results (HR, 0.81; 95% CI, 0.66-0.99). Likewise, inadequately low hepcidin levels were also detected in subjects with prevalent T2DM (n = 76). CONCLUSIONS Hepcidin levels that are inadequately low in relation to body iron stores are an independent predictor for incident T2DM and may contribute to diabetes-related tissue iron overload. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Raimund Pechlaner
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria
| | - Sukhvinder Bansal
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Manuel Mayr
- King's British Heart Foundation Centre, King's College London, London, UK
| | - Peter Santer
- Department of Laboratory Medicine, Hospital of Bruneck, Bruneck, Italy
| | - Barbara Pallhuber
- Department of Internal Medicine, Hospital of Bruneck, Bruneck, Italy
| | | | - Enzo Bonora
- Division of Endocrinology, Diabetes and Metabolic Diseases, University and Hospital Trust of Verona, Verona, Italy
| | - Johann Willeit
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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40
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Baldwin HJ, Green AE, Spellar KM, Arthur PJ, Phillips HG, Patel JV. Tipping the balance: Haemoglobinopathies and the risk of diabetes. World J Diabetes 2016; 7:8-13. [PMID: 26788262 PMCID: PMC4707301 DOI: 10.4239/wjd.v7.i1.8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/08/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To establish a link between the risk of diabetes with haemoglobinopathies by examining available evidence of the effects of iron and blood glucose homeostasis from molecular to epidemiological perspectives.
METHODS: A systematic literature search was performed using electronic literature databases using various search terms. The International Diabetes Federation World Atlas was used to generate a list of populations with high rates of diabetes. PubMed, Scopus and Google Scholar were used to identify which of these populations also had a reported prevalence of haemoglobin abnormalities.
RESULTS: Abnormalities in iron homeostasis leads to increases in reactive oxygen species in the blood. This promotes oxidative stress which contributes to peripheral resistance to insulin in two ways: (1) reduced insulin/insulin receptor interaction; and (2) β-cell dysfunction. Hepcidin is crucial in terms of maintaining appropriate amounts of iron in the body and is in turn affected by haemoglobinopathies. Hepcidin also has other metabolic effects in places such as the liver but so far the extent of these is not well understood. It does however directly control the levels of serum ferritin. High serum ferritin is found in obese patients and those with diabetes and a meta-analysis of the various studies shows that high serum ferritin does indeed increase diabetes risk.
CONCLUSION: From an epidemiological standpoint, it is plausible that the well-documented protective effects of haemoglobinopathies with regard to malaria may have also offered other evolutionary advantages. By contributing to peripheral insulin resistance, haemoglobinopathies may have helped to sculpt the so-called “thrifty genotype”, which hypothetically is advantageous in times of famine. The prevalence data however is not extensive enough to provide concrete associations between diabetes and haemoglobinopathies - more precise studies are required.
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41
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Aregbesola A, Voutilainen S, Virtanen JK, Aregbesola A, Tuomainen TP. Serum hepcidin concentrations and type 2 diabetes. World J Diabetes 2015; 6:978-982. [PMID: 26185605 PMCID: PMC4499531 DOI: 10.4239/wjd.v6.i7.978] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 12/22/2014] [Accepted: 03/20/2015] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is a peptide hormone with both paracrine and endocrine functions that help in maintaining body iron stores. Type 2 diabetes (T2D) is one of the sequelae of excess body iron stores; thus, iron regulatory hormone hepcidin may have a direct or at least an indirect role in the aetiopathogenesis of T2D. Both human and animal studies at molecular and genetic levels have attempted to establish a role for hepcidin in the development of T2D, and a few epidemiologic studies have also showed a link between hepcidin and T2D at population level, but the findings are still inconclusive. Recent data have suggested different pathways in which hepcidin could be associated with T2D with much emphasis on its primary or secondary role in insulin resistance. Some of the suggested pathways are via transcription modulator of hepcidin (STAT3); ferroportin 1 expression on the cells involved in iron transport; transmembrane protease 6 enzyme; and pro-inflammatory cytokines, interleukin (IL)-1, IL-6, tumor necrosis factor-α and IL-10. This review briefly reports the existing evidence on the possible links between hepcidin and T2D and concludes that more data are needed to confirm or refute hepcidin’s role in the development of T2D. Examining this role could provide a further evidence base for iron in the aetiopathogenesis of T2D.
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42
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Peffer K, Verbeek ALM, Swinkels DW, Geurts-Moespot AJ, den Heijer M, Atsma F. Donation intensity and metabolic syndrome in active whole-blood donors. Vox Sang 2015; 109:25-34. [DOI: 10.1111/vox.12258] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 01/08/2015] [Accepted: 01/16/2015] [Indexed: 01/15/2023]
Affiliation(s)
- K. Peffer
- Department of Donor Studies; Sanquin Research; Nijmegen The Netherlands
- Department for Health Evidence; Radboud University Medical Center; Nijmegen The Netherlands
| | - A. L. M. Verbeek
- Department for Health Evidence; Radboud University Medical Center; Nijmegen The Netherlands
| | - D. W. Swinkels
- Laboratory of Genetic, Endocrine and Metabolic Diseases; Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - A. J. Geurts-Moespot
- Laboratory of Genetic, Endocrine and Metabolic Diseases; Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - M. den Heijer
- Department for Health Evidence; Radboud University Medical Center; Nijmegen The Netherlands
- Department of Internal Medicine; VU University Medical Center; Amsterdam The Netherlands
| | - F. Atsma
- Department of Donor Studies; Sanquin Research; Nijmegen The Netherlands
- Scientific Institute for Quality of Healthcare; Radboud University Medical Center; Nijmegen The Netherlands
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Abstract
As an essential element, iron plays a central role in many physiological processes, including redox balance, inflammation, energy metabolism, and environment sensing. Perturbations in iron homeostasis are associated with several conditions, including hyperglycemia and diabetes, both of which have been studied in patients and animal models. To clarify the pleiotropic role of iron homeostasis in diabetes development, the early studies on diseases with iron-overload, studies on clinical iron depletion therapies, associations between iron-related genetic polymorphisms and diabetes, and etiological mechanisms underlying iron perturbations-impaired insulin secretion and insulin sensitivity were carefully reviewed and discussed. Hereditary hemochromatosis, transfusion-dependent thalassemia, and excess heme iron intake can increase the risk of developing diabetes. Genetically modified mice and mice fed a high-iron diet present with discrepant phenotypes due to differences in tissue iron distribution. Moreover, several genetic polymorphisms related to iron homeostasis have been associated with the risk of developing diabetes. Tightly controlled iron metabolism is essential for insulin secretion and insulin sensitivity, and iron overload in pancreatic islets alters reactive oxygen species (ROS) generation, as well as hypoxia-inducible factor-1α (HIF-1α) stability and adenosine triphosphate (ATP) synthesis, thereby impairing the function and viability of β-cells. Decreased levels of adiponectin, macrophage-mediated inflammation, and ROS-mediated liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) activation can contribute to iron overload-induced insulin resistance, whereas iron deficiency could also participate in obesity-related inflammation, hypoxia, and insulin resistance. Because iron homeostasis is closely correlated with many metabolic processes, future studies are needed in order to elucidate the finely tuned network among iron homeostasis, carbohydrate and lipid metabolism, inflammation, and hypoxia.
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Affiliation(s)
- Xinhui Wang
- Department of Nutrition, Research Center for Nutrition and Health, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China
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44
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Ali TM, Genina AM, Abo-Salem OM. The determinants of hepcidin level in chronic kidney disease and hemodialysis Saudi patients. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2014. [DOI: 10.1016/j.bjbas.2014.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot JD. Physiology of iron metabolism. Transfus Med Hemother 2014; 41:213-21. [PMID: 25053935 DOI: 10.1159/000362888] [Citation(s) in RCA: 154] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 12/04/2013] [Indexed: 12/12/2022] Open
Abstract
A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. The purpose of this review is to summarize the recent knowledge that has accumulated, allowing a better comprehension of the mechanisms implicated in iron homeostasis. Iron metabolism is very fine tuned. The free molecule is very toxic; therefore, complex regulatory mechanisms have been developed in mammalian to insure adequate intestinal absorption, transportation, utilization, and elimination. 'Ironomics' certainly will be the future of the understanding of genes as well as of the protein-protein interactions involved in iron metabolism.
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Affiliation(s)
| | - Gérard Waeber
- Service de médecine interne, CHUV, Lausanne, Switzerland
| | | | | | | | - Bernard Favrat
- Department of Ambulatory Care and Community Medicine, Lausanne, Switzerland
| | - Jean-Daniel Tissot
- Service régional vaudois de transfusion sanguine, Epalinges, Switzerland
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46
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Wang H, Li H, Jiang X, Shi W, Shen Z, Li M. Hepcidin is directly regulated by insulin and plays an important role in iron overload in streptozotocin-induced diabetic rats. Diabetes 2014; 63:1506-18. [PMID: 24379355 DOI: 10.2337/db13-1195] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Iron overload is frequently observed in type 2 diabetes mellitus (DM2), but the underlying mechanisms remain unclear. We hypothesize that hepcidin may be directly regulated by insulin and play an important role in iron overload in DM2. We therefore examined the hepatic iron content, serum iron parameters, intestinal iron absorption, and liver hepcidin expression in rats treated with streptozotocin (STZ), which was given alone or after insulin resistance induced by a high-fat diet. The direct effect of insulin on hepcidin and its molecular mechanisms were furthermore determined in vitro in HepG2 cells. STZ administration caused a significant reduction in liver hepcidin level and a marked increase in intestinal iron absorption and serum and hepatic iron content. Insulin obviously upregulated hepcidin expression in HepG2 cells and enhanced signal transducer and activator of transcription 3 protein synthesis and DNA binding activity. The effect of insulin on hepcidin disappeared when the signal transducer and activator of transcription 3 pathway was blocked and could be partially inhibited by U0126. In conclusion, the current study suggests that hepcidin can be directly regulated by insulin, and the suppressed liver hepcidin synthesis may be an important reason for the iron overload in DM2.
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Affiliation(s)
- Heyang Wang
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, Shanghai, China
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47
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Hansen JB, Moen IW, Mandrup-Poulsen T. Iron: the hard player in diabetes pathophysiology. Acta Physiol (Oxf) 2014; 210:717-32. [PMID: 24521359 DOI: 10.1111/apha.12256] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 01/09/2014] [Accepted: 02/03/2014] [Indexed: 12/14/2022]
Abstract
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.
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Affiliation(s)
- J. B. Hansen
- Section for Endocrinological Research; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
- Department of Physiology; University of Toronto; Toronto ON Canada
| | - I. W. Moen
- Section for Endocrinological Research; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
| | - T. Mandrup-Poulsen
- Section for Endocrinological Research; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
- Department of Molecular Medicine and Surgery; Karolinska Institutet; Stockholm Sweden
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Chen Q, Wang L, Ma Y, Wu X, Jin L, Yu F. Increased hepcidin expression in non-small cell lung cancer tissue and serum is associated with clinical stage. Thorac Cancer 2014; 5:14-24. [PMID: 26766967 DOI: 10.1111/1759-7714.12046] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 04/04/2013] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Hepcidin is a small secreted peptide that plays a key role in iron metabolism. A high level of hepcidin expression may be implicated in colorectal cancer; however, the relationship between hepcidin and lung cancer has not yet been studied. METHODS Serum hepcidin-25, bone morphogenetic protein (BMP)-2, and interleukin (IL)-6 concentration in 53 patients and 16 non-cancerous individuals was measured by enzyme-linked immune sorbent assay. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was utilized to study the expression of hepcidin mRNA in paired tumor and non-tumor lung tissues in surgical specimens from 65 patients with non small cell lung cancer (NSCLC), as well as in six types of lung cancer cell lines and human bronchial epithelial (HBE) cells. Hepcidin protein expression and cellular localization in NSCLC was determined by immunohistochemistry. RESULTS The serum hepcidin-25 concentration was higher in patients with NSCLC than in non-cancerous individuals, and was positively correlated with serum BMP2 concentration, but negatively with serum IL-6 levels. Serum hepcidin was also correlated with lymph node metastasis and clinical stage. Hepcidin mRNA expression was higher in cancerous tissues of NSCLC than in normal pulmonary tissues (P = 0.001). Hepcidin mRNA levels in four lung carcinoma cell lines were higher than in HBE cells. Immunohistochemistry showed that hepcidin protein was increased in cancerous tissues of NSCLC. CONCLUSIONS The level of hepcidin expression increased in NSCLC tissue and serum. Serum hepcidin-25 level was associated with lymph node metastasis and tumor clinical stage in patients with NSCLC.
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Affiliation(s)
- Qian Chen
- Department of Cardio-Thoracic Surgery, Second Xiangya Hospital of Central South University Changsha, China
| | - Li Wang
- Department of Cardio-Thoracic Surgery, Second Xiangya Hospital of Central South University Changsha, China
| | - Yuchao Ma
- Department of Cardio-Thoracic Surgery, Second Xiangya Hospital of Central South University Changsha, China
| | - Xianning Wu
- Department of Cardio-Thoracic Surgery, Second Xiangya Hospital of Central South University Changsha, China
| | - Longyu Jin
- Department of Cardio-Thoracic Surgery, Third Xiangya Hospital of Central South University Changsha, China
| | - Fenglei Yu
- Department of Cardio-Thoracic Surgery, Second Xiangya Hospital of Central South University Changsha, China
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Zumbrennen-Bullough K, Babitt JL. The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. Nephrol Dial Transplant 2013; 29:263-73. [PMID: 24235084 DOI: 10.1093/ndt/gft443] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Iron is essential for most living organisms but iron excess can be toxic. Cellular and systemic iron balance is therefore tightly controlled. Iron homeostasis is dysregulated in chronic kidney disease (CKD) and contributes to the anemia that is prevalent in this patient population. Iron supplementation is one cornerstone of anemia management in CKD patients, but has not been rigorously studied in large prospective randomized controlled trials. This review highlights important advances from genetic studies and animal models that have provided key insights into the molecular mechanisms governing iron homeostasis and its disturbance in CKD, and summarizes how these findings may yield advances in the care of this patient population.
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Affiliation(s)
- Kimberly Zumbrennen-Bullough
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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50
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Abstract
PURPOSE OF REVIEW The circulating peptide hepcidin modulates systemic iron balance by limiting the absorption of dietary iron and the release of iron from macrophage stores. Recent studies conducted in humans, animal models, and tissue culture systems have enhanced our understanding of the molecular mechanisms by which hepcidin levels are altered in response to iron stores, inflammation, and erythropoietic activity. RECENT FINDINGS The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 play key, nonredundant roles in mediating hepcidin synthesis through the BMP signaling pathway. Actions of the hereditary hemochromatosis proteins HFE and transferrin receptor 2 may intersect with the BMP pathway. Hepcidin induction in response to inflammation requires cooperative BMP signaling. A variety of innate immune and infectious stimuli induce hepcidin expression. The hypoxia inducible factor pathway appears to suppress hepcidin indirectly through the capacity of erythropoietin to stimulate erythropoiesis. SUMMARY Study of the molecular mechanisms underlying the regulation of hepcidin synthesis has revealed complex biology. Improved understanding of the signaling pathways involved in hepcidin regulation may contribute to improved therapeutic outcomes for patients with genetic and acquired disorders that impact systemic iron balance.
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