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Guo R, Zhang S, Li A, Zhang P, Peng X, Lu X, Fan X. Ginsenoside Rb1 and berberine synergistically protect against type 2 diabetes mellitus via GDF15/HAMP pathway throughout the liver lobules: Insights from spatial transcriptomics analysis. Pharmacol Res 2025; 215:107711. [PMID: 40147680 DOI: 10.1016/j.phrs.2025.107711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Type 2 diabetes mellitus (T2DM) is a significant public health issue with high morbidity and mortality. Ginsenoside Rb1 (Rb1) and berberine (BBR), the main bioactive compounds of Panax ginseng and Coptis chinensis, respectively, are known for their hypoglycemic effects. Nevertheless, the synergistic effects and underlying mechanism of Rb1 and BBR on T2DM remain unclear. In this study, we utilized a leptin receptor-deficient (db/db) mouse model to investigate the protective effects of their combination treatment. Our findings demonstrated that the combined use of Rb1 and BBR at a 1:4 ratio had more pronounced effects than the first-line anti-diabetic drug metformin on reducing the weight ratio of white adipose tissue, ameliorating insulin resistance, and improving glucose and lipid metabolism. Using spatial transcriptomics, we revealed that metformin treatment improved gluconeogenesis and lipogenesis only in the periportal zone, while the combination treatment induced improvements throughout the liver lobule, with distinct key targets across different zones, thus underscoring a more comprehensive modulation of hepatic metabolism. This may be the key reason why this combination therapy demonstrated superior protective effects against T2DM. Additionally, the reversed expression of the key callback gene hepcidin (HAMP) and its regulator growth differentiation factor 15 (GDF15) following the combination therapy across all zones, along with validation experiments, further suggested that GDF15/HAMP pathway might be a key mechanism underlying the beneficial effects of Rb1 and BBR against T2DM. This study also indicates a path toward innovative drug cocktails for treating T2DM, offering a holistic approach to regulate the entire liver lobule metabolism.
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Affiliation(s)
- Rongfang Guo
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Shuying Zhang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
| | - Anyao Li
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ping Zhang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xin Peng
- The Joint‑Laboratory of Clinical Multi‑Omics Research between Zhejiang University and Ningbo Municipal Hospital of TCM, Ningbo Municipal Hospital of TCM, Ningbo 315010, China
| | - Xiaoyan Lu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; State Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China; Jinhua Institute of Zhejiang University, Jinhua 321299, China.
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; State Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China; The Joint‑Laboratory of Clinical Multi‑Omics Research between Zhejiang University and Ningbo Municipal Hospital of TCM, Ningbo Municipal Hospital of TCM, Ningbo 315010, China; Jinhua Institute of Zhejiang University, Jinhua 321299, China.
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Song J, Wang H, Gao X, Yang F, Zhu X, Qiao G, Gan T, Tao J. The serum hepcidin and the hepcidin/ferritin ratio in NAFLD: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:62. [PMID: 39915727 PMCID: PMC11804044 DOI: 10.1186/s12876-025-03620-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/15/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases characterized by hepatic steatosis exceeding 5% in the absence of alcohol and other liver-damaging factors. Clinical studies have identified a potential link between abnormal iron metabolism and the high incidence of NAFLD; however, the results from clinical trials remain inconsistent. This meta-analysis aims to compare serum hepcidin levels and the hepcidin/ferritin ratio between adults with NAFLD and those without to explore their potential relationship with NAFLD. METHODS A systematic search was conducted across the Web of Science platform, Cochrane, Scopus, Embase, and PubMed databases from their inception until December 18, 2024. The analysis primarily focused on serum hepcidin levels and the hepcidin/ferritin ratio. Observational studies comparing serum hepcidin levels and the hepcidin/ferritin ratio between individuals with NAFLD and control groups were included. A random-effects model was employed to calculate effect estimates, and outcomes were reported as standardized mean differences (SMD) with 95% confidence intervals (95% CI). RESULTS Following the systematic review, a total of 19 studies, comprising 2216 patients and 2125 controls, were included. The findings revealed a statistically significant difference in both hepcidin levels (SMD = 1.03, 95% CI: 0.49 to 1.56, p < 0.001) and the hepcidin/ferritin ratio (SMD = -1.13, 95% CI: -1.79 to -0.46, p < 0.001) between NAFLD and controls. Significant heterogeneity was observed across studies for both hepcidin (I² = 98.2%) and the hepcidin/ferritin ratio (I² = 93.3%), and the limited number of studies on hepcidin/ferritin were acknowledged as key limitations. Subgroup analysis revealed that patients with obesity exhibited higher levels of hepcidin (SMD = 1.12, 95% CI: 0.40 to 1.97) than overweight (SMD = 0.88, 95% CI: 0.05 to 1.72). Meta-regression analysis identified the hepcidin measurement method (p < 0.01), male-to-female ratio (p < 0.01), and study quality (p < 0.01) as significant moderators of the observed heterogeneity. CONCLUSION This meta-analysis revealed a significant association between hepcidin levels, the hepcidin/ferritin ratio and NAFLD in adults. Further investigations are needed to fully elucidate the role of these variables in iron metabolism and their potential impact on the diagnosis, prevention, and management of NAFLD.
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Affiliation(s)
- Jingmin Song
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Heqing Wang
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Xiaolian Gao
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China.
- Hubei Shizhen Laboratory, Wuhan, 430065, China.
| | - Fen Yang
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Xinhong Zhu
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Guiyuan Qiao
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Ting Gan
- School of Nursing, Hubei University of Chinese Medicine, Wuhan, 430065, China
- Hubei Shizhen Laboratory, Wuhan, 430065, China
| | - Junxiu Tao
- Hepatic Disease Institute, Hubei Key Laboratory of Theoretical and Applied Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China.
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China.
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China.
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Nong J, Li H, Yang Y, Lu Q, Sun Y, Yin Q, He H. Low serum hepcidin levels in women with polycystic ovary syndrome: evidence from meta-analysis. Gynecol Endocrinol 2024; 40:2375568. [PMID: 38976752 DOI: 10.1080/09513590.2024.2375568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND Iron metabolism plays a significant role in the development of metabolic disorders in women with polycystic ovary syndrome (PCOS). Despite the importance of hepcidin, a key iron regulator, current research on serum hepcidin levels in PCOS patients shows conflicting results. METHODS PubMed, Embase, Web of Science, Cochrane Library and the China National Knowledge Infrastructure (CNKI) database were systematically searched from their inception to 9 September 2023. The search aimed to identify studies in English and Chinese that examined hepcidin levels in women with PCOS compared to healthy control subjects. Standardized mean differences (SMDs) with corresponding 95% confidence intervals (95% CIs) were calculated to evaluate the difference in serum hepcidin levels between women with and without PCOS. RESULTS The meta-analysis included a total of 10 eligible studies, which encompassed 499 PCOS patients and 391 control subjects. The pooled analysis revealed a significant reduction in serum hepcidin levels among the PCOS patients compared to the healthy controls (SMD = -3.49, 95% CI: -4.68 to -2.30, p < .05). There was no statistically significant difference in serum hepcidin levels between PCOS patients with a body mass index (BMI) < 25 and those with a BMI ≥ 25 (p > .05). CONCLUSION The serum hepcidin levels of women with PCOS were significantly lower than those of healthy controls, which suggests that serum hepcidin could be a potential biomarker for PCOS.
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Affiliation(s)
- Jieou Nong
- Department of Clinical Laboratory, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Hua Li
- Department of Clinical Laboratory, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Yunfei Yang
- Department of Clinical Laboratory, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Qiujie Lu
- Department of Clinical Laboratory, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Yifan Sun
- Department of Clinical Laboratory, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang City People's Hospital, Guigang, Guangxi, China
| | - Qi Yin
- Department of Clinical Laboratory, Liuzhou Municipal Liutie Central Hospital, Liuzhou, China
| | - Hongying He
- Department of Gynecology, Liuzhou Municipal Liutie Central Hospital, Liuzhou, 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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Cravo C, Villela-Nogueira CA, Cardoso AC, Perez RM, Leite NC. Relationship of ferritin and hepcidin with disease severity in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. Liver Int 2023; 43:2571-2575. [PMID: 37752888 DOI: 10.1111/liv.15747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/05/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023]
Affiliation(s)
- Claudia Cravo
- Hepatology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cristiane A Villela-Nogueira
- Hepatology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Internal Medicine Department, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Carolina Cardoso
- Hepatology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Renata M Perez
- Hepatology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Internal Medicine Department, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
| | - Nathalie C Leite
- Hepatology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Internal Medicine Department, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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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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Ouni M, Eichelmann F, Jähnert M, Krause C, Saussenthaler S, Ott C, Gottmann P, Speckmann T, Huypens P, Wolter S, Mann O, De Angelis MH, Beckers J, Kirchner H, Schulze MB, Schürmann A. Differences in DNA methylation of HAMP in blood cells predicts the development of type 2 diabetes. Mol Metab 2023; 75:101774. [PMID: 37429525 PMCID: PMC10422014 DOI: 10.1016/j.molmet.2023.101774] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/12/2023] Open
Abstract
OBJECTIVES Better disease management can be achieved with earlier detection through robust, sensitive, and easily accessible biomarkers. The aim of the current study was to identify novel epigenetic biomarkers determining the risk of type 2 diabetes (T2D). METHODS Livers of 10-week-old female New Zealand Obese (NZO) mice, slightly differing in their degree of hyperglycemia and liver fat content and thereby in their diabetes susceptibility were used for expression and methylation profiling. We screened for differences in hepatic expression and DNA methylation in diabetes-prone and -resistant mice, and verified a candidate (HAMP) in human livers and blood cells. Hamp expression was manipulated in primary hepatocytes and insulin-stimulated pAKT was detected. Luciferase reporter assays were conducted in a murine liver cell line to test the impact of DNA methylation on promoter activity. RESULTS In livers of NZO mice, the overlap of methylome and transcriptome analyses revealed a potential transcriptional dysregulation of 12 hepatokines. The strongest effect with a 52% decreased expression in livers of diabetes-prone mice was detected for the Hamp gene, mediated by elevated DNA methylation of two CpG sites located in the promoter. Hamp encodes the iron-regulatory hormone hepcidin, which had a lower abundance in the livers of mice prone to developing diabetes. Suppression of Hamp reduces the levels of pAKT in insulin-treated hepatocytes. In liver biopsies of obese insulin-resistant women, HAMP expression was significantly downregulated along with increased DNA methylation of a homologous CpG site. In blood cells of incident T2D cases from the prospective EPIC-Potsdam cohort, higher DNA methylation of two CpG sites was related to increased risk of incident diabetes. CONCLUSIONS We identified epigenetic changes in the HAMP gene which may be used as an early marker preceding T2D.
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Affiliation(s)
- Meriem Ouni
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Fabian Eichelmann
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; German Institute of Human Nutrition, Department of Molecular Epidemiology, Potsdam-Rehbruecke, Germany
| | - Markus Jähnert
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Christin Krause
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute for Human Genetics, Section Epigenetics & Metabolism, University of Lübeck, Germany; Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Germany
| | - Sophie Saussenthaler
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Christiane Ott
- German Institute of Human Nutrition, Department of Molecular Toxicology, Potsdam-Rehbruecke, Germany; DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Pascal Gottmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Thilo Speckmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Peter Huypens
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Stefan Wolter
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Mann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Hrabé De Angelis
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; School of Life Sciences, Chair of Experimental Genetics, Technical University Munich, Freising, Germany
| | - Johannes Beckers
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; School of Life Sciences, Chair of Experimental Genetics, Technical University Munich, Freising, Germany
| | - Henriette Kirchner
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute for Human Genetics, Section Epigenetics & Metabolism, University of Lübeck, Germany; Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Germany
| | - Matthias B Schulze
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; German Institute of Human Nutrition, Department of Molecular Epidemiology, Potsdam-Rehbruecke, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
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Hilton C, Sabaratnam R, Drakesmith H, Karpe F. Iron, glucose and fat metabolism and obesity: an intertwined relationship. Int J Obes (Lond) 2023; 47:554-563. [PMID: 37029208 PMCID: PMC10299911 DOI: 10.1038/s41366-023-01299-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 03/08/2023] [Accepted: 03/16/2023] [Indexed: 04/09/2023]
Abstract
A bidirectional relationship exists between adipose tissue metabolism and iron regulation. Total body fat, fat distribution and exercise influence iron status and components of the iron-regulatory pathway, including hepcidin and erythroferrone. Conversely, whole body and tissue iron stores associate with fat mass and distribution and glucose and lipid metabolism in adipose tissue, liver, and muscle. Manipulation of the iron-regulatory proteins erythroferrone and erythropoietin affects glucose and lipid metabolism. Several lines of evidence suggest that iron accumulation and metabolism may play a role in the development of metabolic diseases including obesity, type 2 diabetes, hyperlipidaemia and non-alcoholic fatty liver disease. In this review we summarise the current understanding of the relationship between iron homoeostasis and metabolic disease.
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Affiliation(s)
- Catriona Hilton
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
| | - Rugivan Sabaratnam
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Ćwiertnia A, Kozłowski M, Cymbaluk-Płoska A. The Role of Iron and Cobalt in Gynecological Diseases. Cells 2022; 12:117. [PMID: 36611913 PMCID: PMC9818544 DOI: 10.3390/cells12010117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/12/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022] Open
Abstract
Iron and cobalt are micronutrients that play an important role in the regulation of cellular processes, being part of the centre of catalases, peroxidases, cytochromes and metalloproteins such as hemoglobin and myoglobin (Fe). Cobalt primarily functions as a component of hydroxycobalamin, which is essential for regulating red blood cell production. Maintaining normal levels of cobalt and iron in the human body is important, as a deficiency can lead to anaemia. These elements are also involved in reactions during which oxidative stress occurs and are therefore considered to be a cause of tumor formation. This paper will discuss aspects of the influence of cobalt and iron on mechanisms that may contribute to the growth of gynecological tumors, as well as other obstetric-gynecological disease entities, by altering the conditions of the microenvironment. In addition, the following review also highlights the role of cobalt and iron in the treatment of gynecological tumors.
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Affiliation(s)
- Adrianna Ćwiertnia
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
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Ali RB, Ahmed MH, Ibrahim HK, Mahmood HS. Tracking hepcidin level in induced type 2 diabetic rats and how Empagliflozin affects its level. JOURNAL OF POPULATION THERAPEUTICS AND CLINICAL PHARMACOLOGY = JOURNAL DE LA THERAPEUTIQUE DES POPULATIONS ET DE LA PHARMACOLOGIE CLINIQUE 2022; 29:e158-e166. [PMID: 36473727 DOI: 10.47750/jptcp.2022.965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/09/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepcidin is a hormone that contributes to iron homeostasis, produced either through hepatic or extrahepatic pathways. Its production may be affected by proinflammatory mediators released by macrophages, which play a role in the development of peripheral insulin resistance. Insulin itself may increase the production of hepcidin hormone from pancreatic β-cells. OBJECTIVES To evaluate the impact of induction of type 2 diabetes mellitus (T2DM) in albino wister rats on the level of hepcidin. Also, to examine the role of 2-week use of Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2 Inhibitor), on the hepcidin level comparing to control. METHOD An interventional study includes randomization of 36 rats into three groups (A: negative control, B: positive control, and C: Empagliflozin group). Two rats were excluded from the study for different reasons. T2DM was induced using high-fat diet/high-sugar diet (HFD/HSD) for 8 weeks. Empagliflozin was then given to Group C for 2 weeks at a dose of 35 mg/kg/day. Hepcidin level was determined at the baseline, and at week 8 and week 10 intervals. Hepcidin was determined using enzyme-linked immunosorbent assay (ELISA). RESULTS Hepcidin level significantly increased following the induction of T2DM in both B and C Groups. Hepcidin level in Group B insignificantly reduced 2 weeks after discontinuation of HFD/HSD and significantly reduced in Group C. Group A experienced no statistical difference in hepcidin level at week 10 when compared to baseline. CONCLUSION Induction of T2DM is associated with a significant increase in the level of hepcidin. Empagliflozin significantly reduced hepcidin level in newly induced diabetic rats.
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Affiliation(s)
- Riyam Bassil Ali
- Department of Pharmacy, Al-Mansoor Technical Medical Institute/Middle Technical University, Baghdad, Iraq
| | - Majid Hameed Ahmed
- Department of Physiology, College of Medicine, Al-Nahrain University, Baghdad, Iraq
| | - Haidar K Ibrahim
- Pharmacy Department/Clinical Pharmacy, Al-Yarmouk University College, Baghdad, Iraq
| | - Hasanain Sh Mahmood
- Department of Pharmaceutics, College of Pharmacy, University of Karbala, Kerbala, Iraq.,Department of Clinical Pharmacy and Laboratory sciences, College of Pharmacy, University of Alkafeel, Najaf, Iraq;
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Alfawaz HA, Alfaifi AA, Yakout SM, Khattak MNK, Alnaami AM, Al-Thayidi A, Elsaid MA, Al-Daghri NM, Alokail MS. Circulating hepcidin and its associations with low-grade inflammation and iron indices among Arab adults with and without T2DM. Am J Transl Res 2022; 14:7520-7527. [PMID: 36398205 PMCID: PMC9641428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/10/2022] [Indexed: 06/16/2023]
Abstract
We investigated the correlations of serum and dietary intake of iron with low-grade inflammation as well as with circulating hepcidin in adult Arabs with or without type 2 diabetes mellitus (T2DM). Three hundred and twelve (N=312) Saudi adult males and females with a mean age of 56.3 ± 6.5 years were included and divided into two groups, the control group (n=151, 43 males, 108 females), and T2DM group (n=161, 58 males, 103 females). Data included demographic characteristics, medical history, and dietary intake using food frequency and a 24-hour dietary recall for 1 day. Anthropometric measurements were noted and fasting blood samples extracted for the analysis of glucose, lipids, iron indices, hepcidin, 25(OH)D and endotoxin using commercially available assays. Hepcidin levels among T2DM participants were significantly higher than the control group (P<0.001). In all participants, serum hepcidin was positively associated with WHR, HbA1c, TG and TSAT while inversely associated with LDL-C and ferritin. Using hepcidin as dependent variable and age, anthropometrics, blood pressure, glucose, lipids, 25(OH)D, serum iron, transferrin and ferritin as independent variables showed that only glucose and WHR significantly predicted hepcidin by as much as 33.5% of the variances perceived (P<0.001). Sub-analysis in female participants revealed that endotoxin, iron and 25(OH)D were significant predictors of hepcidin, predicting 26.8% of the variances perceived (P<0.001). To conclude, the present study suggests that hepcidin is significantly linked with major cardiometabolic parameters, while its influence in iron indices, including low grade inflammation, appears to be stronger in females.
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Affiliation(s)
- Hanan A Alfawaz
- Department of Food Science & Nutrition, College of Food & Agriculture Science, King Saud UniversityRiyadh 11495, Saudi Arabia
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
| | - Aziza A Alfaifi
- Department of Food Science & Nutrition, College of Food & Agriculture Science, King Saud UniversityRiyadh 11495, Saudi Arabia
| | - Sobhy M Yakout
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
| | | | - Abdullah M Alnaami
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
| | | | - Mohamed A Elsaid
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
| | - Nasser M Al-Daghri
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
| | - Majed S Alokail
- Biochemistry Department, College of Science, King Saud UniversityRiyadh 11451, Saudi Arabia
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12
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OUP accepted manuscript. INTERNATIONAL JOURNAL OF PHARMACY PRACTICE 2022; 30:195-203. [DOI: 10.1093/ijpp/riac003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022]
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Hamad M, Mohammed AK, Hachim MY, Mukhopadhy D, Khalique A, Laham A, Dhaiban S, Bajbouj K, Taneera J. Heme Oxygenase-1 (HMOX-1) and inhibitor of differentiation proteins (ID1, ID3) are key response mechanisms against iron-overload in pancreatic β-cells. Mol Cell Endocrinol 2021; 538:111462. [PMID: 34547407 DOI: 10.1016/j.mce.2021.111462] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022]
Abstract
Iron overload promotes the generation of reactive oxygen species (ROS). Pancreatic β-cells can counter oxidative stress through multiple anti-oxidant responses. Herein, RNA-sequencing was used to describe the expression profile of iron regulatory genes in human islets with or without diabetes. Functional experiments including siRNA silencing, qPCR, western blotting, cell viability, ELISA and RNA-sequencing were performed as means of identifying the genetic signature of the protective response following iron overload-induced stress in human islets and INS-1. FTH1 and FTL genes were highly expressed in human islets and INS-1 cells, while hepcidin (HAMP) was low. FXN, DMT1 and FTHL1 genes were differentially expressed in diabetic islets compared to control. Silencing of Hamp in INS-1 cells impaired insulin secretion and influenced the expression of β-cell key genes. RNA-sequencing analysis in iron overloaded INS-1 cells identified Id1 and Id3 as the top down-regulated genes, while Hmox1 was the top upregulated. Expression of ID1, ID3 and HMOX1 was validated at the protein level in INS-1 cells and human islets. Differentially expressed genes (DEGs) were enriched for TGF-β, regulating stem cells, ferroptosis, and HIF-1 signaling. Hmox1-silenced cells treated with FAC elevated the expression of Id1 and Id3 expression than untreated cells. Our findings suggest that HMOX1, ID1 and ID3 define the response mechanism against iron-overload-induced stress in β-cells.
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Affiliation(s)
- Mawieh Hamad
- Department of Medical Lab. Sciences, College of Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Abdul Khader Mohammed
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Mahmood Y Hachim
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Debasmita Mukhopadhy
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Anila Khalique
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Amina Laham
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Sarah Dhaiban
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Khuloud Bajbouj
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Jalal Taneera
- Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
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Abstract
Iron is an essential element for virtually all living organisms, but its reactivity also makes it potentially harmful. Iron accumulates with aging, and is associated with many age-related diseases; it also shortens the lifespans of several model organisms. Blocking iron absorption through drugs or natural products extends lifespan. Many life-extending interventions, such as rapamycin, calorie restriction, and old plasma dilution can be explained by the effects they have on iron absorption, excretion, and metabolism. Control of body iron stores so that they remain in a low normal range may be an important, lifespan- and healthspan-extending intervention.
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15
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Venkatesan P, Varghese J, Arthi TS, James JV, Anura A, Prasad J, Jacob M. Evidence of dysregulated iron homeostasis in newly diagnosed diabetics, but not in pre-diabetics. J Diabetes Complications 2021; 35:107977. [PMID: 34217587 DOI: 10.1016/j.jdiacomp.2021.107977] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/22/2021] [Accepted: 06/14/2021] [Indexed: 12/22/2022]
Abstract
AIM Diabetes mellitus has been reported to be associated with increased serum levels of ferritin. The basis of this association is unclear. It is also not precisely known whether other iron-related parameters, including hepcidin (the central regulator of systemic iron homeostasis), are affected under these circumstances. This study attempted to determine this. METHODS Adult men (normoglycemic or newly diagnosed with diabetes or pre-diabetes) were recruited. Anthropometric, metabolic, and hematological and iron-related parameters in blood were measured. Indices of insulin resistance (HOMA-IR) and pancreatic beta cell function (HOMA-β) were calculated. RESULTS Subjects in the 3 groups were similar in age, and anthropometric and hematological parameters. Serum ferritin and hepcidin levels were higher in diabetics, than in pre-diabetics and in control subjects. These elevations seen were not linked to the presence of inflammation. HOMA-IR was higher in diabetics, and HOMA-β lower in diabetics and pre-diabetics, than in control subjects. HOMA-IR and serum ferritin were positively correlated with one another. CONCLUSION Elevated levels of serum ferritin and hepcidin in newly diagnosed diabetics (but not pre-diabetics) indicate dysregulated iron homeostasis, with the former positively associated with insulin resistance in these patients.
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Affiliation(s)
- Padmanaban Venkatesan
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India.
| | - Joe Varghese
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India.
| | - T S Arthi
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India
| | - Jithu V James
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India
| | - Anji Anura
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India
| | - Jasmin Prasad
- Department of Community Medicine, Christian Medical College, Vellore 632002, Tamil Nadu, India.
| | - Molly Jacob
- Department of Biochemistry, Christian Medical College, Vellore 632002, Tamil Nadu, India.
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Karamzad N, Eftekhari A, Ashrafi-Asgarabad A, Sullman MJM, Sahebkar A, Safiri S. Serum Hepcidin, the Hepcidin/Ferritin Ratio and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis. Curr Med Chem 2021; 28:1224-1233. [PMID: 32031063 DOI: 10.2174/0929867327666200207120158] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/03/2020] [Accepted: 01/22/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVES To perform a meta-analysis on the relationship type 2 diabetes has with serum hepcidin and the hepcidin/ferritin ratio. METHODS The following databases were searched using all relevant keywords: Web of Science, Medline, Scopus, Embase and Google Scholar. All studies that examined the relationship type 2 diabetes has with serum hepcidin or the hepcidin/ferritin ratio were included in this meta-analysis and systematic review provided, were published in English between 2011 and 2018. A random-effects model was used to pool the standardized mean difference (SMD). RESULTS The SMD of serum hepcidin among patients with type 2 diabetes and healthy controls were compared across eight studies (n cases=878; n controls=2306). The pooled SMD of serum hepcidin did not differ significantly between study groups (SMD: 0.04; 95% confidence interval (CI): -0.29 to 0.35). In contrast, the serum hepcidin/ferritin ratio was examined across five studies (n cases=229; n controls=1426) and was found to be negatively associated with the risk of type 2 diabetes (SMD: -0.52; 95% confidence interval (CI): -0.85 to -0.19). There was no publication bias found for the associations serum hepcidin (Egger´s test: P =0.97) or the hepcidin/ferritin ratio (Egger´s test: P =0.75) had with type 2 diabetes. CONCLUSION Although hepcidin has been proposed as a risk marker for type 2 diabetes, our metaanalysis found that the hepcidin/ferritin ratio was superior to hepcidin alone as a risk marker.
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Affiliation(s)
- Nahid Karamzad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aziz Eftekhari
- Department of Pharmacology and Toxicology, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Ahad Ashrafi-Asgarabad
- Department of Epidemiology, School of Health, Bam University of Medical Sciences, Bam, Iran
| | - Mark J M Sullman
- School of Humanities and Social Sciences, University of Nicosia, Nicosia, Cyprus
| | | | - Saeid Safiri
- Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Ndevahoma F, Mukesi M, Dludla PV, Nkambule BB, Nepolo EP, Nyambuya TM. Body weight and its influence on hepcidin levels in patients with type 2 diabetes: A systematic review and meta-analysis of clinical studies. Heliyon 2021; 7:e06429. [PMID: 33748488 PMCID: PMC7966995 DOI: 10.1016/j.heliyon.2021.e06429] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/21/2021] [Accepted: 03/02/2021] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Iron profiles in patients with type 2 diabetes (T2D) are inconsistent. In this study, we assessed the levels of hepcidin, a regulatory protein involved in iron homoeostasis, in patients with T2D. We further evaluated the surrogate markers of hepcidin action, particularly those associated with erythropoiesis. METHODS This systematic review and meta-analysis was reported following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. We searched for relevant studies in electronic databases from inception until 31 October 2020 without any language restriction. The random effects model was used to calculate effect estimates, and outcomes were reported as either standardised mean difference (SMD) or mean differences (MD), 95 percent confidence interval (95% CI). RESULTS Eleven studies involving 2 620 participants were included in this study. Patients with T2D had a slight increase in hepcidin levels when compared to controls SMD: 0.07 [95% CI: -0.30, 0.44]. The subgroup analysis showed that studies involving patients with T2D who were overweight reported elevated hepcidin levels SMD: 0.35 [95% CI: 0.07, 0.62] whilst those with grade I obesity described reduced levels SMD: -0.42 [95% CI: -1.21, 0.38]. All T2D patients had low levels of haemoglobin MD: -0.23 g/dl [95% CI: -0.46, -0.01] irrespective of body weight. CONCLUSION The levels of hepcidin are altered in patients with T2D and are disproportionately influenced by weight. Moreover, patients with T2D present with subclinical anaemia despite elevated iron stores. The regulation of hepcidin in patients with T2D is dependent on several factors and vary greatly, thus its sole use in clinical settings may be less beneficial.
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Affiliation(s)
- Fransina Ndevahoma
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
| | - Munyaradzi Mukesi
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
| | - Phiwayinkosi V. Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Bongani B. Nkambule
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Elina P. Nepolo
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
| | - Tawanda M. Nyambuya
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
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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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Musina NN, Saprina TV, Prokhorenko TS, Zima AP. [Searching for additional markers of impaired iron metabolism in diabetes mellitus]. ACTA ACUST UNITED AC 2020; 66:61-70. [PMID: 33351349 DOI: 10.14341/probl12277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND It is known that metabolic disorders in diabetes mellitus have a regulating effect on ferrokinetics, and therefore diabetes mellitus is often accompanied by various disorders of iron metabolism, both anemia and secondary iron overload. The main problem is timely and accurate differential diagnosis between anemia of chronic diseases and iron deficiency anemia. It is necessary to establish reliable laboratory markers of anemia of chronic diseases in order to solve this problem, as well as to understand what metabolic disorders can lead to the occurrence and aggravate the course of this type of anemia. AIMS To study the frequency of occurrence of violations of ferrokinetics in patients with diabetes mellitus, as well as to establish clinical and biochemical correlations that are significant in the differential diagnosis of various disorders of iron metabolism: iron deficiency anemia, anemia of chronic diseases and dysmetabolic iron overload syndrome in diabetes mellitus. MATERIALS AND METHODS The research design a single-stage observational single-center research. The research was conducted on the basis of the endocrinological clinic of the Federal State Budgetary Educational Institution of Higher Education Siberian State Medical University in Tomsk. The research included 76 patients with type 1 and type 2 diabetes mellitus. We conducted an assessment of all patients as follows: anthropometric data assessment; glycated hemoglobin study; creatinine level study with the calculation of glomerular filtration rate (GFR) using the CKD-EPI formula. We also evaluated the number of erythrocytes, reticulocytes, the hemoglobin concentration, haematocrit level and biochemical parameters of iron metabolism: serum iron and ferritin concentrations; the concentration of hepsidin and non-specific markers of inflammation: erythrocyte sedimentation rate (ESR) and highly sensitive C-reactive protein (CRP). RESULTS 20 people (26.3%) of the 76 patients included in the study, had type 1 diabetes mellitus and 56 people (73.3%) had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with 20 patients (26.3%) from the 76 ones included into the research had type 1 diabetes mellitus and 56 (73.3%) from them had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with type 2 diabetes mellitus, the levels of CRP (p=0.034) and blood leukocytes (p=0.020) were significantly higher than in patients with type 1 diabetes mellitus. Both in the main group of patients with impaired carbohydrate metabolism, and in patients with type 2 diabetes mellitus, anemia of chronic diseases prevailed in the structure of the anemia syndrome. After dividing the main group of patients into groups by type of anemia syndrome: absence of anemia, anemia of chronic diseases and iron deficiency anemia, a comparative analysis of the average values of markers of inflammation and the level of hepsidin in these groups was performed. It was found that in patients with anemia of chronic diseases, the level of hepsidin is significantly higher than in patients without anemic syndrome (p=0.033). Paired correlation analysis showed a positive correlation of ESR with microalbuminuria (r=0.515; P<0.0001), creatinine level (r=0.467; P<0.0001) and negative — with GFR (r= -0.436; P<0.0001) and iron in serum (r=-0.276; p=0.017). As the result of ROC analysis the most informative in the diagnosis of anemia of chronic disease were: ferritin — sensitivity 78%, specificity 52% with a diagnostic threshold of 75.5 ng/ml (area under the curve 0,695; p=0.006); ESR — sensitivity 67%, specificity 64% with a diagnostic threshold of 15.5 mm/HR (area under the curve of 0.750 in; p=0.040) and the CRP — sensitivity 67%, specificity 64% with a diagnostic threshold of 5.2 ng/ml (area under the curve 0,646; р<0.0001). CONCLUSION Thus, the studied markers of inflammation — ESR and CRP, as well as hepsidin in combination with the classic diagnostic parameter — ferritin, demonstrated high value in the diagnosis of anemia of chronic diseases and can be included in the modified algorithm for differential diagnosis of anemia syndrome in patients with diabetes mellitus.
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Liu J, Hu X, Xue Y, Liu C, Liu D, Shang Y, Shi Y, Cheng L, Zhang J, Chen A, Wang J. Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model. Am J Transl Res 2020; 12:4830-4839. [PMID: 32913554 PMCID: PMC7476126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 07/05/2020] [Indexed: 06/11/2023]
Abstract
Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM) that may be related to iron deposition in the brain. Hepcidin is expressed in the brain and has the ability to regulate iron. Therefore, this study explored the role of hepcidin in hippocampal iron deposition and cognitive impairment in T2DM. The effects of a recombinant adeno-associated virus targeting hepcidin (AAV-hepcidin) for hippocampal iron content and cognitive function were investigated in a T2DM rat model induced by streptozotocin and a high-fat diet. Adult male rats (n = 32) were categorized as either C-saline (normal control), M-saline (T2DM), M-blank (AAV-blank + T2DM), or M-hepcidin (AAV-hepcidin + T2DM). Hippocampal iron content was assessed using quantitative susceptibility mapping. Morris water maze (MWM) testing was used to assess the cognitive function. Magnetic resonance imaging indicated that hippocampal susceptibility values were significantly increased bilaterally in T2DM rats compared with controls (P = 0.044, P = 0.043). Compared with the M-blank group, the M-hepcidin group exhibited significantly decreased hippocampal susceptibility values bilaterally (P = 0.007, P = 0.030). Compared with the M-saline group, susceptibility values from left hippocampus in the M-hepcidin group were significantly reduced (P = 0.002). MWM results showed that the performance of T2DM rats was significantly decreased from that of control rats. Compared with the M-saline and M-blank groups, the performance of the M-hepcidin group was significantly increased. These studies demonstrate that T2DM rats developed cognitive impairment and iron deposits in the hippocampus, both of which were improved by AAV-hepcidin administration.
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Affiliation(s)
- Juan Liu
- Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest UniversityChongqing 400715, PR China
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Xiaofei Hu
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Yuan Xue
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Chen Liu
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Daihong Liu
- Department of Medical Imaging, Chongqing University Cancer HospitalChongqing 400030, PR China
| | - Yongning Shang
- Department of Ultrasound, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Yanshu Shi
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Lin Cheng
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
| | - Jiqiang Zhang
- Department of Neurobiology, Army Medical UniversityChongqing 400038, PR China
| | - Antao Chen
- Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest UniversityChongqing 400715, PR China
| | - Jian Wang
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University)Chongqing 400038, PR China
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Kosaryan M, Rahimi M, Zamanfar D, Darvishi-Khezri H. Liver iron concentration is an independent risk factor for the prediabetic state in β-thalassemia patients. Int J Diabetes Dev Ctries 2020. [DOI: 10.1007/s13410-019-00789-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Tiongco RE, Rivera N, Clemente B, Dizon D, Salita C, Pineda-Cortel MR. Serum ferritin as a candidate diagnostic biomarker of polycystic ovarian syndrome: a meta-analysis. Biomarkers 2019; 24:484-491. [PMID: 31096807 DOI: 10.1080/1354750x.2019.1620335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Objective: In this study, we investigated about the potential of serum ferritin as a complementary diagnostic biomarker of polycystic ovarian syndrome (PCOS) by performing a meta-analysis of existing literature. Materials and methods: Eleven studies written in English were retrieved up to 30 June 2018. Data were extracted from the selected studies by two of the authors and was subjected to statistical analysis. Levels of serum ferritin were compared between women with PCOS and controls using the standardized mean difference (SMD) and 95% confidence interval (CI). Subgroup analysis was also performed and stratified by ethnicity (Asians versus Caucasians). Results: Overall post-outlier outcomes indicated that elevated serum ferritin is strongly associated with PCOS (SMD: 0.52; 95% CI: 0.40-0.64; PA = 10-5). Subgroup analysis by ethnicity showed no significant difference between Asian and Caucasian population. Post-outlier receiving operations characteristics curve were plotted and showed that values for serum ferritin showed good potential in discriminating patients with and without PCOS (AUC = 0.827, p = 0.006). Conclusion: Our findings suggest that high serum ferritin level is significantly associated with PCOS and its potential as a biomarker is evident in its high diagnostic accuracy. However, additional studies are needed to confirm our claims.
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Affiliation(s)
- Raphael Enrique Tiongco
- a Department of Medical Technology, College of Allied Medical Professions , Angeles University Foundation , Angeles City , Philippines
| | - Nicole Rivera
- a Department of Medical Technology, College of Allied Medical Professions , Angeles University Foundation , Angeles City , Philippines
| | - Benjie Clemente
- b Department of Medical Technology, Faculty of Pharmacy , University of Santo Tomas , Manila , Philippines
| | - Dianne Dizon
- a Department of Medical Technology, College of Allied Medical Professions , Angeles University Foundation , Angeles City , Philippines
| | - Crizelda Salita
- a Department of Medical Technology, College of Allied Medical Professions , Angeles University Foundation , Angeles City , Philippines
| | - Maria Ruth Pineda-Cortel
- b Department of Medical Technology, Faculty of Pharmacy , University of Santo Tomas , Manila , Philippines.,c Research Center for the Natural and Applied Sciences , University of Santo Tomas , Manila , Philippines.,d The Graduate School , University of Santo Tomas , Manila , Philippines
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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 193] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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Hossein Rashidi B, Shams S, Shariat M, Bagheri M, Mohebi M, Haghollahi F. The Association of Serum Hepcidin Levels and Insulin Resistance in PCOS Patients: A Case-Control Study. J Family Reprod Health 2018; 12:210-216. [PMID: 31239849 PMCID: PMC6581661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective: To investigate the relationship between insulin resistance and hepcidin levels in patients with PCOS. Materials and methods: In this case-control study fifty- six patients with PCOS and forty - one healthy control subjects were included. Plasma levels of hepcidin, IL-6, Serum Insulin and ferritin using ELISA method, serum iron levels using a spectrophotometric method, and Insulin resistance by using HOMA were measured in the two groups of PCOS (case group) and healthy subjects (control group). The results were analyzed by student's t-test, General Linear Model, Binary logistic and linear regression tests. Results: The mean hepcidin level was 1.97 ± 0.53 pg/ml and 2.40 ± 0.25pg/ml in the case and control groups, respectively. The t-test results showed a significant difference between the two groups (p = 0.0001). The mean of insulin level in case and control group was 30.65 ± 15.02g/dl and 14.71 ± 10.46g/dl, respectively. The t-test analysis indicated a significant difference between the two groups (p = 0.0001). There was an inverse relationship between the level of hepcidin with HOMA-IR (β = -0.629, p = 0.04), and IL-6 (β = -0.243, p = 0.015) in both groups. The adjusted OR proved a statistically significant association between serum hepcidin (OR = 0.063; 95 % CI: 0.01-0.385, p-value = 0. 003) and HOMA (OR = 1.569; 95 % CI: 1.254-1.964, p-value = 0.001) with PolycysticOvarian Syndrome. Conclusion: There was an inverse relationship between hepcidin levels and insulin resistance in both groups meaning decrease in hepcidin levels and increase in insulin resistance may increase the risk of PCOS.
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Affiliation(s)
- Batool Hossein Rashidi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheila Shams
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mamak Shariat
- Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Bagheri
- Department of Reproductive Health, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
| | - Marziyeh Mohebi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fedyeh Haghollahi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Yang Q, Zhou L, Liu C, Liu D, Zhang Y, Li C, Shang Y, Wei X, Li C, Wang J. Brain iron deposition in type 2 diabetes mellitus with and without mild cognitive impairment-an in vivo susceptibility mapping study. Brain Imaging Behav 2018; 12:1479-1487. [PMID: 29297155 DOI: 10.1007/s11682-017-9815-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This study was performed to investigate iron deposition in the brain of type 2 diabetes mellitus (T2DM) patients using quantitative susceptibility mapping (QSM) and the associated cognitive impairments. Sixty patients diagnosed with T2DM were subjected to neuropsychological tests to determine their cognitive status, and the results were used to subdivide the patients into a T2DM without mild cognitive impairment (MCI) group (n = 30) and a T2DM with MCI group (n = 30). All patients underwent high-resolution susceptibility-weighted imaging, and data processing was performed using SMART (Susceptibility Mapping and Phase Artifacts Removal Toolbox) software. The susceptibility values of the bilateral parietal cortex, frontal white matter, caudate nucleus (CN), putamen (PU), globus pallidus, thalamus, red nucleus, substantia nigra (SN), hippocampus (HP) and dentate nucleus were analyzed and correlated with the neuropsychological cognitive scores. Compared with the normal controls (n = 30), the T2DM without MCI group exhibited significantly increased susceptibility values in the left HP, whereas the T2DM with MCI group showed significantly increased susceptibility values in the bilateral CN, HP, left PU and right SN. Compared with the T2DM without MCI group, the T2DM with MCI group exhibited significantly increased susceptibility values in the right CN, SN and left PU. The susceptibility values for the right CN, SN and left PU were closely correlated with neuropsychological cognitive scores. Our results provide a new relation between T2DM and brain iron deposition and suggested that QSM may be a helpful tool in the detection and evaluation of their cognitive impairment in T2DM.
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Affiliation(s)
- Qifang Yang
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Medical imaging, PLA No.44 Hospital, Guizhou, China
| | - Lina Zhou
- Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Chen Liu
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Daihong Liu
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yang Zhang
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Chang Li
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yongning Shang
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xin Wei
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Chuanming Li
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Jian Wang
- Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
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Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease. Sci Rep 2018; 8:9353. [PMID: 29921869 PMCID: PMC6008459 DOI: 10.1038/s41598-018-27107-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/23/2018] [Indexed: 02/07/2023] Open
Abstract
Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, H-ferritin), and/or decreased ferroportin abundance. This demonstrates that tubular iron accumulation may result from increased iron uptake and/or inadequate iron export. Iron deposition associated with oxidative injury as indicated by heme oxygenase-1 abundance. In conclusion, iron deposition is relatively common in CKD, and may result from altered molecular iron handling and may contribute to renal injury.
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Serum and salivary ferritin and Hepcidin levels in patients with chronic periodontitis and type 2 diabetes mellitus. BMC Oral Health 2018; 18:63. [PMID: 29636044 PMCID: PMC5894201 DOI: 10.1186/s12903-018-0524-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 03/26/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Iron disorder and abnormal expression of hepcidin play important roles in many diseases, but it is still unclear in chronic periodontitis (CP) and type 2 diabetes mellitus (T2DM). We aimed to assess ferritin and hepcidin levels in serum and saliva of CP patients with or without T2DM. METHODS Serum and unstimulated whole saliva samples were collected from 88 participants, who were categorized into 4 groups based on the presence or absence of CP or T2DM. Demographics and general health parameters were recorded. Full-mouth clinical periodontal parameters including probing pocket depth, clinical attachment loss, bleeding index, and plaque index were recorded. Chemiluminescence microparticle immunoassay and enzyme-linked immunosorbent assay were used to detect ferritin and hepcidin concentrations, respectively, in serum and saliva. RESULTS Serum ferritin and hepcidin levels in the CP and CP with T2DM groups were higher than in the control group (P < 0.05). Serum hepcidin and serum ferritin are linear correlated (P < 0.001). Serum hepcidin/ferritin values in the CP with T2DM group were significantly lower than those in the T2DM and control groups. Moreover, salivary ferritin levels in the CP and T2DM groups were higher than those in the control group (P < 0.05). There was positively correlation between salivary ferritin and serum ferritin (P = 0.017). Hepcidin concentrations were relatively low in saliva. CONCLUSIONS These results suggest that iron overload and hepcidin inadequacy existed in CP with T2DM patients. Salivary ferritin might provide a reference for body iron load. TRIAL REGISTRATION ChiCTR-ROC-17012780.
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Vela D, Sopi RB, Mladenov M. Low Hepcidin in Type 2 Diabetes Mellitus: Examining the Molecular Links and Their Clinical Implications. Can J Diabetes 2018; 42:179-187. [DOI: 10.1016/j.jcjd.2017.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 04/18/2017] [Accepted: 04/21/2017] [Indexed: 01/14/2023]
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Vela D. Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker. Mol Med 2018; 24:5. [PMID: 30134796 PMCID: PMC6016890 DOI: 10.1186/s10020-018-0008-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/13/2018] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.
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Affiliation(s)
- Driton Vela
- Department of Physiology, Faculty of Medicine, University of Prishtina, Martyr's Boulevard n.n, Prishtina, 10000, Kosovo.
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Ambachew S, Biadgo B. Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients. Acta Haematol 2017; 138:183-193. [PMID: 29136618 DOI: 10.1159/000481391] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 09/08/2017] [Indexed: 12/21/2022]
Abstract
The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism.
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Affiliation(s)
- Sintayehu Ambachew
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Moreno-Navarrete JM, Rodríguez A, Becerril S, Valentí V, Salvador J, Frühbeck G, Fernández-Real JM. Increased Small Intestine Expression of Non-Heme Iron Transporters in Morbidly Obese Patients With Newly Diagnosed Type 2 Diabetes. Mol Nutr Food Res 2017; 62. [PMID: 29082606 DOI: 10.1002/mnfr.201700301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Revised: 08/04/2017] [Indexed: 01/01/2023]
Abstract
SCOPE To investigate intestinal markers of iron absorption in morbidly obese subjects according to glucose tolerance. METHODS AND RESULTS Gene expression of both non-heme (SLC40A1 (ferroportin), SLC11A2) and heme iron (SLC46A1 (HCP1), HMOX1) transporters is analyzed in 38 small intestine tissue samples [11 with normal glucose tolerance, 14 with glucose intolerance (GI), and 13 with newly diagnosed type 2 diabetes (T2D)]. SLC40A1 (r = 0.43, p = 0.008) and SLC11A2 (r = 0.35, p = 0.03) mRNA levels are positively correlated with ferritin-to-hepcidin ratio and with fasting glucose, being significantly increased in patients with T2D. Only ferroportin is negatively associated with serum hepcidin (r = -0.617, p < 0.0001). In multivariate regression analysis, fasting glucose contributes independently to intestinal SLC40A1 (p = 0.009) and SLC11A2 (p = 0.04) variance after controlling for age, sex, and BMI. When circulating hepcidin is incorporated into the model, fasting glucose contributes significantly and independently to intestinal SLC40A1 (p = 0.02), but not to SLC11A2 (p = 0.07) variance. SLC46A1 and HMOX1 are similar in all groups. CONCLUSION The expression of ferroportin and SLC11A2 is increased in the intestine of patients with T2D in association with iron stores and serum hepcidin levels. Increased intestinal iron absorption is a potential mechanism that could explain the increased body iron stores frequently observed in patients with T2D.
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Affiliation(s)
- José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain
| | - Víctor Valentí
- Department of Surgery, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain
| | - Javier Salvador
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain.,Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
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Fernández Real JM, Moreno-Navarrete JM, Manco M. Iron influences on the Gut-Brain axis and development of type 2 diabetes. Crit Rev Food Sci Nutr 2017; 59:443-449. [DOI: 10.1080/10408398.2017.1376616] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- José Manuel Fernández Real
- University Hospital of Girona ‘Dr JosepTrueta’, Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona IdibGi
- CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
| | - José Maria Moreno-Navarrete
- University Hospital of Girona ‘Dr JosepTrueta’, Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona IdibGi
- CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
| | - Melania Manco
- Research Area for multifactorial diseases, Bambino Gesù Children's Hospital and Research Institute, Research Unit for Multifactorial Disease, Rome, Italy
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Uncoupled iron homeostasis in type 2 diabetes mellitus. J Mol Med (Berl) 2017; 95:1387-1398. [PMID: 28971221 DOI: 10.1007/s00109-017-1596-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 09/16/2017] [Accepted: 09/21/2017] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus is frequently associated with iron overload conditions, such as primary and secondary hemochromatosis. Conversely, patients affected by type 2 diabetes mellitus (T2DM) show elevated ferritin levels, a biomarker for increased body iron stores. Despite these documented associations between dysregulated iron metabolism and T2DM, the underlying mechanisms are poorly understood. Here, we show that T2DM patients have reduced serum levels of hepcidin, the iron-regulated hormone that maintains systemic iron homeostasis. Consistent with this finding, we also observed an increase in circulating iron and ferritin levels. Our analysis of db/db mice demonstrates that this model recapitulates the systemic alterations observed in patients. Interestingly, db/db mice show an overall hepatic iron deficiency despite unaltered expression of ferritin and the iron importer TfR1. In addition, the liver correctly senses increased circulating iron levels by activating the BMP/SMAD signaling pathway even though hepcidin expression is decreased. We show that increased AKT phosphorylation may override active BMP/SMAD signaling and decrease hepcidin expression in 10-week old db/db mice. We conclude that the metabolic alterations occurring in T2DM impact on the regulation of iron homeostasis on multiple levels. As a result, metabolic perturbations induce an "iron resistance" phenotype, whereby signals that translate increased circulating iron levels into hepcidin production, are dysregulated. KEY MESSAGES T2DM patients show increased circulating iron levels. T2DM is associated with inappropriately low hepcidin levels. Metabolic alterations in T2DM induce an "iron resistance" phenotype.
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Vela D, Leshoski J, Vela Z, Jakupaj M, Mladenov M, Sopi RB. Insulin treatment corrects hepcidin but not YKL-40 levels in persons with type 2 diabetes mellitus matched by body mass index, waist-to-height ratio, C-reactive protein and Creatinine. BMC Endocr Disord 2017; 17:53. [PMID: 28841871 PMCID: PMC5574085 DOI: 10.1186/s12902-017-0204-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 08/21/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND It has been shown that hepcidin and YKL-40 levels change in persons with insulin resistance in different circumstances. However, variations of the levels of these parameters through the stages of prediabetes and type 2 diabetes mellitus are unclear. We hypothesized that hepcidin levels will decrease in persons with prediabetes, while these levels will tend to correct when persons with diabetes are treated with insulin. Finally we sought to determine the levels of YKL-40 in all groups of participants included in the study. METHODS Serum hepcidin levels and YKL-40 levels were measured in control group (n = 20), persons with prediabetes (n = 30) and persons with diabetes on insulin therapy (n = 30) using ELISA method. Patients in all three groups were matched by Body Mass Index, Waist-to-Height Ratio, C-Reactive Protein and creatinine levels. RESULTS Hepcidin levels were lower in persons with prediabetes compared to control, while persons with diabetes on insulin therapy had higher values than those with prediabetes (p = 0,00001). YKL-40 levels showed no significant changes. CONCLUSIONS Serum hepcidin levels in matched persons with prediabetes are a stronger marker of early changes in glucose metabolism compared to YKL-40 levels. Also, treatment with insulin corrects hepcidin levels, but not YKL-40 levels. Correcting levels of hepcidin is important for reducing iron-overload, which is a risk factor for diabetes.
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Affiliation(s)
- Driton Vela
- Faculty of Medicine, University of Prishtina, Martyr’s Boulevard n.n, 10000 Prishtina, Kosovo
| | - Jovica Leshoski
- Institute of Biology, Faculty of Natural Sciences, “Sts. Cyril and Methodius” University, Skopje, 1000 Macedonia
| | - Zana Vela
- Faculty of Medicine, University of Prishtina, Martyr’s Boulevard n.n, 10000 Prishtina, Kosovo
| | - Muharrem Jakupaj
- Faculty of Medicine, University of Prishtina, Martyr’s Boulevard n.n, 10000 Prishtina, Kosovo
| | - Mitko Mladenov
- Institute of Biology, Faculty of Natural Sciences, “Sts. Cyril and Methodius” University, Skopje, 1000 Macedonia
| | - Ramadan B. Sopi
- Faculty of Medicine, University of Prishtina, Martyr’s Boulevard n.n, 10000 Prishtina, Kosovo
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Wang M, Xin H, Tang W, Li Y, Zhang Z, Fan L, Miao L, Tan B, Wang X, Zhu YZ. AMPK Serves as a Therapeutic Target Against Anemia of Inflammation. Antioxid Redox Signal 2017; 27:251-268. [PMID: 27923278 DOI: 10.1089/ars.2016.6846] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS Anemia of inflammation (AI), the second prevalent anemia, is associated with worse prognosis and increased mortality in numerous chronic diseases. We recently reported that the gasotransmitter hydrogen sulfide (H2S) suppressed the inflammatory activation of signal transducer and activator of transcription 3 (STAT3) and hepcidin, the critical mediators of AI. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a novel inflammatory regulator and might be activated by H2S. In this study, we determined whether AMPK played a role in H2S-mediated anti-inflammatory response in AI and evaluated the therapeutic potential of AMPK against AI by pharmacological and clinical approaches. RESULTS We showed that AMPK mediated the inhibition of STAT3, hepcidin, and AI by H2S during inflammation. Moreover, pharmacological and genetic activation of AMPK ameliorated hepcidin production, corrected iron dysregulation, and relieved hypoferremia and anemia in both acute and chronic inflammation models in mice. Mechanistic studies indicated that AMPK suppressed STAT3/hepcidin activation by promoting proteasome-mediated Janus kinase 2 (JAK2) degradation, which was dependent on the intact function of suppressor of cytokine signaling 1 (SOCS1) and increased interactions between SOCS1 and JAK2. Most importantly, the AMPK activator metformin was associated with decreased serum hepcidin content and anemia morbidity in Chinese type 2 diabetes mellitus patients. INNOVATION This is the first study to demonstrate the inhibition of inflammatory hepcidin and AI by AMPK-induced JAK2 degradation. Our work uncovered AMPK as a novel therapeutic target, and metformin as a potential therapy against AI. CONCLUSION The present work demonstrated that AMPK mediated the therapeutic effects of H2S and relieved AI by promoting SOCS1-mediated JAK2 degradation. Antioxid. Redox Signal. 27, 251-268.
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Affiliation(s)
- Minjun Wang
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .,2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China
| | - Hong Xin
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Wenbo Tang
- 3 Department of Oncology, School of Medicine, Fudan University , Shanghai, China
| | - Yiming Li
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Zhaoyun Zhang
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Linling Fan
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Lei Miao
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Bo Tan
- 5 Department of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, China
| | - Xiling Wang
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Yi Zhun Zhu
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .,2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China
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Hossein Rashidi B, Shams S, Shariat M, Kazemi Jaliseh H, Mohebi M, Haghollahi F. Evaluation of serum hepcidin and iron levels in patients with PCOS: a case-control study. J Endocrinol Invest 2017; 40:779-784. [PMID: 28276006 DOI: 10.1007/s40618-017-0632-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/01/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation with a prevalence of 5-10% in women of reproductive age. The etiology of this disease is not well known, and hepcidin is one of the factors affecting the pathogenesis of the disease. The aim of this study was to evaluate plasma levels of hepcidin in patients with PCOS and its correlation with serum iron level. METHODS In this case-control study, plasma levels of hepcidin, IL-6, and ferritin using ELISA method and serum iron levels using a spectrophotometric method were tested on 56 women with PCOS (case group) and 41 healthy subjects (control group). The results were analyzed using t test, General Linear Model, Binary logistic regression, and linear regression tests. RESULTS The mean hepcidin levels were 1.97 ± 0.53 and 2.40 ± 0.25 pg/ml in the case and control groups, respectively. The t-test results showed significant difference between the two groups (p = 0.0001). The mean serum iron levels were 72.89 ± 28.97 and 70.62 ± 31.18 g/dl in the case and control groups, respectively. The t test analysis indicated no significant difference between the two groups. The serum ferritin and iron levels had no significant relation with serum hepcidin level in two groups. CONCLUSION Despite the differences in the serum levels of hepcidin between the two groups, no significant relation was observed between serum iron levels and hepcidin level in this group of patients. This implies the need for more comprehensive studies on gene expression in hepcidin and iron pathways using real-time and Western techniques to investigate more precisely serum hepcidin level and its relationship with the factors mentioned.
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Affiliation(s)
- B Hossein Rashidi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - S Shams
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - M Shariat
- Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - H Kazemi Jaliseh
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - M Mohebi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - F Haghollahi
- Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Cellular citrate levels establish a regulatory link between energy metabolism and the hepatic iron hormone hepcidin. J Mol Med (Berl) 2017; 95:851-860. [PMID: 28585096 DOI: 10.1007/s00109-017-1551-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/10/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023]
Abstract
Expression of the hepatic peptide hormone hepcidin responds to iron levels via BMP/SMAD signaling, to inflammatory cues via JAK/STAT signaling, to the nutrient-sensing mTOR pathway, as well as to proliferative signals and gluconeogenesis. Here, we asked the question whether hepcidin expression is altered by metabolites generated by intermediary metabolism. To identify such metabolites, we took advantage of a comprehensive RNAi screen, which revealed effectors involved in citrate metabolism. We show that the inhibition of citrate-consuming enzymes increases hepcidin mRNA expression in primary murine hepatocytes. Consistently, citrate treatment of primary murine hepatocytes or intravenous injection of citrate in mice increases cellular citrate concentrations and hepcidin expression. We further demonstrate that the hepcidin response to citrate involves the SMAD signaling pathway. These results reveal links between iron homeostasis and energy metabolism that may help to explain why iron levels are frequently altered in metabolic disorders. KEY MESSAGES • Elevated citrate levels increase hepcidin mRNA expression in primary hepatocytes. • Citrate treatment in primary hepatocytes activates hepcidin expression. • Intravenous injection of citrate in mice increases hepcidin mRNA levels. • The hepcidin response to citrate involves the BMP/SMAD signaling pathway.
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Azimzadeh K, Nasrollahi Nargesabad R, Vousooghi N. Evaluation of plasma sphingosine 1-phosphate, hepcidin and cardiovascular damage biomarkers (cardiac troponin I and homocysteine) in rats infected with brucellosis and vaccinated (Rev-1, RB-51). Microb Pathog 2017; 109:67-70. [PMID: 28533142 DOI: 10.1016/j.micpath.2017.05.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 05/13/2017] [Accepted: 05/19/2017] [Indexed: 11/26/2022]
Abstract
Brucellosis is known as one of important zoonosis. Studying the histological and biochemical effects of the disease could help to increase our knowledge about it. The aim of the present study was to evaluate changes of plasma parameters after intraperitoneal injection of two species of Brucella (Brucella melitensis and Brucella abortus) and two vaccines (Rev-1, RB-51) in the rat. Forty male rats were divided into five groups (n = 8 in each group). Two groups received suspensions of Brucella abortus and Brucella melitensis and two other groups were injected intraperitoneally with two mentioned vaccines and the last group received only distilled water. The results showed a significant increase in sphingosine 1-phosphate, Malondialdehyde, hepcidin, homocysteine, cardiac troponin I and copper levels and a considerable decrease in the levels of iron and zinc (P ≤ 0.01) in infected groups compared to the control animals. In vaccinated groups, hepcidin was increased but other parameters were not changed in comparison to the control group. It can be concluded that increase of homocysteine and cardiac troponin I in brucellosis could be a warning for cardiac adverse effects. Besides, increase of sphingosine 1-phosphate probably indicates its stimulant and modulatory effects in anti- Brucellosis biochemical pathways of the host.
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Affiliation(s)
- Kaveh Azimzadeh
- Young Researcher and Elite Club, Urmia Branch, Islamic Azad University, Urmia, Iran.
| | | | - Nasim Vousooghi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
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Shi W, Wang H, Zheng X, Jiang X, Xu Z, Shen H, Li M. HNF-4alpha Negatively Regulates Hepcidin Expression Through BMPR1A in HepG2 Cells. Biol Trace Elem Res 2017; 176:294-304. [PMID: 27660075 DOI: 10.1007/s12011-016-0846-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/06/2016] [Indexed: 12/19/2022]
Abstract
Hepcidin synthesis is reported to be inadequate according to the body iron store in patients with non-alcoholic fatty liver disease (NAFLD) undergoing hepatic iron overload (HIO). However, the underlying mechanisms remain unclear. We hypothesize that hepatocyte nuclear factor-4α (HNF-4α) may negatively regulate hepcidin expression and contribute to hepcidin deficiency in NAFLD patients. The effect of HNF-4α on hepcidin expression was observed by transfecting specific HNF-4α small interfering RNA (siRNA) or plasmids into HepG2 cells. Both direct and indirect mechanisms involved in the regulation of HNF-4α on hepcidin were detected by real-time PCR, Western blotting, chromatin immunoprecipitation (chIP), and reporter genes. It was found that HNF-4α suppressed hepcidin messenger RNA (mRNA) and protein expressions in HepG2 cells, and this suppressive effect was independent of the potential HNF-4α response elements. Phosphorylation of SMAD1 but not STAT3 was inactivated by HNF-4α, and the SMAD4 response element was found essential to HNF-4α-induced hepcidin reduction. Neither inhibitory SMADs, SMAD6, and SMAD7 nor BMPR ligands, BMP2, BMP4, BMP6, and BMP7 were regulated by HNF-4α in HepG2 cells. BMPR1A, but not BMPR1B, BMPR2, ActR2A, ActR2B, or HJV, was decreased by HNF-4α, and HNF4α-knockdown-induced stimulation of hepcidin could be entirely blocked when BMPR1A was interfered with at the same time. In conclusion, the present study suggests that HNF-4α has a suppressive effect on hepcidin expression by inactivating the BMP pathway, specifically via BMPR1A, in HepG2 cells.
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Affiliation(s)
- Wencai Shi
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China
- Department of Clinical Nutrition, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Heyang Wang
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China
| | - Xuan Zheng
- Department of Clinical Nutrition, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xin Jiang
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China
| | - Zheng Xu
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China
| | - Hui Shen
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China
| | - Min Li
- Military Hygiene Department, Faculty of Naval Medicine, Second Military Medical University, No. 800 Xiangyin Road, Shanghai, 200433, China.
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Mao X, Chen H, Tang J, Wang L, Shu T. Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression. Endocr Connect 2017; 6:121-128. [PMID: 28179377 PMCID: PMC5424768 DOI: 10.1530/ec-16-0115] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/08/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. DESIGN We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. METHODS MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. RESULTS Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. CONCLUSIONS Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.
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Affiliation(s)
- Xuhua Mao
- Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China
| | - Hucheng Chen
- Department of Nuclear MedicineNanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junmin Tang
- Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China
| | - Liangliang Wang
- Department of NeurologyYixing People's Hospital Affiliated to Jiangsu University, Yixing, Wuxi, Jiangsu, China
| | - Tingting Shu
- Department of Central LaboratoryJiangsu Province Official Hospital, Nanjing, Jiangsu, China
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Vela D, Leshoski J, Gjorgievska ES, Hadzi-Petrushev N, Jakupaj M, Sopi RB, Mladenov M. The Role of Insulin Therapy in Correcting Hepcidin Levels in Patients with Type 2 Diabetes Mellitus. Oman Med J 2017; 32:195-200. [PMID: 28584599 DOI: 10.5001/omj.2017.37] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES Iron overload can cause or contribute to the pathogenesis of type 2 diabetes mellitus (T2DM), but how the major parameters of iron metabolism change in different settings of diabetes are still unclear. The aim of this study was to determine the relationship between iron, ferritin, and hepcidin levels in diabetic patients and the effect of insulin treatment. METHODS The study included 80 subjects, 60 with T2DM and 20 without (control group). Serum hepcidin, insulin, ferritin, and iron levels were determined as well as other clinical parameters. The associations between these parameters were analyzed between both groups. RESULTS Hepcidin levels expressed as mean± standard deviation between groups showed no significant changes (14.4±6.7 ng/mL for the control group, and 18.4±7.9 ng/mL for patients with diabetes, p = 0.069). Parameters of iron metabolism showed modest correlation with the parameters of glucose metabolism. However, the correlation between ferritin and insulin in both groups was statistically significant (p = 0.032; ρ = 0.480 vs. p = 0.011; ρ = 0.328). CONCLUSIONS Our study showed that hepcidin levels in patients with T2DM on insulin therapy do not change, which might be a result of treatment with insulin. In this context, insulin treatment can be used as a novel method for correction of hepcidin levels. By correcting hepcidin levels, we can prevent cellular iron overload and reduce the risk of diabetes.
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Affiliation(s)
- Driton Vela
- Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
| | - Jovica Leshoski
- Institute of Biology, Faculty of Natural Sciences, Saints Cyril and Methodius University of Skopje, Skopje, Macedonia
| | - Elizabeta S Gjorgievska
- Faculty of Dental Medicine, Saints Cyril and Methodius University of Skopje, Skopje, Macedonia
| | - Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Sciences, Saints Cyril and Methodius University of Skopje, Skopje, Macedonia
| | | | - Ramadan B Sopi
- Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
| | - Mitko Mladenov
- Institute of Biology, Faculty of Natural Sciences, Saints Cyril and Methodius University of Skopje, Skopje, Macedonia
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Cikomola JC, Flórez MR, Costas-Rodríguez M, Anoshkina Y, Vandepoele K, Katchunga PB, Kishabongo AS, Speeckaert MM, Vanhaecke F, Delanghe JR. Whole blood Fe isotopic signature in a sub-Saharan African population. Metallomics 2017; 9:1142-1149. [DOI: 10.1039/c7mt00170c] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The Fe isotopic composition of an individual's whole blood has recently been shown to be an interesting clinical indicator of Fe status.
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Affiliation(s)
- Justin C. Cikomola
- Department of Internal Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | - María R. Flórez
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | | | - Yulia Anoshkina
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | - Karl Vandepoele
- Laboratory of Molecular Diagnostics and Hematology
- Ghent University Hospital
- Ghent
- Belgium
| | - Philippe B. Katchunga
- Department of Internal Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | - Antoine S. Kishabongo
- Department of Laboratory Medicine
- Hôpital provincial général de référence de Bukavu
- Catholic University of Bukavu
- Bukavu
- Democratic Republic of the Congo
| | | | - Frank Vanhaecke
- Department of Analytical Chemistry
- Ghent University
- B-9000 Ghent
- Belgium
| | - Joris R. Delanghe
- Department of Clinical Chemistry
- Ghent University Hospital
- De Pintelaan 185 B-9000 Ghent
- Belgium
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Krisai P, Leib S, Aeschbacher S, Kofler T, Assadian M, Maseli A, Todd J, Estis J, Risch M, Risch L, Conen D. Relationships of iron metabolism with insulin resistance and glucose levels in young and healthy adults. Eur J Intern Med 2016; 32:31-7. [PMID: 27113814 DOI: 10.1016/j.ejim.2016.03.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 02/21/2016] [Accepted: 03/18/2016] [Indexed: 12/09/2022]
Abstract
AIMS Several biomarkers within the iron metabolism pathway have been related to the occurrence of diabetes mellitus, but underlying mechanisms are unknown. The aim of our study was to investigate the differential relationships of iron metabolism with a broad range of diabetes markers in young and healthy adults. DESIGN 2160 participants aged 25 to 41years were enrolled in a population-based study. Established cardiovascular disease, diabetes or a body mass index >35kg/m(2) were exclusion criteria. Multivariable linear regression models were built to assess the associations of ferritin and transferrin saturation (TSAT) with blood levels of glucagon-like peptide-1 (GLP-1), insulin, homeostatic model assessment-insulin resistance (HOMA-IR), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). RESULTS Median (interquartile range) age was 37 (31, 40) years. In multivariable linear regression analyses, β-coefficients (95% confidence intervals) per 1-SD increase in ferritin were 0.04 (0.02; 0.07, p=0.0008) for GLP-1, 0.06 (0.04; 0.08, p<0.0001) for insulin, 0.07 (0.04; 0.09, p<0.0001) for HOMA-IR, 0.004 (-0.00; 0.01, p=0.07) for FPG and -0.003 (-0.01; -0.00, p=0.07) for HbA1c. β-coefficients (95% CI) per 1-SD increase in TSAT were -0.07 (-0.09; -0.05, p<0.0001) for GLP-1, -0.06 (-0.08; -0.04, p<0.0001) for insulin, -0.07(-0.09; -0.05, p<0.0001) for HOMA-IR, -0.01 (-0.01; -0.00, p<0.0001) for FPG and -0.01 (-0.01; -0.00, p=0.0004) for HbA1c. CONCLUSIONS Markers of insulin resistance are strongly related with markers of iron metabolism in healthy subjects. These relationships were inconsistent and weaker for short-term and long-term glucose levels. These results may provide insights in the relationships between iron metabolism and diabetes occurrence.
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Affiliation(s)
- Philipp Krisai
- Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland
| | - Stefanie Leib
- Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland
| | | | - Thomas Kofler
- Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland
| | - Mustafa Assadian
- Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland
| | - Anna Maseli
- Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland
| | - John Todd
- Singulex, Inc., 1701 Harbor Bay Parkway Suite 200, Alameda, CA 94502, USA
| | - Joel Estis
- Singulex, Inc., 1701 Harbor Bay Parkway Suite 200, Alameda, CA 94502, USA
| | - Martin Risch
- Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein; Division of Laboratory Medicine, Kantonsspital Graubünden, Chur, Switzerland
| | - Lorenz Risch
- Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein; Division of Clinical Biochemistry, Medical University Innsbruck, Austria; Private University, Triesen, Liechtenstein
| | - David Conen
- Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland.
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Lu S, Bennett RG, Kharbanda KK, Harrison-Findik DD. Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver. World J Hepatol 2016; 8:211-225. [PMID: 26855692 PMCID: PMC4733464 DOI: 10.4254/wjh.v8.i4.211] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/14/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD).
METHODS: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction.
RESULTS: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes.
CONCLUSION: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.
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Pechlaner R, Weiss G, Bansal S, Mayr M, Santer P, Pallhuber B, Notdurfter M, Bonora E, Willeit J, Kiechl S. Inadequate hepcidin serum concentrations predict incident type 2 diabetes mellitus. Diabetes Metab Res Rev 2016; 32:187-92. [PMID: 26378394 DOI: 10.1002/dmrr.2711] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 06/15/2015] [Accepted: 08/17/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is closely associated with elevated body iron stores. The hormone hepcidin is the key regulator of iron homeostasis. Inadequately low hepcidin levels were recently reported in subjects with manifest T2DM. We investigated whether alterations of hepcidin levels precede the manifestation of T2DM and predict T2DM development independently of established risk conditions. METHODS This prospective population-based study included 675 subjects aged 50-89 years, 51.9% of whom were female. Hepcidin levels were measured by gold standard tandem mass spectrometry. Diabetes was diagnosed according to American Diabetes Association criteria, and incident diabetes was recorded between baseline in 2000 and 2010. RESULTS The baseline hepcidin-to-ferritin ratio in subjects that subsequently developed diabetes during follow-up was reduced on average by 29.8% as compared with subjects with normal glucose tolerance (95% confidence interval, -50.7% to -0.2%; p = 0.049). After adjustment for age, sex, and serum ferritin, higher hepcidin levels were associated with reduced risk of incident diabetes (hazard ratio per 1-unit higher log2 hepcidin, 0.80; 95% confidence interval, 0.64-0.98; p = 0.035; 33 events). Additional adjustment for established diabetes risk factors and determinants of hepcidin concentration did not appreciably change these results (HR, 0.81; 95% CI, 0.66-0.99). Likewise, inadequately low hepcidin levels were also detected in subjects with prevalent T2DM (n = 76). CONCLUSIONS Hepcidin levels that are inadequately low in relation to body iron stores are an independent predictor for incident T2DM and may contribute to diabetes-related tissue iron overload. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Raimund Pechlaner
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria
| | - Sukhvinder Bansal
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Manuel Mayr
- King's British Heart Foundation Centre, King's College London, London, UK
| | - Peter Santer
- Department of Laboratory Medicine, Hospital of Bruneck, Bruneck, Italy
| | - Barbara Pallhuber
- Department of Internal Medicine, Hospital of Bruneck, Bruneck, Italy
| | | | - Enzo Bonora
- Division of Endocrinology, Diabetes and Metabolic Diseases, University and Hospital Trust of Verona, Verona, Italy
| | - Johann Willeit
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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46
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Baldwin HJ, Green AE, Spellar KM, Arthur PJ, Phillips HG, Patel JV. Tipping the balance: Haemoglobinopathies and the risk of diabetes. World J Diabetes 2016; 7:8-13. [PMID: 26788262 PMCID: PMC4707301 DOI: 10.4239/wjd.v7.i1.8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/08/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To establish a link between the risk of diabetes with haemoglobinopathies by examining available evidence of the effects of iron and blood glucose homeostasis from molecular to epidemiological perspectives.
METHODS: A systematic literature search was performed using electronic literature databases using various search terms. The International Diabetes Federation World Atlas was used to generate a list of populations with high rates of diabetes. PubMed, Scopus and Google Scholar were used to identify which of these populations also had a reported prevalence of haemoglobin abnormalities.
RESULTS: Abnormalities in iron homeostasis leads to increases in reactive oxygen species in the blood. This promotes oxidative stress which contributes to peripheral resistance to insulin in two ways: (1) reduced insulin/insulin receptor interaction; and (2) β-cell dysfunction. Hepcidin is crucial in terms of maintaining appropriate amounts of iron in the body and is in turn affected by haemoglobinopathies. Hepcidin also has other metabolic effects in places such as the liver but so far the extent of these is not well understood. It does however directly control the levels of serum ferritin. High serum ferritin is found in obese patients and those with diabetes and a meta-analysis of the various studies shows that high serum ferritin does indeed increase diabetes risk.
CONCLUSION: From an epidemiological standpoint, it is plausible that the well-documented protective effects of haemoglobinopathies with regard to malaria may have also offered other evolutionary advantages. By contributing to peripheral insulin resistance, haemoglobinopathies may have helped to sculpt the so-called “thrifty genotype”, which hypothetically is advantageous in times of famine. The prevalence data however is not extensive enough to provide concrete associations between diabetes and haemoglobinopathies - more precise studies are required.
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Zhang S, Ntasis E, Kabtni S, van den Born J, Navis G, Bakker SJL, Krämer BK, Yard BA, Hauske SJ. Hyperglycemia Does Not Affect Iron Mediated Toxicity of Cultured Endothelial and Renal Tubular Epithelial Cells: Influence of L-Carnosine. J Diabetes Res 2016; 2016:8710432. [PMID: 26788523 PMCID: PMC4691606 DOI: 10.1155/2016/8710432] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 07/28/2015] [Accepted: 08/10/2015] [Indexed: 12/22/2022] Open
Abstract
Iron has been suggested to affect the clinical course of type 2 diabetes (T2DM) as accompanying increased intracellular iron accumulation may provide an alternative source for reactive oxygen species (ROS). Although carnosine has proven its therapeutic efficacy in rodent models of T2DM, little is known about its efficacy to protect cells from iron toxicity. We sought to assess if high glucose (HG) exposure makes cultured human umbilical vein endothelial cells (HUVECs) and renal proximal tubular epithelial cells (PTECs) more susceptible to metal induced toxicity and if this is ameliorated by L-carnosine. HUVECs and PTECs, cultured under normal glucose (5 mM, NG) or HG (30 mM), were challenged for 24 h with FeCl3. Cell viability was not impaired under HG conditions nor did HG increase susceptibility to FeCl3. HG did not change the expression of divalent metal transporter 1 (DMT1), ferroportin (IREG), and transferrin receptor protein 1 (TFRC). Irrespective of glucose concentrations L-carnosine prevented toxicity in a dose-dependent manner, only if it was present during the FeCl3 challenge. Hence our study indicates that iron induced cytotoxicity is not enhanced under HG conditions. L-Carnosine displayed a strong protective effect, most likely by chelation of iron mediated toxicity.
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Affiliation(s)
- Shiqi Zhang
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Emmanouil Ntasis
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Department of Cardiology, Pulmonology, Intensive Care and Vascular Medicine, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Sarah Kabtni
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Jaap van den Born
- Department of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Gerjan Navis
- Department of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Stephan J. L. Bakker
- Department of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Bernhard K. Krämer
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Benito A. Yard
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- *Benito A. Yard:
| | - Sibylle J. Hauske
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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Yalcin MM, Altinova AE, Akturk M, Gulbahar O, Arslan E, Ors Sendogan D, Yetkin I, Toruner FB. GDF-15 and Hepcidin Levels in Nonanemic Patients with Impaired Glucose Tolerance. J Diabetes Res 2016; 2016:1240843. [PMID: 27642607 PMCID: PMC5014962 DOI: 10.1155/2016/1240843] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 06/20/2016] [Accepted: 08/02/2016] [Indexed: 12/28/2022] Open
Abstract
Aims. Growth Differentiation Factor-15 (GDF-15) has been suggested as one of the regulators of hepcidin, an important regulatory peptide for iron deposition. Current data is conflicting about the relationship between hepcidin and disorders of glucose metabolism. We aimed to investigate serum hepcidin and GDF-15 concentrations and their associations with each other, in nonanemic subjects with impaired glucose tolerance (IGT) in comparison with the nonanemic subjects with normal glucose tolerance (NGT). Methods. Thirty-seven subjects with IGT and 32 control subjects with NGT, who were age-, gender-, and body mass index- (BMI-) matched, were included in the study. Results. Serum GDF-15 levels were significantly higher in IGT compared to NGT. There were no differences in hepcidin, interleukin-6, and high sensitive C-reactive protein levels between the groups. We found a positive correlation between GDF-15 and hepcidin levels. There were also positive correlations between GDF-15 and age, uric acid, creatinine, and area under the curve for glucose (AUC-G). Hepcidin was correlated positively with ferritin levels. In the multiple regression analysis, GDF-15 concentrations were independently associated with age, uric acid, and AUC-G. Conclusions. Impaired glucose tolerance is associated with increased GDF-15 levels even in the absence of anemia, but the levels of hepcidin are not significantly altered in prediabetic state.
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Affiliation(s)
- Mehmet Muhittin Yalcin
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
- *Mehmet Muhittin Yalcin:
| | - Alev Eroglu Altinova
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Mujde Akturk
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Ozlem Gulbahar
- Department of Biochemistry, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Emre Arslan
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Damla Ors Sendogan
- Department of Internal Medicine, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Ilhan Yetkin
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
| | - Fusun Balos Toruner
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, 06560 Ankara, Turkey
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49
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Chen TS, Chen YT, Liu CH, Sun CC, Mao FC. Effect of Chromium Supplementation on Element Distribution in a Mouse Model of Polycystic Ovary Syndrome. Biol Trace Elem Res 2015; 168:472-80. [PMID: 26041153 DOI: 10.1007/s12011-015-0384-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 05/26/2015] [Indexed: 01/01/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder and one of the most common causes of anovulatory infertility. In addition, insulin resistance is commonly associated with PCOS and contributed to pathophysiology connected to dietary minerals including chromium (Cr), copper (Cu), iron (Fe), and zinc (Zn). The aims of this study were to explore whether PCOS in mice alters levels of these elements and determine if Cr supplementation resolves changes. Twenty-four female BALB/c mice were divided into three groups of eight mice [normal control (NC), PCOS+placebo milk (PP), and PCOS+Cr-containing milk (PCr)]. Each group received a high-fat diet for 4 weeks. Our results show significantly higher levels of dehydroepiandrosterone (DHEA) (p<0.001), fasting glucose (p<0.05), and fasting insulin (p<0.05) in the PP group compared with both NC and PCr group. However, Cr levels were significantly lower in muscle, bone, and serum in the PP group (p<0.05) compared with NC and PCr groups. In liver, bone, and serum, Fe levels were significantly higher in the PP group compared with the NC group (p<0.05). In addition, we found significant correlations between Cu/Zn ratio and fasting insulin in all mice (r=0.61; p=0.002). Given that significant research shows that Cr supplementation improves fasting glucose, fasting insulin, and metal metabolism disorders for PCOS mice, our data suggest that trace element levels can serve as biomarkers to prescribe therapeutic supplementation to maintain a healthy metabolic balance and treat disease conditions.
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Affiliation(s)
- Tsung-Sheng Chen
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, 402, Taiwan
| | - Yi-Ting Chen
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, 402, Taiwan
| | - Chia-Hsin Liu
- Department of Research and Development, Maxluck Biotechnology Corporation, Taichung, 402, Taiwan
| | - Chi-Ching Sun
- Department of Research and Development, Maxluck Biotechnology Corporation, Taichung, 402, Taiwan
| | - Frank Chiahung Mao
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, 402, Taiwan.
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50
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Suárez-Ortegón MF, Moreno M, Arbeláez A, Xifra G, Mosquera M, Moreno-Navarrete JM, Aguilar-de Plata C, Esteve E, Ricart W, Fernández-Real JM. Circulating hepcidin in type 2 diabetes: A multivariate analysis and double blind evaluation of metformin effects. Mol Nutr Food Res 2015; 59:2460-70. [PMID: 26394887 DOI: 10.1002/mnfr.201500310] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 09/02/2015] [Accepted: 09/04/2015] [Indexed: 12/13/2022]
Abstract
SCOPE Very few studies have evaluated serum hepcidin in patients with type 2 diabetes and they have reported conflicting results. In addition, the effect of antidiabetic drugs on circulating hepcidin has not been explored so far. The aims of the study were to evaluate hepcidin concentrations and hepcidin/ferritin ratio in type 2 diabetes subjects and healthy non-diabetic controls and to evaluate the effect of metformin on hepcidin concentrations. METHODS AND RESULTS Study 1: Cross-sectional multivariate study of 239 non-diabetic individuals and 65 people with type 2 diabetes. The multivariate analysis included covariates of chronic inflammation, BMI, pharmacological treatment, menopausal status and insulin resistance. Study 2: Randomized, double-blinded, placebo-controlled 4-month trial metformin compared to placebo among 36 type 2 diabetic patients. In both groups diet was controlled by maintaining a hypocaloric intake across the trial. Hepcidin levels were significantly lower in patients with type 2 diabetes than in non-diabetic individuals either in crude or adjusted regression models (P<0.05). Hepcidin decreased in both arms of the trial (Placebo, p = 0.004; metformin, p = 0.022). CONCLUSION Circulating hepcidin was significantly and independently lower in type 2 diabetes. Metformin treatment is not associated with reductions in hepcidin but hypocaloric diet could be involved.
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Affiliation(s)
- Milton Fabián Suárez-Ortegón
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.,Nutrition Group, Universidad del Valle, Cali, Colombia
| | - María Moreno
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Alejandra Arbeláez
- Nutrition Group, Universidad del Valle, Cali, Colombia.,Physiological Sciences Department, Universidad del Valle, Cali, Colombia
| | - Gemma Xifra
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Mildrey Mosquera
- Nutrition Group, Universidad del Valle, Cali, Colombia.,Physiological Sciences Department, Universidad del Valle, Cali, Colombia
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Cecilia Aguilar-de Plata
- Nutrition Group, Universidad del Valle, Cali, Colombia.,Physiological Sciences Department, Universidad del Valle, Cali, Colombia
| | - Eduardo Esteve
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
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