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Wu B, Wang J, Yan X, Jin G, Wang Q. Cordycepin ameliorates diabetic nephropathy injury by activating the SLC7A11/GPX4 pathway. J Diabetes Investig 2025. [PMID: 40120097 DOI: 10.1111/jdi.14407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/23/2024] [Accepted: 01/02/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Cordycepin (CRD) has been identified to alleviate diabetes-induced injuries and complications including diabetic nephropathy (DN). Here, this work focused on probing the specific effects and potential mechanisms of CRD on DN progression. METHODS High glucose (HG)-induced mouse podocyte cell line (MPC5) was used for in vitro functional analyses. Cell proliferation and apoptosis were determined using cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, and flow cytometry, respectively. ELISA analysis detected inflammatory factors. Cell ferroptosis was assessed by measuring the levels of Fe2+, glutathione, reactive oxygen species, and malonaldehyde. RESULTS CRD treatment suppressed HG-induced apoptosis, inflammation, and ferroptosis in podocytes. CRD treatment elevated SLC7A11 and GPX4 expression in HG-treated podocytes. The overexpression of SLC7A11 or GPX4 suppressed HG-evoked apoptosis, inflammation, and ferroptosis in podocytes. Moreover, the silencing of SLC7A11 or GPX4 abolished the protective effects of CRD on HG-treated podocytes. Moreover, CRD ameliorated renal structure injury and inflammation in STZ-induced diabetic mice by modulating SLC7A11 or GPX4 expression. CONCLUSIONS Cordycepin suppressed HG-induced apoptosis, inflammation, and ferroptosis in podocytes in vitro, and ameliorated renal injury and inflammation in STZ-induced diabetic mice by activating the SLC7A11/GPX4 pathway.
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Affiliation(s)
- Bing Wu
- Department of Nephrology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Jing Wang
- Department of Nephrology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Xiaohui Yan
- Department of Nephrology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Gang Jin
- Department of Nephrology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Qiong Wang
- Department of Nephrology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
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2
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Nandha SR, Checker R, Patwardhan RS, Sharma D, Sandur SK. Anti-oxidants as therapeutic agents for oxidative stress associated pathologies: future challenges and opportunities. Free Radic Res 2025; 59:61-85. [PMID: 39764687 DOI: 10.1080/10715762.2025.2450504] [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: 09/20/2024] [Revised: 12/13/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025]
Abstract
Free radicals have been implicated in the pathogenesis of cancer along with cardiovascular, neurodegenerative, pulmonary and inflammatory disorders. Further, the relationship between oxidative stress and disease is distinctively established. Clinical trials using anti-oxidants for the prevention of disease progression have indicated some beneficial effects. However, these trials failed to establish anti-oxidants as therapeutic agents due to lack of efficacy. This is attributed to the fact that living systems are under dynamic redox control wherein their redox behavior is compartmentalized and simple aggregation of redox couples, distributed throughout the system, is of miniscule importance while determining their overall redox state. Further, free radical metabolism is intriguingly complex as they play plural roles segregated in a spatio-temporal manner. Depending on quality, quantity and site of generation, free radicals exhibit beneficial or harmful effects. Use of nonspecific, non-targeted, general ROS scavengers lead to systemic elimination of all types of ROS and interferes in cellular signaling. Failure of anti-oxidants to act as therapeutic agents lies in this oversimplification of extremely dynamic cellular redox environment as a static and non-compartmentalized redox state. Rather than generalizing the term "oxidative stress" if we can identify the "type of oxidative stress" in different types of diseases, a targeted and more specific anti-oxidant therapy may be developed. In this review, we discuss the concept of redox dynamics, role and type of oxidative stress in disease conditions, and current status of anti-oxidants as therapeutic agents. Further, we probe the possibility of developing novel, targeted and efficacious anti-oxidants with drug-like properties.
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Affiliation(s)
- Shivani R Nandha
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Rahul Checker
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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3
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Kirkutyte I, Latunde-Dada GO. Relationship Between Hepatic Iron Concentration and Glycemic Metabolism, Prediabetes, and Type 2 Diabetes: A Systematic Review. Nutr Rev 2024:nuae197. [PMID: 39724915 DOI: 10.1093/nutrit/nuae197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
CONTEXT Emerging research has suggested a potential link between high iron levels, indicated by serum ferritin levels, and the development of type 2 diabetes (T2D). However, the role of hepatic iron concentration (HIC) on T2D development and progression is not well understood. OBJECTIVES This study aims to systematically review the literature on HIC and/or the degree of hepatic iron overload (HIO) in individuals with prediabetes and/or diagnosed T2D, and to analyze associations between HIC and markers of glucose metabolism. DATA SOURCES The databases Medline, PubMed, Embase, CINAHL, and Web of Knowledge were searched for studies published in English from 1999 to March 2024. This review followed the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. DATA EXTRACTION Data were extracted following the established eligibility criteria. Study characteristics and biomarkers related to prediabetes, T2D, and HIO were extracted. The risk of bias was analyzed using the Newcastle-Ottawa Scale. Data were stratified by the exposure and analyzed in subgroups according to the outcome. Data regarding the HIC values in controls, individuals with prediabetes, and individuals with T2D and the association estimates between HIC or HIO and markers of glycemic metabolism, prediabetes, or T2D were extracted. DATA ANALYSIS A total of 12 studies were identified, and data from 4110 individuals were analyzed. HIO was not consistently observed in prediabetic/T2D populations; however, elevated HIC was frequently observed in prediabetic and T2D individuals, and was associated with the disruption of certain glycemic markers in some cases. CONCLUSION The extent of iron overload, as indicated by hepatic iron load, varied among the prediabetic and T2D populations studied. Further research is needed to understand the distribution and regulation of iron in T2D pathology.
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Affiliation(s)
- Indre Kirkutyte
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom
| | - Gladys Oluyemisi Latunde-Dada
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom
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Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9:271. [PMID: 39396974 PMCID: PMC11486532 DOI: 10.1038/s41392-024-01969-z] [Citation(s) in RCA: 64] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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Zhou D, Yang Y, Han R, He J, Liu D, Xia W, Cai Y, Perek B, Xia Z. Ferroptosis and its Potential Determinant Role in Myocardial Susceptibility to Ischemia/Reperfusion Injury in Diabetes. Rev Cardiovasc Med 2024; 25:360. [PMID: 39484139 PMCID: PMC11522832 DOI: 10.31083/j.rcm2510360] [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] [Received: 03/26/2024] [Revised: 06/12/2024] [Accepted: 06/20/2024] [Indexed: 11/03/2024] Open
Abstract
Myocardial ischemia/reperfusion injury (MIRI) is a major cause of cardiac death particularly in patients with diabetes. When the coronary artery is partially or completely blocked, restoration of blood perfusion can normally be achieved within a certain time due to the development of advanced techniques such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) surgery. However, cardiac tissue injury may aggravate progressively even after the ischemic myocardium is restored to normal perfusion. MIRI is often associated with various forms of cell death, including apoptosis, autophagy, programmed necrosis, pyroptosis, and ferroptosis, among others. Ferroptosis is known as iron-dependent cell death that is distinct from other programmed modes of cell death. Ferroptosis is under constitutive control by glutathione peroxidase 4 (GPX4), and the reduction of GPX4 may result in ferroptosis even if iron homeostasis is physiologically maintained. The essences of ferroptosis are substantial iron accumulation and lipid peroxidation that trigger cell death. Under impaired antioxidant system, cellular reactive oxygen species (ROS) accumulation leads to lipid peroxidation which consequently results in ferroptosis. Ferroptosis shares a few common features with several types of cell death and interplays with various forms of cell death such as autophagy and apoptosis in the development of cardiovascular diseases. More and more recent studies have demonstrated that ferroptosis plays an important role in MIRI. However, few studies have addressed the relative importance of ferroptosis in MIRI relative to other forms of cell deaths. In this review, we summarized the basic aspects and advances regarding the molecular pathogenesis of ferroptosis, evaluated its role in MIRI, and propose that the levels of ferroptosis may function as a major determinant of myocardial susceptibility to ischemia/reperfusion injury (IRI) in general and of the enhanced vulnerability to MIRI specifically in diabetes.
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Affiliation(s)
- Dongcheng Zhou
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
| | - Yuhui Yang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
| | - Ronghui Han
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
| | - Jianfeng He
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
| | - Danyong Liu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
| | - Weiyi Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
- Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Yin Cai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Bartłomiej Perek
- Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, 524000 Zhanjiang, Guangdong, China
- Doctoral Training Platform for Research and Translation, 431913 Zhongxiang, Hubei, China
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Zhang Y, Zou L, Li X, Guo L, Hu B, Ye H, Liu Y. SLC40A1 in iron metabolism, ferroptosis, and disease: A review. WIREs Mech Dis 2024; 16:e1644. [PMID: 38508867 DOI: 10.1002/wsbm.1644] [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: 08/07/2023] [Revised: 12/26/2023] [Accepted: 02/27/2024] [Indexed: 03/22/2024]
Abstract
Solute carrier family 40 member 1 (SLC40A1) plays an essential role in transporting iron from intracellular to extracellular environments. When SLC40A1 expression is abnormal, cellular iron metabolism becomes dysregulated, resulting in an overload of intracellular iron, which induces cell ferroptosis. Numerous studies have confirmed that ferroptosis is closely associated with the development of many diseases. Here, we review recent findings on SLC40A1 in ferroptosis and its association with various diseases, intending to explore new directions for research on disease pathogenesis and new therapeutic targets for prevention and treatment. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Metabolic Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Yan Zhang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Liyi Zou
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, China
| | - Xiaodan Li
- People's Hospital of Longhua District, Shenzhen, Guangdong, China
| | - Long Guo
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Baoguang Hu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Hua Ye
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yi Liu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong, China
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Sun Y, Liu M, Sun W, Tang X, Zhou Y, Zhang J, Yang B. A Hemoglobin Bionics-Based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2405002. [PMID: 38738270 DOI: 10.1002/adma.202405002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/09/2024] [Indexed: 05/14/2024]
Abstract
Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.
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Affiliation(s)
- Yihan Sun
- Joint Laboratory of Opto, Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Material, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, P. R. China
| | - Manxuan Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, P. R. China
| | - Weihong Sun
- Joint Laboratory of Opto, Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Material, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, P. R. China
| | - Xiaoduo Tang
- Joint Laboratory of Opto, Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Material, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, P. R. China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, P. R. China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, P. R. China
| | - Junhu Zhang
- Joint Laboratory of Opto, Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Material, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, P. R. China
| | - Bai Yang
- Joint Laboratory of Opto, Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Material, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, P. R. China
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8
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Pang H, Huang G, Xie Z, Zhou Z. The role of regulated necrosis in diabetes and its complications. J Mol Med (Berl) 2024; 102:495-505. [PMID: 38393662 DOI: 10.1007/s00109-024-02421-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 12/21/2023] [Accepted: 01/16/2024] [Indexed: 02/25/2024]
Abstract
Morphologically, cell death can be divided into apoptosis and necrosis. Apoptosis, which is a type of regulated cell death, is well tolerated by the immune system and is responsible for hemostasis and cellular turnover under physiological conditions. In contrast, necrosis is defined as a form of passive cell death that leads to a dramatic inflammatory response (also referred to as necroinflammation) and causes organ dysfunction under pathological conditions. Recently, a novel form of cell death named regulated necrosis (such as necroptosis, pyroptosis, and ferroptosis) was discovered. Distinct from apoptosis, regulated necrosis is modulated by multiple internal or external factors, but meanwhile, it results in inflammation and immune response. Accumulating evidence has indicated that regulated necrosis is associated with multiple diseases, including diabetes. Diabetes is characterized by hyperglycemia caused by insulin deficiency and/or insulin resistance, and long-term high glucose leads to various diabetes-related complications. Here, we summarize the mechanisms of necroptosis, pyroptosis, and ferroptosis, and introduce recent advances in characterizing the associations between these three types of regulated necrosis and diabetes and its complications.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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Kortas JA, Reczkowicz J, Juhas U, Ziemann E, Świątczak A, Prusik K, Olszewski S, Soltani N, Rodziewicz-Flis E, Flis D, Żychowska M, Gałęzowska G, Antosiewicz J. Iron status determined changes in health measures induced by nordic walking with time-restricted eating in older adults- a randomised trial. BMC Geriatr 2024; 24:300. [PMID: 38553690 PMCID: PMC10979559 DOI: 10.1186/s12877-024-04876-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 03/05/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND AND AIMS This study evaluated whether stored iron determines the adaptive response induced by Nordic walking (NW) training combined with 10 hours' time-restricted eating (TRE) in older adults. TRIAL DESIGN AND METHODS Twenty-four participants underwent 12-week NW training supported by 10 h of TRE. The group was divided due to baseline ferritin concentration low < 75 ng/ml (LF) and high level ≥ 75 ng/ml (HF). Body composition, physical fitness and blood collection were assessed at baseline and post-intervention. RESULTS NW + TRE induced a statistically significant decrease in ferritin levels in all participants (p = 0.01). Additionally, statistically significant intergroup differences in the LF vs. HF in the reduction of serum ferritin levels (p = 0.04) were observed. The procedure NW + TRE diminished HbA1c levels (p < 0.01) and glucose in all participants (p = 0.05). The range of HbA1c drop was more pronounced among those participants who experienced a greater decrease in the stored iron (p = 0.04, [Formula: see text]=0.17, F=4.59). Greater changes in body weight and percent of body fat were recorded in the HF group (for both p<0.01). CONCLUSION Body iron stores determine the effects of a 12-week NW + TRE intervention on serum ferritin. The changes in HbA1c are more pronounced in subjects with a higher decrease in serum ferritin. TRIAL REGISTRATION All experimental protocols were approved by the Bioethical Committee of the Regional Medical Society in Gdansk, Poland (NKBBN/330/2021) according to the Declaration of Helsinki. We confirm that all methods were carried out in accordance with relevant guidelines and regulations. The trial was registered as a clinical trial (NCT05229835, date of first registration: 14/01/2022, direct link: https://classic. CLINICALTRIALS gov/ct2/show/NCT05229835 ). Informed consent was obtained from all subjects.
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Affiliation(s)
- Jakub Antoni Kortas
- Department of Health and Natural Sciences, Gdansk University of Physical Education and Sport, 80-336, Gdansk, Poland
| | - Joanna Reczkowicz
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Ulana Juhas
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Ewa Ziemann
- Department of Athletics, Strength and Conditioning, Poznan University of Physical Education, 61-871, Poznan, Poland
| | - Aleksandra Świątczak
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdansk, 80-308, Gdansk, Poland
| | - Katarzyna Prusik
- Faculty of Tourism and Recreation, Department of Health Promotion, Gdansk University of Physical Education and Sport, 80-336, Gdansk, Poland
| | - Szczepan Olszewski
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Nakisa Soltani
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Ewa Rodziewicz-Flis
- Department of Physiotherapy, Gdansk University of Physical Education and Sport, 80-336, Gdansk, Poland
| | - Damian Flis
- Department of Pharmaceutical Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, 80-210, Gdansk, Poland
| | - Małgorzata Żychowska
- Department of Sport, Faculty of Physical Education, Kazimierz Wielki University in Bydgoszcz, 85-064, Bydgoszcz, Poland
| | - Grażyna Gałęzowska
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Jędrzej Antosiewicz
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 80-211, Gdansk, Poland.
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10
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Meinilä J, Virtanen JK. Meat and meat products - a scoping review for Nordic Nutrition Recommendations 2023. Food Nutr Res 2024; 68:10538. [PMID: 38449706 PMCID: PMC10916397 DOI: 10.29219/fnr.v68.10538] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 08/22/2022] [Accepted: 01/23/2024] [Indexed: 03/08/2024] Open
Abstract
Meat is not only a source of several nutrients but also a proposed risk factor for several non-communicable diseases. Here, we describe the totality of evidence for the role of meat intake for chronic disease outcomes, discuss potential mechanistic pathways, knowledge gaps, and limitations of the literature. Use of the scoping review is based on a de novo systematic review (SR) and meta-analysis on the association between poultry intake and cardiovascular disease (CVD) and type 2 diabetes (T2D), qualified SRs (as defined in the Nordic Nutrition Recommendations 2023 project) on meat intake and cancer by the World Cancer Research Fund (WCRF), the International Agency for Research on Cancer (IARC), and a systematic literature search of SRs and meta-analyses. The quality of the SRs was evaluated using a modified AMSTAR 2 tool, and the strength of evidence was evaluated based on a predefined criteria developed by the WCRF. The quality of the SRs was on average critically low. Our findings indicate that the evidence is too limited for conclusions for most of the chronic disease outcomes. However, findings from qualified SRs indicate strong evidence that processed meat increases the risk of colorectal cancer and probable evidence that red meat (unprocessed, processed, or both) increases the risk. The evidence suggests that both unprocessed red meat and processed meat (also including processed poultry meat) are probable risk factors for CVD mortality and stroke, and that total red meat and processed meat are risk factors for CHD. We found no sufficient evidence suggesting that unprocessed red meat, processed red meat, total red meat, or processed meat (including red and white meat) would be protective of any chronic disease. There was also no sufficient evidence to conclude on protective effect of poultry on any chronic diseases; effects on the risk of CVD, stroke, and T2D, to any direction, were regarded as unlikely.
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Affiliation(s)
- Jelena Meinilä
- Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
| | - Jyrki K. Virtanen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
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11
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Sam RM, Shetty SS, Kumari N S, KP S, Bhandary P. Association between iron profile status and insulin resistance in patients with type 2 diabetes mellitus. J Diabetes Metab Disord 2023; 22:1453-1458. [PMID: 37975116 PMCID: PMC10638270 DOI: 10.1007/s40200-023-01268-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 07/19/2023] [Indexed: 11/19/2023]
Abstract
Introduction Individuals' burden of insulin resistance and metabolic syndrome, such as type 2 diabetes mellitus, is increasing. This indicates to intrigue into various facets of prevention, early screening, prognostication and feasible treatment alternatives in this arena. Aim This study targets to evaluate iron profile status among people diagnosed with type 2 diabetes mellitus and normoglycemic in order to deduce association between iron parameters and insulin resistance, if any exist. Methodology A case-control study of total 123 subjects, comprising males and females in the age group of 30 - 70 years were recruited for the study. Case group constituted 81 participants who were diagnosed with type 2 diabetes mellitus and control group constituted 42 healthy individuals who attended routine health check-ups in the hospital. Iron profile parameters including Serum Iron, Serum Ferritin, Total Iron binding Capacity and Glycemic profile parameter like fasting blood glucose, serum insulin were estimated. Transferrin saturation and HOMA-IR were calculated. Result Ferritin and Transferrin saturation was found to be higher in cases than in controls with significance of p = 0.003 and p = 0.021 respectively and TIBC (total iron-binding capacity) was lesser in cases with p = 0.031. Comparison of Serum Iron values did not yield a significant result. Correlation study between ferritin and insulin resistance parameters yielded a satisfactory result in the cases (p<0.05) and controls (p<0.01) separately. Conclusion This study implies that there is a clear link between iron profile status, notably ferritin, and the emergence of insulin resistance, and hence insulin production. This study supports the function of the micronutrient iron in the etiology of type 2 diabetes and its consequences.
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Affiliation(s)
- Reeba Maryam Sam
- KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
| | - Shilpa S Shetty
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
| | - Suchetha Kumari N
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
- Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
| | - Sharmila KP
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
| | - Prajna Bhandary
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
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12
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Banerjee S, Lu S, Jain A, Wang I, Tao H, Srinivasan S, Nemeth E, He P. Targeting PKC alleviates iron overload in diabetes and hemochromatosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.28.569107. [PMID: 38076948 PMCID: PMC10705472 DOI: 10.1101/2023.11.28.569107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Diabetes is one of the most prevalent chronic diseases worldwide. Iron overload increases the incidence of diabetes and aggravates diabetic complications that cause mortality. Reciprocally, diabetes potentially promotes body iron loading, but the mechanism remains not well understood. In this study, we demonstrated systemic iron excess and the upregulation of iron exporter ferroportin (Fpn) in the enterocytes and macrophages of multiple diabetic mouse models. Increased Fpn expression and iron efflux was also seen in the enterocytes of type 2 diabetic human patients. We further showed that protein kinase C (PKC), which is activated in hyperglycemia, was responsible for the sustained membrane expression of Fpn in physiological and in diabetic settings. For the first time, we identified that PKCs were novel binding proteins and positive regulators of Fpn. Mechanistically, hyperactive PKC promoted exocytotic membrane insertion while inhibited the endocytic trafficking of Fpn in the resting state. PKC also protected Fpn from internalization and degradation by its ligand hepcidin dependent on decreased ubiquitination and increased phosphorylation of Fpn. Importantly, the loss-of-function and pharmacological inhibition of PKC alleviated systemic iron overload in diabetes and hemochromatosis. Our study thus highlights PKC as a novel target in the control of systemic iron homeostasis.
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An JR, Wang QF, Sun GY, Su JN, Liu JT, Zhang C, Wang L, Teng D, Yang YF, Shi Y. The Role of Iron Overload in Diabetic Cognitive Impairment: A Review. Diabetes Metab Syndr Obes 2023; 16:3235-3247. [PMID: 37872972 PMCID: PMC10590583 DOI: 10.2147/dmso.s432858] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023] Open
Abstract
It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.
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Affiliation(s)
- Ji-Ren An
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
- College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, People’s Republic of China
| | - Qing-Feng Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Gui-Yan Sun
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jia-Nan Su
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jun-Tong Liu
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Chi Zhang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Li Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Dan Teng
- He University, Shenyang, 110163, People’s Republic of China
| | - Yu-Feng Yang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Yan Shi
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
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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: 83] [Impact Index Per Article: 41.5] [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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15
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Abstract
High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal features: decreased insulin secretion, insulin resistance, and increased hepatic gluconeogenesis. This is true across the normal range of tissue iron levels and in pathologic iron overload. Because of iron's central role in metabolic processes (e.g., fuel oxidation) and metabolic regulation (e.g., hypoxia sensing), iron levels participate in determining metabolic rates, gluconeogenesis, fuel choice, insulin action, and adipocyte phenotype. The risk of diabetes related to iron is evident in most or all tissues that determine diabetes phenotypes, with the adipocyte, beta cell, and liver playing central roles. Molecular mechanisms for these effects are diverse, although there may be integrative pathways at play. Elucidating these pathways has implications not only for diabetes prevention and treatment, but also for the pathogenesis of other diseases that are, like T2DM, associated with aging, nutrition, and iron.
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Affiliation(s)
- Alexandria V Harrison
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
| | - Felipe Ramos Lorenzo
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
- Department of Veterans Affairs, W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina, USA
| | - Donald A McClain
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
- Department of Veterans Affairs, W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina, USA
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16
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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17
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James JV, Varghese J, John NM, Deschemin JC, Vaulont S, McKie AT, Jacob M. Insulin resistance and adipose tissue inflammation induced by a high-fat diet are attenuated in the absence of hepcidin. J Nutr Biochem 2023; 111:109175. [PMID: 36223834 DOI: 10.1016/j.jnutbio.2022.109175] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 06/15/2022] [Accepted: 08/17/2022] [Indexed: 11/09/2022]
Abstract
Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations is unclear. To attempt to investigate this, we studied the development of IR and associated inflammation in adipose tissue in the presence of increased body iron stores. Male hepcidin knock-out (Hamp1-/-) mice, which have increased body iron stores, and wild-type (WT) mice were fed a high-fat diet (HFD) for 12 and 24 weeks. Development of IR and metabolic parameters linked to this, insulin signaling in various tissues, and inflammation and iron-related parameters in visceral adipose tissue were studied in these animals. HFD-feeding resulted in impaired glucose tolerance in both genotypes of mice. In response to the HFD for 24 weeks, Hamp1-/- mice gained less body weight and developed less systemic IR than corresponding WT mice. This was associated with less lipid accumulation in the liver and decreased inflammation and lipolysis in the adipose tissue in the knock-out mice, than in the WT animals. Fewer macrophages infiltrated the adipose tissue in the knockout mice than in wild-type mice, with these macrophages exhibiting a predominantly anti-inflammatory (M2-like) phenotype and indirect evidence of a possible lowered intracellular iron content. The absence of hepcidin was thus associated with attenuated inflammation in the adipose tissue and increased whole-body insulin sensitivity, suggesting a role for it in these processes.
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Affiliation(s)
- Jithu Varghese James
- Department of Biochemistry, Christian Medical College, Vellore, India; Department of Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Joe Varghese
- Department of Biochemistry, Christian Medical College, Vellore, India
| | | | - Jean-Christophe Deschemin
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Sophie Vaulont
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Andrew Tristan McKie
- Department of Haematology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK
| | - Molly Jacob
- Department of Biochemistry, Christian Medical College, Vellore, India.
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The Effect of Dietary Protein Intake on the Risk of Gestational Diabetes. J FOOD QUALITY 2022. [DOI: 10.1155/2022/8368113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background. The results of epidemiological studies on the association between dietary protein intake and gestational diabetes mellitus (GDM) are controversial. Thus, this systematic review and meta-analysis of cohort studies were established to attain comprehensive findings regarding the association between dietary protein and the risk of GDM. Methods. Bibliographic databases including PubMed, Scopus, Web of Science, and Google Scholar were searched to discover papers related to dietary protein and the risk of GDM. The summary relative risks with 95% confidence intervals (CIs) were estimated through a random effect model for the analysis of the highest versus the lowest categories of dietary proteins. Results. A significantly increased risk of GDM among women who consumed the highest amount of animal protein was observed (summarized risk estimate: 1.52; 95% CI: 1.07, 2.17; I2 = 50.8%). No significant associations were identified regarding vegetable protein (summarized risk estimate:0.99, 95% CI: 0.80 to 1.23, I2 = 63.8%) and total protein (summarized risk estimate: 1.12; 95% CI: 0.88, 1.41; I2 = 35.4%). Conclusion. This review revealed that total protein intake had no relationship with the risk of GDM, while animal protein increases this risk. Further larger prospective cohort studies are required to confirm our results.
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Prasad M K, Mohandas S, Kunka Mohanram R. Role of ferroptosis inhibitors in the management of diabetes. Biofactors 2022; 49:270-296. [PMID: 36468443 DOI: 10.1002/biof.1920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022]
Abstract
Ferroptosis, the iron-dependent, lipid peroxide-mediated cell death, has garnered attention due to its critical involvement in crucial physiological and pathological cellular processes. Indeed, several studies have attributed its role in developing a range of disorders, including diabetes. As accumulating evidence further the understanding of ferroptotic mechanisms, the impact this specialized mode of cell death has on diabetic pathogenesis is still unclear. Several in vivo and in vitro studies have highlighted the association of ferroptosis with beta-cell death and insulin resistance, supported by observations of marked alterations in ferroptotic markers in experimental diabetes models. The constant improvement in understanding ferroptosis in diabetes has demonstrated it as a potential therapeutic target in diabetic management. In this regard, ferroptosis inhibitors promise to rescue pancreatic beta-cell function and alleviate diabetes and its complications. This review article elucidates the key ferroptotic pathways that mediate beta-cell death in diabetes, and its complications. In particular, we share our insight into the cross talk between ferroptosis and other hallmark pathogenic mediators such as oxidative and endoplasmic reticulum stress regulators relevant to diabetes progression. Further, we extensively summarize the recent developments on the role of ferroptosis inhibitors and their therapeutic action in alleviating diabetes and its complications.
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Affiliation(s)
- Krishna Prasad M
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Ramkumar Kunka Mohanram
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
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Mokgalaboni K, Phoswa W. Cross-link between type 2 diabetes mellitus and iron deficiency anemia. A mini-review. CLINICAL NUTRITION OPEN SCIENCE 2022. [DOI: 10.1016/j.nutos.2022.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Dietary iron modulates hepatic glucose homeostasis via regulating gluconeogenesis. J Nutr Biochem 2022; 109:109104. [PMID: 35863586 DOI: 10.1016/j.jnutbio.2022.109104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 11/24/2022]
Abstract
Iron exerts significant influences on glucose metabolism. However, the regulatory mechanisms underlying disordered glucose response remains largely unclear. The aim of this study was to examine the impact of dietary iron on hepatic gluconeogenesis in mice and in rat liver-derived cells. High iron models of C57BL/6J mice were fed with 1.25 g Fe/kg diets for 9 weeks, and high-iron BRL-3A cell models were treated with 250 μmol/L FeSO4 for 12 h and 24 h. Our data showed that higher iron intake resulted in higher hepatic iron without iron toxicity, and reduced body weight gain with no difference of food intakes. High dietary iron significantly increased 61% of hepatic glycogen deposition, but exhibited impairment in glucose responses in mice. Moreover, high dietary iron suppressed hepatic gluconeogenesis by repressing the expression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Meanwhile, mice fed with higher iron diets exhibited both decreased AMP-activated protein kinase (AMPK) activity and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protein levels. Furthermore, in BRL-3A cells, iron treatment increased cellular glucose uptake, and altered gluconeogenesis rhythmically by regulating the activation of AMPK and expression of PGC-1α successively. This study demonstrated that dietary high iron was able to increase hepatic glycogen deposition by enhancement of glucose uptake, and suppress hepatic gluconeogenesis by regulation of AMPK and PGC-1α.
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22
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Jaccard E, Seyssel K, Gouveia A, Vergely C, Baratali L, Gubelmann C, Froissart M, Favrat B, Marques-Vidal P, Tappy L, Waeber G. Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial. EClinicalMedicine 2022; 48:101434. [PMID: 35706490 PMCID: PMC9092517 DOI: 10.1016/j.eclinm.2022.101434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 04/01/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022] Open
Abstract
Background Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 μU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 μUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 μUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.
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Affiliation(s)
- Evrim Jaccard
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Kévin Seyssel
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, rue du Bugnon 7a, Lausanne 1005, Switzerland
| | - Alexandre Gouveia
- Center for Primary Care and Public Health, University of Lausanne, rue du Bugnon 44, Lausanne, Switzerland
| | - Catherine Vergely
- Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2, EA7460),UFR des Sciences de Santé, University of Bourgogne Franche-Comté, 7 boulevard Jeanne d’ Arc, Dijon 21079, France
| | - Laila Baratali
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Cédric Gubelmann
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Marc Froissart
- Clinical Research Center, CHUV, University of Lausanne, Switzerland
| | - Bernard Favrat
- Center for Primary Care and Public Health, University of Lausanne, rue du Bugnon 44, Lausanne, Switzerland
| | - Pedro Marques-Vidal
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Luc Tappy
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, rue du Bugnon 7a, Lausanne 1005, Switzerland
| | - Gérard Waeber
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
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23
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Ikeda Y, Funamoto M, Tsuchiya K. The role of iron in obesity and diabetes. THE JOURNAL OF MEDICAL INVESTIGATION 2022; 69:1-7. [PMID: 35466128 DOI: 10.2152/jmi.69.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Iron is an essential trace metal for all life, but excess iron causes oxidative stress through catalyzing the toxic hydroxy-radical production via the Fenton reaction. The number of patients with obesity and diabetes has been increasing worldwide, and their onset and development are affected by diet. In both clinical and experimental studies, a high body iron content was associated with obesity and diabetes, and the reduction of body iron content to an appropriate level can ameliorate the status and development of obesity and diabetes. Macrophages play an essential role in the pathophysiology of obesity and diabetes, and in the metabolism and homeostasis of iron in the body. Recent studies demonstrated that macrophage polarization is related to adipocyte hypertrophy and insulin resistance through their capabilities of iron handling. Control of iron in macrophages is a potential therapeutic strategy for obesity and diabetes. J. Med. Invest. 69 : 1-7, February, 2022.
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Affiliation(s)
- Yasumasa Ikeda
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masafumi Funamoto
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Koichiro Tsuchiya
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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Hamada Y, Hirano E, Sugimoto K, Hanada K, Kaku T, Manda N, Tsuchida K. A farewell to phlebotomy-use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report. J Med Case Rep 2022; 16:26. [PMID: 35065677 PMCID: PMC8784004 DOI: 10.1186/s13256-021-03230-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/14/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis. CASE PRESENTATION A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue. CONCLUSION The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.
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Affiliation(s)
- Yuki Hamada
- Hamada Clinic for Gastroenterology and Hepatology, Sapporo, Japan
| | - Eiichi Hirano
- Research Institute, Japan Bio Products Co., Ltd., 1-1 Kurume Research Center bldg. 2F, Hyakunenkoen, Kurume, Fukuoka 839-0864 Japan
| | - Koji Sugimoto
- Research Institute, Japan Bio Products Co., Ltd., 1-1 Kurume Research Center bldg. 2F, Hyakunenkoen, Kurume, Fukuoka 839-0864 Japan
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Zhu G, Zheng T, Xia C, Qi L, Papandonatos GD, Ming Y, Zeng Z, Zhang X, Zhang H, Li Y. Plasma levels of trace element status in early pregnancy and the risk of gestational diabetes mellitus: A nested case-control study. J Trace Elem Med Biol 2021; 68:126829. [PMID: 34358794 DOI: 10.1016/j.jtemb.2021.126829] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/24/2021] [Accepted: 07/30/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE We investigated the impacts of plasma levels of magnesium (Mg), zinc (Zn), calcium (Ca), iron (Fe), copper (Cu), selenium (Se), and chromium (Cr) on GDM risk and the potential mediation effect of blood glucose levels on the relationship between trace elements and GDM risk. METHODS This nested case-control study was based on data from a birth cohort study conducted in Wuhan, China in 2013-2016. A total of 305 GDM cases and 305 individually-matched controls were included in the study. Conditional logistic regression models were used to estimate the associations between plasma trace element concentrations and GDM risk. A mediation analysis was conducted to explore whether blood glucose levels act as a mediator between trace element levels and GDM risk. RESULTS An IQR increment in plasma levels of Fe and Cu was associated with a significant increase in GDM risk [OR = 2.04 (95 % CI 1.62, 2.57) and OR = 1.52 (95 % CI 1.25, 1.82)], respectively. On the other hand, an IQR increment in plasma levels of Zn and Ca was associated with a significant decrease in GDM risk [OR = 0.55 (95 % CI 0.43, 0.71) and OR = 0.72 (95 % CI 0.56, 0.92)], respectively. The mediation analysis showed significant mediation of the association between Cu and GDM risk via the FBG (%mediated: 19.27 %), 1 h-PBG (12.64 %), 2h-PBG (28.44 %) pathways. CONCLUSIONS Plasma levels of Zn and Ca were negatively associated with GDM risk, while Fe and Cu were positively associated. Blood glucose levels act as a mediator between plasma trace element exposures and GDM risk.
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Affiliation(s)
- Gangjiao Zhu
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China
| | - Tongzhang Zheng
- Department of Epidemiology, Brown School of Public Health, Providence, RI, USA
| | - Chang Xia
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China
| | - Ling Qi
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China
| | | | - Yu Ming
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China
| | - Zhi Zeng
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China
| | - Xichi Zhang
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, 1518 Clifton Rd, NE, Atlanta, GA, 30322, USA
| | - Hongling Zhang
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China.
| | - Yuanyuan Li
- Key Laboratory of Environment and Health (Huazhong University of Science and Technology), Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial. Sci Rep 2021; 11:22097. [PMID: 34764381 PMCID: PMC8586019 DOI: 10.1038/s41598-021-01606-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/29/2021] [Indexed: 11/23/2022] Open
Abstract
Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577–0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.
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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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Huang Y, Cao D, Chen Z, Chen B, Li J, Wang R, Guo J, Dong Q, Liu C, Wei Q, Liu L. Iron intake and multiple health outcomes: Umbrella review. Crit Rev Food Sci Nutr 2021; 63:2910-2927. [PMID: 34583608 DOI: 10.1080/10408398.2021.1982861] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Iron is an essential trace element, while excess iron can lead to different levels of physical abnormalities or diseases. This umbrella review aimed to conduct a systematic evaluation of the possible relationships between iron intake and various health outcomes. We retrieved PubMed, Embase, Web of Science, Scopus, and the Cochrane Database of Systematic Reviews from inception through May 2021. A total of 34 meta-analyses with 46 unique health outcomes were identified. Heme iron intake was positively associated with nine outcomes, including colorectal cancer, type 2 diabetes mellitus, and cardiovascular disease mortality, while dietary total iron intake could decrease the risk of colorectal adenoma, esophageal cancer, coronary heart disease, and depression. Iron supplementation was a protective factor against eight outcomes. However, it was associated with decreased length and weight gain. The quality of evidence for most outcomes was "low" or "very low" with the remaining eleven as "high" or "moderate". All outcomes were categorized as class III, IV, or NS based on evidence classification. Although high iron intake has been identified to be significantly associated with a range of outcomes, firm universal conclusions about its beneficial or negative effects cannot be drawn given the low quality of evidence for most outcomes.
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Affiliation(s)
- Yin Huang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Dehong Cao
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Zeyu Chen
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Bo Chen
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jin Li
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Ruyi Wang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianbing Guo
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Dong
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengfei Liu
- Department of Urologic Surgery, UC Davis School of Medicine, Sacramento, California, USA
| | - Qiang Wei
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Liangren Liu
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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Yadav AK, Ghosh A, Divyaveer S, Mukhopadhyay B, Kundu M, Kumar V, Lele SS, Rajapurkar MM, Jha V. Serum catalytic iron and progression of chronic kidney disease: findings from the ICKD study. Nephrol Dial Transplant 2021; 37:gfab271. [PMID: 34534345 DOI: 10.1093/ndt/gfab271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The non-transferrin bound catalytic iron moiety catalyses production of toxic reactive oxygen species and is associated with adverse outcomes. We hypothesized that serum catalytic iron (SCI) is associated with progression of chronic kidney disease (CKD). METHODS Baseline samples of the Indian Chronic Kidney Disease participants with at least one follow up visit were tested for total iron, iron binding capacity, transferrin saturation, SCI, ferritin and hepcidin. SCI was measured using the bleomycin-detectable iron assay that detects biologically active iron. Association with the incidence of major kidney endpoints, (MAKE, a composite of kidney death, kidney failure or > 40% loss of eGFR) was examined using Cox proportional hazards model adjusted for sex and age. RESULTS 2002 subjects (49.9 ± 11.6 years, 68.1% males, baseline eGFR 41.01 ml/min/1.73m2) were enrolled. After a median follow up of 12.6 (12.2, 16.7) months, the composite MAKE occurred in 280 (14%). After adjusting for age and sex, increase from 25th to 75th percentile in SCI, transferrin saturation, ferritin and hepcidin were associated with 78% (43-122%), 34% (10-62%), 57% (24-100%) and 74% (35-124%) increase in hazard of MAKE, respectively. SCI was associated with MAKE and kidney failure after adjustment for occupational exposure, hypertension, diabetes, tobacco, alcohol use, history of AKI, baseline eGFR, uACR, and allowing baseline hazard to vary by centre. CONCLUSIONS SCI is strongly and independently associated with composite MAKE in patients with mild to moderate CKD. Confirmation in other studies will allow consideration of SCI as a risk marker and treatment target.
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Affiliation(s)
- Ashok K Yadav
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh
| | - Arpita Ghosh
- George Institute for Global Health India, New Delhi
| | - Smita Divyaveer
- Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh
| | | | - Monica Kundu
- George Institute for Global Health India, New Delhi
| | - Vivek Kumar
- Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh
| | - Suhas S Lele
- Department of Cardiology, Bhailal Amin General Hospital, Baroda
| | | | - Vivekanand Jha
- George Institute for Global Health India, New Delhi
- School of Public Health, Imperial College, London, UK
- Manipal Academy of Higher Education, Manipal, India
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Winn NC, Wolf EM, Cottam MA, Bhanot M, Hasty AH. Myeloid-specific deletion of ferroportin impairs macrophage bioenergetics but is disconnected from systemic insulin action in adult mice. Am J Physiol Endocrinol Metab 2021; 321:E376-E391. [PMID: 34338042 PMCID: PMC8461794 DOI: 10.1152/ajpendo.00116.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/28/2021] [Accepted: 07/25/2021] [Indexed: 12/28/2022]
Abstract
Tissue iron overload is associated with insulin resistance and mitochondrial dysfunction in rodents and humans; however, the mechanisms or cell types that mediate this phenotype are not completely understood. Macrophages (Mɸs) are known to contribute to iron handling; thus, we hypothesized that perturbed iron handling by Mɸs impairs mitochondrial energetics and evokes systemic insulin resistance in mice. Male and female mice with myeloid-targeted (LysMCre) deletion of the canonical iron exporter, ferroportin (Fpn, encoded by Slc40a1), floxed littermates, and C57BL/6J wild-type mice were used to test our hypotheses. Myeloid-targeted deletion of Fpn evoked multitissue iron accumulation and reduced mitochondrial respiration in bone marrow-derived Mɸs, liver leukocytes, and Mɸ-enriched populations from adipose tissue (AT). In addition, a single bolus of exogenous iron administered to C57BL/6J mice phenocopied the loss of Fpn, resulting in a reduction in maximal and mitochondrial reserve capacity in Mɸ-enriched cellular fractions from liver and AT. In vivo exogenous iron chelation restored mitochondrial reserve capacity in liver leukocytes from Fpn LysMCre mice, but had no effect in AT myeloid populations. However, despite the impairments in mitochondrial respiration, neither loss of myeloid-specific Fpn nor exogenous iron overload perturbed glucose homeostasis or systemic insulin action in lean or obese mice, whereas aging coupled with lifelong loss of Fpn unmasked glucose intolerance. Together these data demonstrate that iron handling is critical for the maintenance of macrophage mitochondrial function, but perturbing myeloid iron flux via the loss of Fpn action is not sufficient to evoke systemic insulin resistance in young adult mice. These findings also suggest that if Mɸs are capable of storing iron properly, they have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance that may be age dependent.NEW & NOTEWORTHY We used myeloid-specific knockout of ferroportin to determine whether macrophage iron enrichment alters systemic metabolism. We found that macrophages in several tissues showed mitochondrial defects such as a reduction in mitochondrial reserve capacity. However, insulin action in the mice was preserved. These findings also suggest that Mɸs have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance, which appears to be age dependent.
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Affiliation(s)
- Nathan C Winn
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Elysa M Wolf
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Matthew A Cottam
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Monica Bhanot
- Division of Diabetes, Endocrinology and Metabolism, Vanderbilt Medical Center, Nashville, Tennessee
| | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
- VA Tennessee Valley Healthcare System, Nashville, Tennessee
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Zapora-Kurel A, Kuźma Ł, Zakrzewska M, Żórawski M, Dobrzycki S, Twardowska-Kawalec M, Małyszko J. Novel Iron Parameters in Patients with Type 2 Diabetes Mellitus in Relation to Kidney Function. J Clin Med 2021; 10:jcm10163732. [PMID: 34442028 PMCID: PMC8397038 DOI: 10.3390/jcm10163732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS Anemia of chronic disease is a common feature in diabetes and chronic kidney disease. Hepcidin is the key element involved in iron metabolism; however, studies on new indices of iron status are still ongoing. The aim of the study was to assess novel iron parameters in patients with type 2 diabetes mellitus in relation to kidney function. METHODS The study included 80 type 2 diabetic patients and 23 healthy volunteers. Standard laboratory measurements were used to measure the iron status, complete blood count, creatinine, the estimated glomerular filtration rate (eGFR), serum lipids, and brain natriuretic peptides (BNPs). Commercially available kits were used to measure hepcidin-25, the soluble transferrin receptor (sTfR), growth differentiation factor-15 (GDF-15), and hypoxia-inducible factor-1 alpha. RESULTS Anemia was present in 65% of the studied patients. The control group was found to have significantly higher hepcidin, sTfR, and GDF-15, and lower hemoglobin and iron. When compared with patients with eGFR values ≥60 mL/min/1.73 m2 and <60 mL/min/1.73 m2, we found that patients with higher eGFR had higher hemoglobin, ferritin, and HIF-1 alpha, lower BNP, and were younger. We found that levels of HIF-1 alpha are negligible in the studied population and were related to age only in patients with eGFR values ≥60 mL/min/1.73 m2. CONCLUSION A comprehensive assessment of iron status is rarely performed. Novel biomarkers of iron metabolism are not generally related to kidney function. Whether the assessment of HIF-1 alpha would be a marker of efficient anemia therapy with HIF-prolyl hydroxylase inhibitors is still a matter for further study.
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Affiliation(s)
- Agnieszka Zapora-Kurel
- 2nd Department of Nephrology with Hypertension and Dialysis, Medical University of Bialystok, 15-089 Bialystok, Poland; (A.Z.-K.); (M.Z.)
| | - Łukasz Kuźma
- Department of Invasive Cardiology, Medical University of Bialystok, 15-089 Bialystok, Poland; (L.K.); (S.D.)
| | - Magdalena Zakrzewska
- 2nd Department of Nephrology with Hypertension and Dialysis, Medical University of Bialystok, 15-089 Bialystok, Poland; (A.Z.-K.); (M.Z.)
| | - Marcin Żórawski
- Department of Clinical Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Sławomir Dobrzycki
- Department of Invasive Cardiology, Medical University of Bialystok, 15-089 Bialystok, Poland; (L.K.); (S.D.)
| | | | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Correspondence: ; Tel.: +48-22-599-2660
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Abbate M, Montemayor S, Mascaró CM, Casares M, Gómez C, Ugarriza L, Tejada S, Abete I, Zulet MÁ, Sureda A, Martínez JA, Tur JA. Albuminuria Is Associated with Hepatic Iron Load in Patients with Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome. J Clin Med 2021; 10:jcm10143187. [PMID: 34300354 PMCID: PMC8305023 DOI: 10.3390/jcm10143187] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Increased albuminuria is associated with increased serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Liver iron accumulation is also related to hyperferritinemia, insulin resistance, and NAFLD; however, there is no evidence on its relationship with albuminuria. Aims: To assess the relationship between hepatic iron load and urine albumin-to-creatinine ratio (UACR) in patients with metabolic syndrome (MetS) and NAFLD. Methods: In total, 75 MetS and NAFLD patients (aged 40–60 years, BMI 27–40 kg/m2) were selected from a cohort according to available data on hepatic iron load (HepFe) by magnetic resonance imaging (MRI). Subjects underwent anthropometric measurements, biochemistry testing, and liver MRI. Increased albuminuria was defined by UACR. Results: UACR correlated with NAFLD, HepFe, triglycerides, serum ferritin, fasting insulin, insulin resistance (calculated using the homeostatic model assessment for insulin resistance—HOMA-IR- formula), and platelets (p < 0.05). Multiple regression analysis adjusted for gender, age, eGFR, HbA1c, T2DM, and stages of NAFLD, found that HepFe (p = 0.02), serum ferritin (p = 0.04), fasting insulin (p = 0.049), and platelets (p = 0.009) were associated with UACR (R2 = 0.370; p = 0.007). UACR, liver fat accumulation, serum ferritin, and HOMA-IR increased across stages of HepFe (p < 0.05). Patients with severe NAFLD presented higher HepFe, fasting insulin, HOMA-IR, and systolic blood pressure as compared to patients in NAFLD stage 1 (p < 0.05). Conclusion: Hepatic iron load, serum ferritin, fasting insulin, and platelets were independently associated with albuminuria. In the context of MetS, increased stages of NAFLD presented higher levels of HepFe. Higher levels of HepFe were accompanied by increased serum ferritin, insulin resistance, and UACR. The association between iron accumulation, MetS, and NAFLD may represent a risk factor for the development of increased albuminuria.
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Affiliation(s)
- Manuela Abbate
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Sofía Montemayor
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Catalina M. Mascaró
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Miguel Casares
- Radiodiagnosis Service, Red Asistencial Juaneda, 07011 Palma de Mallorca, Spain;
| | - Cristina Gómez
- Clinical Analysis Service, University Hospital Son Espases, 07120 Palma de Mallorca, Spain;
| | - Lucía Ugarriza
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- Camp Redó Primary Health Care Center, 07010 Palma de Mallorca, Spain
| | - Silvia Tejada
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
| | - Itziar Abete
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
| | - M. Ángeles Zulet
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
| | - Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
| | - J. Alfredo Martínez
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
- Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM-CSIC, 28049 Madrid, Spain
| | - Josep A. Tur
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Correspondence: ; Tel.: +34-971-1731; Fax: +34-9-7117-3184
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Wen S, Sha Y, Li Y, Rui Z, Si C, Zhou Y, Yan F, Wang B, Hu J, Han X, Shi D. Serum Iron and Ferritin Levels Are Correlated with Complement C3. Biol Trace Elem Res 2021; 199:2482-2488. [PMID: 32935207 DOI: 10.1007/s12011-020-02379-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023]
Abstract
Iron is one of the most important trace elements in the body, and its homeostasis is essential to the normal function of the immune system. Complement component C3, which is the converging of three main pathways of complement system activation, plays a key role in the innate immunity. However, the relationship between iron homeostasis and complement C3 remains unknown. The aim of our study was to analyze the relationship between serum iron and ferritin level and complement C3 and C4. A total of 590 healthy individuals were recruited in our study. Higher serum complement C3 level (p < 0.001) was found in individuals with higher serum ferritin level (> 104.0 μg/L). Moreover, serum iron level and serum ferritin level were positively correlated with complement C3 (r = 0.133, p = 0.001; r = 0.221, p < 0.001) and complement C4 (r = 0.117, p = 0.004; r = 0.123, p = 0.003). The linear regression analysis displayed that both serum iron level and serum ferritin level were linearly correlated with serum complement C3 level (adjusted beta: 2.382, 95% CI: 0.841-3.923; adjusted beta: 42.911, 95% CI: 29.070-56.751). To explore the relationship between iron homeostasis and complement C3 further, the serum samples from C3-/- mice and the wild-type (WT) control mice were obtained. Significantly lower serum iron level and higher ferritin level were found in C3-/- mice than those in WT mice (p < 0.001; p < 0.001), indicating that complement C3 might influence iron distribution and utilization. Overall, these data suggested that serum iron and ferritin levels were correlated with complement C3. The deficiency of complement C3 may disrupt the regular iron metabolism in the body.
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Affiliation(s)
- Shuang Wen
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yeqin Sha
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yinling Li
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Zhilian Rui
- Department of Laboratory Medicine, Liyang People's Hospital, Liyang, 213300, Jiangsu, China
| | - Chenhong Si
- Department of Pediatrics, Liyang Women and Children Health Hospital, Liyang, 213000, Jiangsu, China
| | - Yuning Zhou
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Fengfeng Yan
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Bicheng Wang
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Jingming Hu
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Xu Han
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Dongyan Shi
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
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Sha W, Hu F, Xi Y, Chu Y, Bu S. Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus. J Diabetes Res 2021; 2021:9999612. [PMID: 34258295 PMCID: PMC8257355 DOI: 10.1155/2021/9999612] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022] Open
Abstract
Ferroptosis is a novel form of nonapoptotic regulated cell death (RCD). It features iron-dependent lipid peroxide accumulation accompanied by inadequate redox enzymes, especially glutathione peroxidase 4 (GPX4). RAS-selective lethal 3 (RSL3), erastin, and ferroptosis inducing 56 (FIN56) induce ferroptosis via different manners targeting GPX4 function. Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) participate in the production of lipid peroxides. Heat shock protein family B member 1 (HSPB1) and nuclear receptor coactivator 4 (NCOA4) regulate iron homeostasis preventing ferroptosis caused by the high concentration of intracellular iron. Ferroptosis is ubiquitous in our body as it exists in both physiologic and pathogenic processes. It is involved in glucose-stimulated insulin secretion (GSIS) impairment and arsenic-induced pancreatic damage in the pathogenesis of diabetes. Moreover, iron and the iron-sulfur (Fe-S) cluster influence each other, causing mitochondrial iron accumulation, more reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, failure in biosynthesis of insulin, and ferroptosis in β-cells. In addition, ferroptosis also engages in the pathogenesis of diabetic complications such as myocardial ischemia and diabetic cardiomyopathy (DCM). In this review, we summarize the mechanism of ferroptosis and especially its association with type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Wenxin Sha
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China
| | - Fei Hu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China
- Cixi Biomedical Research Institute, Wenzhou Medical University, Cixi 315300, China
| | - Yang Xi
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China
| | - Yudong Chu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China
- Department of Nephrology, Ningbo Medical Center Lihuili Hospital, Ningbo 315100, China
| | - Shizhong Bu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China
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Dietary iron to total energy intake ratio and type 2 diabetes incidence in a longitudinal 12-year analysis of the Korean Genome and Epidemiology Cohort Study. Eur J Nutr 2021; 60:4453-4461. [PMID: 34085096 DOI: 10.1007/s00394-021-02596-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/21/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Recent study found iron consumption has been associated with an increased risk of type 2 diabetes (T2DM). Even though, high iron intake is correlated with total caloric intake, most studies have evaluated the individual effect of iron and total caloric intake. The aim of this study was to investigate the effect of iron intake, in conjunction with total energy intake, on developing T2DM. We also investigated the interactions between dietary iron and energy ratios (IERs) and iron-related single nucleotide polymorphisms (SNPs) in the development of T2DM. METHODS The study was carried out in Ansan and Ansung, Korea, between March 2001 and December 2014. A total of 6413 participants (3073 men and 3340 women), aged 40-69 years, were enrolled in this study. The mean follow-up period was 8.4 years. The study population was divided into quartiles based on IERs with cut-off points at 4.54, 5.41, and 6.29. The odds ratios (ORs) for new-onset T2DM were calculated across each quartile of IERs and a random forest model was constructed using the default settings to predict new-onset T2DM. To confirm the interaction among IERs, SNPs, and the incidence of T2DM, we measured the predictive power of new-onset T2DM using IER and six SNPs in genes related to iron metabolism [rs855791 (TPMRSS6), rs38116479 (TF), rs1799852 (TF), rs2280673, rs1799945 (HFT), rs180562 (HFE)]. RESULTS The prevalence of T2DM was 762 (11.8%). IERs showed a positive association with T2DM. The ORs were 1.30 (95% CI 1.02-1.67), 1.20 (95% CI 0.94-1.56), and 1.43 (95% CI 1.11-1.86) across the IER quartiles after adjusting for non-dietary and dietary metabolic risk factors. When the IER was 1.89-fold higher than the reference group, the risk of developing T2DM increased by 43% (OR 1.43; 95% CI 1.11-1.86). CONCLUSION A higher IER was positively associated with developing T2DM independent of dietary or non-dietary risk factors. We also found the possible interactions between the identified SNPs and iron intake in relations to T2DM.
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Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166142. [PMID: 33839281 DOI: 10.1016/j.bbadis.2021.166142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/23/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.
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Ortiz-Flores AE, Martínez-García MÁ, Nattero-Chávez L, Álvarez-Blasco F, Fernández-Durán E, Quintero-Tobar A, Escobar-Morreale HF, Luque-Ramírez M. Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes. J Clin Endocrinol Metab 2021; 106:e1559-e1573. [PMID: 33462622 DOI: 10.1210/clinem/dgaa978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Indexed: 12/13/2022]
Abstract
CONTEXT Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. OBJECTIVES (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. DESIGN Randomized, parallel, open-label, clinical trial. SETTING Academic hospital. PATIENTS Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. INTERVENTION After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. MAIN OUTCOME MEASURES Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. RESULTS From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. CONCLUSIONS Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.
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Affiliation(s)
- Andrés E Ortiz-Flores
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
- Department of Endocrinology and Nutrition. Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain
| | - María Ángeles Martínez-García
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Lía Nattero-Chávez
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Francisco Álvarez-Blasco
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Elena Fernández-Durán
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Alejandra Quintero-Tobar
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Héctor F Escobar-Morreale
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Manuel Luque-Ramírez
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
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Si S, Shen Y, Xin X, Mo M, Shao B, Wang S, Luo W, Chen Z, Liu H, Chen D, Yu Y. Hemoglobin concentration and iron supplement during pregnancy were associated with an increased risk of gestational diabetes mellitus. J Diabetes 2021; 13:211-221. [PMID: 32755052 DOI: 10.1111/1753-0407.13101] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/30/2020] [Accepted: 07/22/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Hemoglobin (Hb) measurement is a conventional test during perinatal visits. Hb concentration is related to iron supplement. However, studies focusing on Hb levels, iron supplement, and pregnancy outcomes are scarce. This study aimed to determine whether Hb levels and iron supplement were associated with the risk of gestational diabetes mellitus (GDM). METHODS A running hospital-based cohort was conducted from August, 2011. The demographic data and medical information were collected individually through questionnaires and patient medical records. Multiple linear regression was applied for the association between Hb levels, iron supplement, and blood glucose. Multiple logistic regression was used for evaluating odds ratios between Hb levels, iron supplement, and GDM. RESULTS Hb levels during first (T1) and second trimester (T2) of pregnancy were significantly and positively associated with blood glucose and GDM risk. After adjusting for age, prepregnancy body mass index, and other risk factors, pregnant women with Hb ≥ 11 g/dL and iron supplement had higher postprandial blood glucose at 1 hour (Hb ≥ 11 g/dL in T2 and iron supplement in T1: β = 0.860，P = <0.001; Hb ≥ 11 g/dL in T2 and iron supplement in T2: β = 0.960，P < 0.001; Hb ≥ 11 g/dL in T1 and iron supplement in T2: β = 1.133, P = 0.033) and GDM risks (odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.05-2.24; OR = 1.92, 95% CI: 1.13-3.35; OR = 2.15, 95% CI: 1.07-4.34, respectively), compared with those with Hb < 11 g/dL and without iron supplement. CONCLUSION High Hb concentration and iron supplements without anemia increased postprandial blood glucose and risks for GDM. It indicates that pregnant women with good Hb levels should not be advised to take iron supplements during pregnancy.
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Affiliation(s)
- Shuting Si
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Shen
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xing Xin
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Minjia Mo
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bule Shao
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shuojia Wang
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenliang Luo
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zexin Chen
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hui Liu
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Danqing Chen
- Department of Obstetrics and Gynecology, Woman's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yunxian Yu
- Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
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Masi LN, Lotufo PA, Ferreira FM, Rodrigues AC, Serdan TDA, Souza‐Siqueira T, Braga AA, Saldarriaga MEG, Alba‐Loureiro TC, Borges FT, Cury DP, Hirata MH, Gorjão R, Pithon‐Curi TC, Lottenberg SA, Fedeli LMG, Nakaya HTI, Bensenor IJM, Curi R, Hirabara SM. Profiling plasma-extracellular vesicle proteins and microRNAs in diabetes onset in middle-aged male participants in the ELSA-Brasil study. Physiol Rep 2021; 9:e14731. [PMID: 33587339 PMCID: PMC7883809 DOI: 10.14814/phy2.14731] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
We measured plasma-derived extracellular vesicle (EV) proteins and their microRNA (miRNA) cargos in normoglycemic (NG), glucose intolerant (GI), and newly diagnosed diabetes mellitus (DM) in middle-aged male participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brazil). Mass spectrometry revealed decreased IGHG-1 and increased ITIH2 protein levels in the GI group compared with that in the NG group and higher serotransferrin in EVs in the DM group than in those in the NG and GI groups. The GI group also showed increased serum ferritin levels, as evaluated by biochemical analysis, compared with those in both groups. Seventeen miRNAs were differentially expressed (DEMiRs) in the plasma EVs of the three groups. DM patients showed upregulation of miR-141-3p and downregulation of miR-324-5p and -376c-3p compared with the NG and GI groups. The DM and GI groups showed increased miR-26b-5p expression compared with that in the NG group. The DM group showed decreased miR-374b-5p levels compared with those in the GI group and higher concentrations than those in the NG group. Thus, three EV proteins and five DEMiR cargos have potential prognostic importance for diabetic complications mainly associated with the immune function and iron status of GI and DM patients.
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Affiliation(s)
- Laureane N. Masi
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Paulo A. Lotufo
- Center for Clinical and Epidemiologic ResearchUniversity of Sao PauloSao PauloBrazil
| | | | - Alice C. Rodrigues
- Department of PharmacologyInstitute of Biomedical SciencesUniversity of Sao PauloSao PauloBrazil
| | - Tamires D. A. Serdan
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Talita Souza‐Siqueira
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Aécio A. Braga
- Faculty of Pharmaceutical SciencesUniversity of São PauloSao PauloBrazil
| | | | - Tatiana C. Alba‐Loureiro
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Fernanda T. Borges
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Diego P. Cury
- Department of AnatomyInstitute of Biomedical SciencesUniversity of Sao PauloSao PauloBrazil
| | - Mario H. Hirata
- Faculty of Pharmaceutical SciencesUniversity of São PauloSao PauloBrazil
| | - Renata Gorjão
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Tania C. Pithon‐Curi
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
| | - Simão A. Lottenberg
- Faculty of MedicineUniversity of Sao PauloHospital das ClínicasSao PauloBrazil
| | - Ligia M. G. Fedeli
- Center for Clinical and Epidemiologic ResearchUniversity of Sao PauloSao PauloBrazil
| | - Helder T. I. Nakaya
- Department of PharmacologyInstitute of Biomedical SciencesUniversity of Sao PauloSao PauloBrazil
| | | | - Rui Curi
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
- Butantan InstituteSão PauloBrazil
| | - Sandro M. Hirabara
- Interdisciplinary Post‐graduate Program in Health SciencesCruzeiro do Sul UniversitySao PauloBrazil
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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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Priyadarshini S, Brar JK. Biofortification of chromium in fenugreek seeds. J Trace Elem Med Biol 2020; 61:126521. [PMID: 32330855 DOI: 10.1016/j.jtemb.2020.126521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 02/11/2020] [Accepted: 02/20/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Fenugreek and chromium are known to have anti-diabetic properties and this has been well demonstrated by multiple studies. Researches have been undertaken to study thebiofortification of chromium (Cr3+) in fenugreek. Some of the researchers have studied the biofortification from the soil irrigated with tannery waste water or from soil amended by tannery-sludge, with a view of enhancing the anti-diabetic effect of fenugreek plants. The present research work was also undertaken to increase the chromium content of fenugreek seeds, but through direct treatment of chromium picolinate solution to fenugreek seeds. METHODS Fenugreek seeds were procured and divided in four groups having three batches of 10 g seeds- treatment1, treatment2, control1 and control2. Control1 group was kept raw and was given no treatment and control2 group was germinated using double distilled water. Treatment1 and treatment2, on the other hand, were given treatment of 0.02 g and 0.04 g chromium picolinate solution, on first day and 0.01 g and 0.02 g chromium picolinate solution on second day, respectively. The germinated samples were then completely dried, powdered, digested with di-acid mixture and assayed using Inductively Coupled Plasma optical emission spectrometry method for chromium content. The treatment1 sample was selected for further nutritional analysis along with control1 and control2 group to compare the nutritional composition of raw, germinated and chromium treated fenugreek seed flour. Fifteen sprouts from treatment1 group (treatment1A group) and fifteen sprouts from control2 group (control3 group) were sown in earthen pots for the analysis of chromium content in seeds of new plants. RESULTS The fenugreek seeds treated with two different concentrations of chromium picolinate viz. treatment1 and treatment2 group attained 55 and 80 times higher chromium content as compared to control2 group, respectively. All the estimated minerals and bioactive compounds were significantly high (p ≤ 0.01) in germinated fenugreek seed flour and chromium treated fenugreek seed flour compared to raw fenugreek seed flour. Germinated fenugreek seed flour and chromium treated fenugreek seed flour were statistically comparable to each other in respect of all the parameters analysed. Hence, it was evident that enriching fenugreek seeds with chromium, did not affect the nutritional content of fenugreek seed by any mean. Also, there was no significant difference between the chromium content in seeds of control3 group and T1A group. CONCLUSIONS Treatment of fenugreek seeds with chromium solution seems to be an efficient and safe method for increasing their chromium concentration as compared to application of chromium to the soil for biofortification with minimal to no chance of chromium accumulation and inheritance in next generation plants. However, there is a need of more research to see how reliable these observations would be when different chromium salts and/or varied chromium concentration are used.
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Affiliation(s)
- Shweta Priyadarshini
- Department of Food and Nutrition, College of Community Science, Punjab Agricultural University, Ludhiana 141004, Punjab, India.
| | - Jaswinder Kaur Brar
- Department of Food and Nutrition, College of Community Science, Punjab Agricultural University, Ludhiana 141004, Punjab, India.
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Berthault C, Staels W, Scharfmann R. Purification of pancreatic endocrine subsets reveals increased iron metabolism in beta cells. Mol Metab 2020; 42:101060. [PMID: 32763423 PMCID: PMC7498953 DOI: 10.1016/j.molmet.2020.101060] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/23/2020] [Accepted: 07/30/2020] [Indexed: 11/18/2022] Open
Abstract
Objectives The main endocrine cell types in pancreatic islets are alpha, beta, and delta cells. Although these cell types have distinct roles in the regulation of glucose homeostasis, inadequate purification methods preclude the study of cell type-specific effects. We developed a reliable approach that enables simultaneous sorting of live alpha, beta, and delta cells from mouse islets for downstream analyses. Methods We developed an antibody panel against cell surface antigens to enable isolation of highly purified endocrine subsets from mouse islets based on the specific differential expression of CD71 on beta cells and CD24 on delta cells. We rigorously demonstrated the reliability and validity of our approach using bulk and single cell qPCR, immunocytochemistry, reporter mice, and transcriptomics. Results Pancreatic alpha, beta, and delta cells can be separated based on beta cell-specific CD71 surface expression and high expression of CD24 on delta cells. We applied our new sorting strategy to demonstrate that CD71, which is the transferrin receptor mediating the uptake of transferrin-bound iron, is upregulated in beta cells during early postnatal weeks. We found that beta cells express higher levels of several other genes implicated in iron metabolism and iron deprivation significantly impaired beta cell function. In human beta cells, CD71 is similarly required for iron uptake and CD71 surface expression is regulated in a glucose-dependent manner. Conclusions This study provides a novel and efficient purification method for murine alpha, beta, and delta cells, identifies for the first time CD71 as a postnatal beta cell-specific marker, and demonstrates a central role of iron metabolism in beta cell function.
CD71 is a marker that is highly expressed in murine pancreatic beta-cells. CD71 and CD24 can be used to purify live murine alpha-, beta-, and delta-cells. Iron metabolism in murine beta-cells is increased compared to that in alpha-, and delta-cells. Human beta-cells regulate CD71 surface expression in a glucose-dependent manner.
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Affiliation(s)
- C Berthault
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 123 Boulevard de Port Royal, 75014 Paris, France.
| | - W Staels
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 123 Boulevard de Port Royal, 75014 Paris, France; Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium; Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital of Brussels, Laarbeeklaan 101, Jette, Belgium
| | - R Scharfmann
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 123 Boulevard de Port Royal, 75014 Paris, France.
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The effects of first-trimester hemoglobin on adverse pregnancy outcomes. JOURNAL OF SURGERY AND MEDICINE 2020. [DOI: 10.28982/josam.773306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Development of insulin resistance preceded major changes in iron homeostasis in mice fed a high-fat diet. J Nutr Biochem 2020; 84:108441. [PMID: 32629238 PMCID: PMC7115812 DOI: 10.1016/j.jnutbio.2020.108441] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 03/10/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) have been associated with dysregulation of iron metabolism. The basis for this association is not completely understood. To attempt to investigate this, we studied temporal associations between onset of insulin resistance (IR) and dysregulated iron homeostasis, in a mouse model of T2DM. Male C57Bl/6 mice (aged 8 weeks) were fed a high-fat diet (HFD; 60% energy from fat) or a control diet (CD; 10% energy from fat) for 4, 8, 12, 16, 20 and 24 weeks. Development of IR was documented, and various metabolic, inflammatory and iron-related parameters were studied in these mice. HFD-feeding induced weight gain, hepato-steatosis and IR in the mice. Onset of IR occurred from 12 weeks onwards. Hepatic iron stores progressively declined from 16 weeks onwards. Accompanying changes included a decrease in hepatic hepcidin (Hamp1) mRNA expression and serum hepcidin levels and an increase in iron content in the epididymal white adipose tissue (eWAT). Iron content in the liver negatively correlated with that in the eWAT. Factors known to regulate hepatic Hamp1 expression (such as serum iron levels, systemic inflammation, and bone marrow-derived erythroid regulators) were not affected by HFD-feeding. In conclusion, the results show that the onset of IR in HFD-fed mice preceded dysregulation of iron homeostasis, evidence of which were found both in the liver and visceral adipose tissue.
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Abstract
Reviewed here are multiple mouse models of vertical sleeve gastrectomy (VSG) and Roux-en Y gastric bypass (RYGB) that have emerged over the past decade. These models use diverse approaches to both operative and perioperative procedures. Scrutinizing the benefits and pitfalls of each surgical model and what to expect in terms of post-operative outcomes will enhance our assessment of studies using mouse models, as well as advance our understanding of their translational potential. Two mouse models of bariatric surgery, VSG-lembert and RYGB-small pouch, demonstrate low mortality and most closely recapitulate the human forms of surgery. The use of liquid diets can be minimized, and in mice, RYGB demonstrates more reliable and longer lasting effects on weight loss compared to that of VSG.
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Iron Status in Elderly Women Impacts Myostatin, Adiponectin and Osteocalcin Levels Induced by Nordic Walking Training. Nutrients 2020; 12:nu12041129. [PMID: 32316589 PMCID: PMC7231223 DOI: 10.3390/nu12041129] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/09/2020] [Accepted: 04/15/2020] [Indexed: 01/26/2023] Open
Abstract
Impaired iron metabolism is associated with increased risk of many morbidities. Exercise was shown to have a beneficial role; however, the mechanism is not well understood. The purpose of this study was to assess the relationship between exerkines and iron metabolism in elderly women before and after 12 weeks of Nordic Walking (NW) training. Exerkines like myostatin, adiponectin, and osteocalcin have been shown to have several positive effects on metabolism. Thirty-six post-menopausal women (66 ± 5 years old, mean ± SD) were randomly assigned to a NW intervention group (n = 18; body mass, 68.8 ± 11.37 kg; fat, 23.43 ± 7.5 kg; free fat mass, 45.37 ± 5.92 kg) or a control group (n = 18; body mass, 68.34 ± 11.81 kg; fat, 23.61 ± 10.03 kg; free fat mass, 44.73 ± 3.9 kg). The training was performed three times a week for 12 weeks, with the intensity adjusted to 70% of the individual maximum ability. Before and one day after the 12-weeks intervention, performance indices were assessed using a senior fitness test. Blood samples (5 mL) were obtained from the participants between 7 and 8 AM, following an overnight fast, at baseline and one day immediately after the 12-week training program. A significant and large time × group interaction was observed for iron (NW: 98.6 ± 26.68 to 76.1 ± 15.31; CON: 100.6 ± 25.37 to 99.1 ± 27.2; p = 0.01; ηp2 = 0.21), myostatin (NW: 4.42 ± 1.97 to 3.83 ± 1.52; CON: 4.11 ± 0.95 to 4.84 ± 1.19; p = 0.00; ηp2 = 0.62), adiponectin (NW: 12.0 ± 9.46 to 14.6 ± 10.64; CON: 12.8 ± 8.99 to 11.9 ± 8.53; p = 0.00; ηp2 = 0.58), and osteocalcin (NW: 38.9 ± 26.04 to 41.6 ± 25.09; CON: 37.1 ± 33.2 to 37.2 ± 32.29; p = 0.03; ηp2 = 0.13). Furthermore, we have observed the correlations: basal ferritin levels were inversely correlated with changes in myostatin (r = −0.51, p = 0.05), change in adiponectin, and change in serum iron (r = −0.45, p = 0.05), basal iron, and osteocalcin after training (r = -0.55, p = 0.04). These findings indicate that iron modulates NW training-induced changes in exerkine levels.
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Macías-Rodríguez RU, Inzaugarat ME, Ruiz-Margáin A, Nelson LJ, Trautwein C, Cubero FJ. Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death? Int J Mol Sci 2020; 21:1651. [PMID: 32121273 PMCID: PMC7084577 DOI: 10.3390/ijms21051651] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic.
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Affiliation(s)
- Ricardo U. Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico;
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab (LFN Lab), Mexico City 14080, Mexico
| | - María Eugenia Inzaugarat
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico;
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab (LFN Lab), Mexico City 14080, Mexico
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, UK;
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
| | - Francisco Javier Cubero
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
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Su JB, Wu YY, Xu F, Wang X, Cai HL, Zhao LH, Zhang XL, Chen T, Huang HY, Wang XQ. Serum complement C3 and islet β-cell function in patients with type 2 diabetes: A 4.6-year prospective follow-up study. Endocrine 2020; 67:321-330. [PMID: 31786774 DOI: 10.1007/s12020-019-02144-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 11/18/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Serum complement C3 has been shown to contribute to the incidence of type 2 diabetes (T2D), but how serum complement C3 affects islet β-cell function throughout the course of T2D is unclear. This study explored whether serum complement C3 is independently associated with changes in islet β-cell function over time in patients with T2D. METHODS Serum complement C3 was measured, and endogenous β-cell function was evaluated by area under the C-peptide curve (AUCcp) during an oral glucose tolerance test (OGTT) in 411 patients with T2D at baseline from 2011 to 2015. Next, 347 of those patients with available data were pooled for a final follow-up analysis from 2014 to 2018. Changes in islet β-cell function at follow-up were evaluated by AUCcp percentage changes (ΔAUCcp%). In addition, other possible clinical risks for diabetes were also examined. RESULTS The 347 patients included in the analysis had a diabetes duration of 4.84 ± 3.63 years at baseline. Baseline serum complement C3 (baseline C3) levels were positively correlated with baseline natural logarithm of AUCcp (lnAUCcp) (n = 347, r = 0.288, p < 0.001), and baseline C3 was independently associated with baseline lnAUCcp (β = 0.17, t = 3.52, p < 0.001) after adjustment for baseline glycemic status and other clinical confounders by multivariate liner regression analysis. Compared with the baseline values, complement C3 changes (ΔC3) and ΔAUCcp% was -0.15 ± 0.28 mg/ml and -17.2 ± 18.4%, respectively, at a follow-up visit 4.57 ± 0.78 years later. Moreover, ΔC3 was positively correlated with ΔAUCcp% (n = 347, r = 0.302, p < 0.001). Furthermore, each 0.1 mg/ml increase in ΔC3 was associated with a higher ΔAUCcp% (1.41% [95% CI, 0.82-2.00%]) after adjusting for changes in glycemic status and other clinical confounders at follow-up. CONCLUSIONS In addition to serum complement C3 being independently associated with islet β-cell function at baseline, its changes were also independently associated with changes in islet β-cell function over time in patients with T2D.
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Affiliation(s)
- Jian-Bin Su
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China.
| | - Yun-Yu Wu
- Medical School of Nantong University, No. 19, Qixiu Road, Nantong, 226001, China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Xing Wang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Hong-Li Cai
- Department of Geriatrics, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6 North Haierxiang Road, Nantong, 226001, China
| | - Li-Hua Zhao
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Xiu-Lin Zhang
- Department of Clinical Laboratory, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Tong Chen
- Department of Clinical Laboratory, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Hai-Yan Huang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China
| | - Xue-Qin Wang
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People's Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China.
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Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118621. [DOI: 10.1016/j.bbamcr.2019.118621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/08/2019] [Accepted: 12/03/2019] [Indexed: 12/22/2022]
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Kellon EM, Gustafson KM. Possible dysmetabolic hyperferritinemia in hyperinsulinemic horses. Open Vet J 2020; 9:287-293. [PMID: 32042647 PMCID: PMC6971364 DOI: 10.4314/ovj.v9i4.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 09/15/2019] [Indexed: 01/02/2023] Open
Abstract
Background Hyperinsulinemia associated with equine metabolic syndrome and pituitary pars intermedia dysfunction is a risk factor for laminitis. Research in other species has shown elevated body iron levels as both a predictor and consequence of insulin resistance. In humans, this is known as dysmetabolic hyperferritinemia. Aim To explore the relationship between equine hyperinsulinemia and body iron levels. Methods We reviewed case histories and laboratory results from an open access database maintained by the Equine Cushing's and Insulin Resistance Group Inc. (ECIR). We identified 33 horses with confirmed hyperinsulinemia and laboratory results for serum iron, total iron binding capacity, and ferritin. Pearson correlation was used to test the relationship between insulin and iron indices. Additionally, we performed a secondary analysis of a previously reported controlled trial that was originally designed to test the correlation between iron status and the insulin response in horses. Here, we used a t-test to compare the mean values of insulin and ferritin between horses we categorized as normal or hyperinsulinemic based on their response to an oral challenge. Results Serum ferritin exceeded published reference range in 100% of the horses identified from the ECIR database. There were no statistically significant associations between insulin indices (RISQI, log insulin) and iron indices (log serum iron, log TSI%, log ferritin). There were trends for a negative association between RISQI and log iron [r(31) = -0.33, p = 0.058] and a positive association between age and ferritin [r(30) = 0.34, p = 0.054]. From the secondary data analysis of published data, we found significantly elevated ferritin (p = 0.05) in horses considered hyperinsulinemic by dynamic insulin testing compared to horses with a normal response. Conclusion These results suggest the potential for iron overload in hyperinsulinemic horses, a feature documented in other species and should stimulate further study into the relationship between insulin and iron dysregulation in the horse.
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Affiliation(s)
- Eleanor M. Kellon
- Equine Cushing’s and Insulin Resistance Group, Inc, 2307 Rural Road, Tempe, AZ 85282, USA
| | - Kathleen M. Gustafson
- Equine Cushing’s and Insulin Resistance Group, Inc, 2307 Rural Road, Tempe, AZ 85282, USA
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