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Conway RB, Pratte KA, Bowler RP, Young KA, Kinney GL, Austin E, Li Y, McClain D, Hokanson J, Crapo JD. Plasma Proteomic Markers of Iron and Risk of Diabetes in a Cohort of African American and White American Current and Former Smokers. Diabetes Metab Syndr Obes 2024; 17:4767-4776. [PMID: 39678225 PMCID: PMC11646377 DOI: 10.2147/dmso.s492124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024] Open
Abstract
Background Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers. Methods NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes. The SomaScan was used to determine the relative amounts of natural log-transformed ferritin, transferrin, and hepcidin. Findings During an average of 5.6 years of follow-up, diabetes incidence was 7.9%. Ferritin at follow-up was higher in NHB than NHW participants (p = <0.0001). Ferritin at follow-up was associated with increased diabetes risk (OR = 1.36, 95% CI = 1.08-1.70), while transferrin was associated with decreased risk (OR = 0.25, 95% CI = 0.08-0.77) controlling for age, sex, BMI, smoking pack-years, hepcidin, CRP, and Il-6. Race-specifically, increased risk associated with higher ferritin levels among NHB (OR = 1.56, 95% CI = 1.13-2.16) but not NHW (OR = 1.22, 95% CI = 0.89-1.68) participants. Sex-specifically, ferritin's relationship was similar among NHB men and women and NHW women (ORs ranging from 1.41-1.59); but not NHW men (OR = 0.98, 95% CI = 0.64-1.49). Similarly, transferrin ORs non-significantly ranged from 0.19-0.30 for NHB men and women and NHW women, but was significant for NHW men (OR = 0.07, 95% CI = 0.01-0.63). Interpretation Higher body iron stores is associated with increased diabetes risk among both NHB and NHW people. Unsuspected elevated iron stores may increase diabetes risk in NHB patients and should be monitored.
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Affiliation(s)
- Rebecca Baqiyyah Conway
- Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Katherine A Pratte
- Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO, 80206, USA
| | - Russell Paul Bowler
- Department of Genomic Sciences, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Kendra A Young
- Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Gregory l Kinney
- Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Erin Austin
- Department of Mathematical and Statistical Sciences, Denver, University of Colorado, Denver, CO, 80204, USA
| | - Yisha Li
- Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Donald McClain
- Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - John Hokanson
- Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - James D Crapo
- Department of Medicine, National Jewish Health, Denver, CO, 80206, USA
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Duță C, Muscurel C, Dogaru CB, Stoian I. Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 2024; 25:8838. [PMID: 39201524 PMCID: PMC11354749 DOI: 10.3390/ijms25168838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.
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AlQarni AM, Alghamdi AA, Aljubran HJ, Bamalan OA, Abuzaid AH, AlYahya MA, AlAwami AM, Al Shubbar MD, Al Yousif GF. Exploring the Impact of Iron Deficiency Anaemia on Glycated Haemoglobin A1c Levels in Pregnant and Non-Pregnant Women: A Systematic Review. Int J Womens Health 2024; 16:797-809. [PMID: 38765207 PMCID: PMC11100956 DOI: 10.2147/ijwh.s462163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 05/05/2024] [Indexed: 05/21/2024] Open
Abstract
Haemoglobin A1C (HbA1c) is fundamental in monitoring glycaemic control during pregnancy. However, several conditions could affect this test's accuracy, including iron deficiency anaemia (IDA). Hence, this systematic review delves into the underexplored connection between IDA, iron replacement therapy (IRT), and haemoglobin A1C (HbA1c) during pregnancy. An electronic search of the Cochrane, MEDLINE, and Embase databases was conducted by six authors. From a comprehensive search strategy, 968 records were obtained. After applying the inclusion and exclusion criteria, seven studies were included, comprising 365 women selected for analysis. Six studies indicated a positive correlation between IDA and HbA1c levels, while one found no correlation. The average HbA1c level of the included studies in pregnant women was 5.64%. In comparison, it was found that non-pregnant women had lower HbA1c levels. Among the included studies, the mean HbA1c levels decreased from 5.1% to 4.89% after treating pregnant women with IRT. The review emphasises the complexity of interpreting HbA1c levels in pregnant women with IDA, highlighting the influence of pregnancy-induced physiological changes. In addition, this suggests that HbA1c should not be the sole criterion for diabetes management in pregnant women with IDA. Future research should focus on alternative glycaemic monitoring methods unaffected by IDA.
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Affiliation(s)
- Amani M AlQarni
- Department of Family and Community Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Amal A Alghamdi
- Department of Family and Community Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hussain J Aljubran
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Omar A Bamalan
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Abdullah H Abuzaid
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohammed A AlYahya
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Ahmed M AlAwami
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | | | - Ghada F Al Yousif
- Department of Family and Community Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Seyyar SA, Tokuç EÖ, Soysal GG. Effect of diabetic macular oedema on serum iron status indicators. Clin Exp Optom 2024; 107:313-317. [PMID: 37309021 DOI: 10.1080/08164622.2023.2218997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/24/2023] [Indexed: 06/14/2023] Open
Abstract
CLINICAL RELEVANCE The role of subclinical inflammation in the pathophysiology of diabetic macular oedema (DME), which is known to be quite complex, is of much interest. Serum ferritin level, which is an indicator of body iron stores, is both an inflammatory marker for various neurodegenerative diseases and an important indicator in the evaluation of iron-induced oxidative stress. BACKGROUND Iron metabolism indicators play a role in the formation and development of diabetic retinopathy, which is known to be associated with subclinical inflammation, and may also play a role in the pathogenesis of DME. The aim of this study was to investigate the role of serum iron metabolism markers in the pathogenesis of DME. MATERIALS AND METHODS The files of all nonproliferative diabetic retinopathy (NPDR) patients who were scheduled for the first intravitreal injection for DME in the eye clinic between January 2019 and January 2020 were reviewed retrospectively. By examining the files of all diabetes mellitus patients who attended the outpatient eye clinic on the same dates, those without retinopathy and those with NPDR but not DME were recorded. All results, including a comprehensive ophthalmological examination, laboratory data of fasting blood tests, and an internal medicine outpatient examination were collected for analysis. RESULTS Of the 157 participants, 44 were NPDR patients with oedema, 50 were NPDR patients without oedema, and 63 were patients without retinopathy. There was a significant difference between the groups in respect of creatinine, high-density lipoprotein, mean corpuscular volume, serum iron and ferritin, total iron binding capacity and transferrin saturation (p < 0.050). Ferritin values were found to be significantly higher in patients with macular oedema. Other iron status markers were found to be significantly lower (p < 0.050). CONCLUSION Evaluation of serum iron status indicators in the routine follow-up of diabetic patients may be of diagnostic and/or prognostic benefit in terms of DME.
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Affiliation(s)
- Sevim Ayça Seyyar
- Ophthalmology Department, Gaziantep University Hospital, Gaziantep, Turkey
| | - Ecem Önder Tokuç
- Ophthalmology Department, Kocaeli University Hospital, Kocaeli, Turkey
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Qin Y, Huang Y, Li Y, Qin L, Wei Q, Chen X, Yang C, Zhang M. Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1143919. [PMID: 37077360 PMCID: PMC10107407 DOI: 10.3389/fendo.2023.1143919] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/14/2023] [Indexed: 04/05/2023] Open
Abstract
OBJECTIVE Abnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM. METHODS A total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity. RESULTS Compared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity. CONCLUSION Elevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM.
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Affiliation(s)
- Yao Qin
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yiting Huang
- Department of Clinical Nutrition, the Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuxiao Li
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lu Qin
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qianying Wei
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chuanhui Yang
- Department of Endocrinology, the First People’s Hospital of Lianyungang, Lianyungang, China
| | - Mei Zhang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Mei Zhang,
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Firdous P, Nissar K, Bashir H, Hussain QA, Masoodi SR, Ganai BA. Environmental Factors as Diabetic Mediators: A Mechanistic Approach. Curr Diabetes Rev 2022; 18:e301221199656. [PMID: 34967298 DOI: 10.2174/1573399818666211230104327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/13/2021] [Accepted: 09/29/2021] [Indexed: 11/22/2022]
Abstract
Despite substantial investment in research and treatment options, diabetes mellitus remains a pressing public health concern with potential epidemic proportions globally. There are reports that by the end of 2040, 642 million people will be suffering from diabetes. Also, according to an estimation, 1.6 million deaths were caused directly by diabetes in 2016. Diabetes is a metabolic disorder characterized by impaired glucose regulation in the body due to the destruction of pancreatic β-cells or insulin resistance. Genetic propensity, unhealthy and imbalanced diet, obesity and increasing urbanization are the common risk factors for diabetes. Besides this, it has been reported that environmental pollutants like organic pesticides, heavy metals, and air pollutants act as strong predisposing factors for diabetes owing to their highly bio-accumulative nature. These pollutants disturb glucose homeostasis either by up-regulating or down-regulating the expression of diabetic marker genes like insulin (INS) and glucokinase (GCK). Unfortunately, the molecular mechanism of the role of pollutants in causing diabetes is not very clear. This mechanistic review provides evidence of different environmental determinants, including persistent organic pollutants (POPs), air pollutants, toxic metals, etc., in inducing diabetes and proposes a framework for the possible mechanisms involved. It also illuminates the current status and future challenges, which will not only broaden our understanding but can also be a reasonable platform for further investigation.
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Affiliation(s)
- Parveena Firdous
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
| | - Kamran Nissar
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
- Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
| | - Humayra Bashir
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
| | - Qazi A Hussain
- P.G. Department of Environmental Science, Sri Pratap College Campus, Cluster University Srinagar, Jammu and Kashmir 190001, India
| | | | - Bashir Ahmad Ganai
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir 190006, India
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He XC, Chen HY, Qiu Y, Tian L, Bao BS, Hao XP, Chen YH. Associations of iron status with breast cancer risk factors in adult women: Findings from National Health and Nutrition Examination Survey 2017-2018. J Trace Elem Med Biol 2021; 68:126867. [PMID: 34592676 DOI: 10.1016/j.jtemb.2021.126867] [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: 04/05/2021] [Revised: 08/24/2021] [Accepted: 09/22/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE This study examined the association between iron status and a set of breast cancer risk factors among U.S. adult women aged 20-80 years. METHODS Data from National Health and Nutrition Examination Survey (2017-2018) were used to examine the relation between serum ferritin, serum iron and transferrin saturation with a set of breast cancer risk factors [body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), fasting plasma glucose, insulin and HOMA-IR]. The multivariable linear regressions were used controlling for age, race/ethnicity, menopause status, education level, smoking status, alcohol consumption, physical activity, high-sensitivity C-reactive protein (hsCRP) and total energy intake. RESULTS HbA1c, BMI and waist circumference data were available for 1902 women with a fasting sample (n = 913) for fasting plasma glucose, insulin and HOMA-IR. Transferrin saturation had significant, inverse associations with BMI, waist circumference and HbA1c. The size of difference observed were that participants in the fourth quartile of transferrin saturation had a 4.50 kg/m2 smaller BMI, a 9.36 cm smaller waist circumference and a 0.1 % lower HbA1c level than participants in the first quartile. Similarly, serum iron concentrations were inversely associated with BMI and waist circumference. In addition, serum iron had significant, inverse associations with insulin and HOMA-IR. Sensitivity analyses among men gave similar results. For serum ferritin, there was a trend towards a positive association between waist circumference, HbA1c and fasting plasma glucose with serum ferritin. However, the associations did not reach statistical significance among women. CONCLUSIONS Iron status may impact breast cancer risk via effects on adiposity or glucose metabolism. The findings should be confirmed with further prospective data.
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Affiliation(s)
- Xiao-Chong He
- Department of Nursing Administration, Army Medical University, Chongqing, 400038, China.
| | - Hong-Ye Chen
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Yue Qiu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Lin Tian
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Bao-Shi Bao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Xiao-Peng Hao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Yu-Hui Chen
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100039, China.
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El-Sikaily A, Helal M. Environmental pollution and diabetes mellitus. World J Meta-Anal 2021; 9:234-256. [DOI: 10.13105/wjma.v9.i3.234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) is a chromic metabolic disease that affects a large segment of the population worldwide. Physical inactivity, poor nutrition, and genetic predisposition are main risk factors for disease development. In the last decade, it was clear to the scientific community that DM development is linked to a novel disease inducer that was later defined as diabetogenic factors of pollution and endocrine disrupting agents. Environmental pollution is exponentially increasing in uncontrolled manner in several countries. Environmental pollutants are of diverse nature and toxicities, including polyaromatic hydrocarbons (PAHs), pesticides, and heavy metals. In the current review, we shed light on the impact of each class of these pollutants and the underlined molecular mechanism of diabetes induction and biological toxicities. Finally, a brief overview about the connection between coronavirus disease 2019 and diabetes pandemics is presented.
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Affiliation(s)
- Amany El-Sikaily
- National Institute of Oceanography and Fisheries (NIOF), Cairo 21513, Egypt
| | - Mohamed Helal
- National Institute of Oceanography and Fisheries (NIOF), Cairo 21513, Egypt
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Value of liver iron concentration in healthy volunteers assessed by MRI. Sci Rep 2020; 10:17887. [PMID: 33087836 PMCID: PMC7577999 DOI: 10.1038/s41598-020-74968-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 09/24/2020] [Indexed: 01/09/2023] Open
Abstract
Iron overload is a relatively common clinical condition resulting from disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, and myelodysplasia that can lead to progressive fibrosis and eventually cirrhosis of the liver. Therefore, it is essential to recognize the disease process at the earliest stage. Liver biopsy is the reference test for the assessment of liver fibrosis. It also allows for quantifying liver iron concentration (LIC) in patients. However, this is an invasive method with significant limitations and possible risks. Magnetic resonance imaging (MRI) and evaluation of the R2* relaxation rate can be an alternative to biopsy for assessing LIC. However, it causes a need for accurate R2* data corresponding to standard value for further comparison with examined patients. This study aimed to assess the normative values of liver R2* in healthy individuals. A total of 100 volunteers that met established criteria were enrolled in the study: 36 (36%) men and 64 (64%) women. The mean age was 22.9 years (range 20 to 32 years). R2* was estimated by an MRI exam with a 1.5 T clinical magnetic resonance scanner. Images for measuring the LIC and liver fat concentration were obtained using the IDEAL-IQ technique for liver imaging. The Mean (SD) liver R2* was 28.34 (2.25) s−1 (95% CI, 27.78–28.90, range 23.67–33.00 s−1) in females, 29.57 (3.20) s−1 (95% CI, 28.49–30.66, range 23.93–37.77 s−1) in males, and 28.72 (2.69) s−1 (range 23.67–37.77 s−1) in the whole group. R2* value in this particular population with a high proportion of young women did not exceed 38 s−1. In the absence of fibrosis or steatosis, liver stiffness and fat fraction did not show any relationship with R2*.
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Liu J, Li Q, Yang Y, Ma L. Iron metabolism and type 2 diabetes mellitus: A meta-analysis and systematic review. J Diabetes Investig 2020; 11:946-955. [PMID: 31975563 PMCID: PMC7378429 DOI: 10.1111/jdi.13216] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 12/19/2019] [Accepted: 01/16/2020] [Indexed: 12/25/2022] Open
Abstract
AIMS/INTRODUCTION Iron metabolism can directly or indirectly affect the occurrence and development of type 2 diabetes. This meta-analysis and systematic review aimed to analyze the association between serum iron metabolism indicators and type 2 diabetes. MATERIALS AND METHODS The databases PubMed and Embase were searched for studies on the correlations between serum iron metabolism indicators (iron, ferritin, transferrin, hepcidin and soluble transferrin receptor) and type 2 diabetes since January 2006. Relevant data were extracted from the included studies, and meta-analysis was carried out. RESULTS A total of 12 case-control and cohort studies were analyzed. Of the 12 studies, 11 described the correlation between serum ferritin levels and type 2 diabetes. The median and high serum ferritin concentrations were significantly associated with the risks of type 2 diabetes (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.08-1.33 and OR 1.43, 95% CI 1.29-1.59, respectively). However, the low concentration was not correlated with the risk of type 2 diabetes (OR 0.99, 95% CI 0.89-1.11). No significant association was observed between serum soluble transferrin receptor and type 2 diabetes, whereas the soluble transferrin receptor-to-ferritin ratio was significantly inversely related to the risk of type 2 diabetes in the median and high ratio subgroups (OR 0.71, 95% CI 0.51, 0.99 and OR 0.65, 95% CI 0.45-0.95). CONCLUSIONS The elevated serum ferritin was one of the risk factors for type 2 diabetes, and soluble transferrin receptor-to-ferritin ratio was inversely related to the risk of type 2 diabetes. A systematic review showed that serum transferrin and hepcidin might be directly or indirectly related to the development of diabetes.
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Affiliation(s)
- Jingfang Liu
- Department of EndocrinologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Qingxiu Li
- Department of EndocrinologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Yaxian Yang
- Department of EndocrinologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Lihua Ma
- Department of EndocrinologyThe First Hospital of Lanzhou UniversityLanzhouChina
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11
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Development of insulin resistance preceded major changes in iron homeostasis in mice fed a high-fat diet. J Nutr Biochem 2020; 84:108441. [PMID: 32629238 PMCID: PMC7115812 DOI: 10.1016/j.jnutbio.2020.108441] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 03/10/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) have been associated with dysregulation of iron metabolism. The basis for this association is not completely understood. To attempt to investigate this, we studied temporal associations between onset of insulin resistance (IR) and dysregulated iron homeostasis, in a mouse model of T2DM. Male C57Bl/6 mice (aged 8 weeks) were fed a high-fat diet (HFD; 60% energy from fat) or a control diet (CD; 10% energy from fat) for 4, 8, 12, 16, 20 and 24 weeks. Development of IR was documented, and various metabolic, inflammatory and iron-related parameters were studied in these mice. HFD-feeding induced weight gain, hepato-steatosis and IR in the mice. Onset of IR occurred from 12 weeks onwards. Hepatic iron stores progressively declined from 16 weeks onwards. Accompanying changes included a decrease in hepatic hepcidin (Hamp1) mRNA expression and serum hepcidin levels and an increase in iron content in the epididymal white adipose tissue (eWAT). Iron content in the liver negatively correlated with that in the eWAT. Factors known to regulate hepatic Hamp1 expression (such as serum iron levels, systemic inflammation, and bone marrow-derived erythroid regulators) were not affected by HFD-feeding. In conclusion, the results show that the onset of IR in HFD-fed mice preceded dysregulation of iron homeostasis, evidence of which were found both in the liver and visceral adipose tissue.
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Saraf SL, Gordeuk VR. Iron. ESSENTIAL AND TOXIC TRACE ELEMENTS AND VITAMINS IN HUMAN HEALTH 2020:83-102. [DOI: 10.1016/b978-0-12-805378-2.00006-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Elsaid MI, John T, Li Y, Koduru S, Ali SZ, Catalano C, Narayanan N, Rustgi VK. Health Care Utilization and Economic Burdens of Hemochromatosis in the United States: A Population-Based Claims Study. J Manag Care Spec Pharm 2019; 25:1377-1386. [PMID: 31778618 PMCID: PMC10397675 DOI: 10.18553/jmcp.2019.25.12.1377] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Little is known about the health care burden of hemochromatosis in the United States, despite its increased morbidity and mortality due to associated advanced liver diseases. OBJECTIVE To evaluate the health care utilization and economic burdens of hemochromatosis in the United States using real-world claims data. METHODS We performed a case-control analysis of adult participants in the Truven Health MarketScan Commercial Claims database from 2010 to 2015. 37,092 hemochromatosis cases were matched 1:1 by demographics and comorbidities to hemochromatosis-free controls with chronic liver disease using propensity scores. Total and service-specific health care parameters were quantified for the 12 months following versus the 12 months before the first date of hemochromatosis diagnosis and over the 12 months following a randomly selected date for controls. Incremental differences in health care burdens between cases and controls were examined using Wilcoxon signed rank tests and McNemar tests for continuous and dichotomous measures, respectively. Adjusted multivariable regression analyses using generalized linear models were used to compare the health care burdens for cases with controls. RESULTS In comparison with the year before, the 12 months following first hemochromatosis diagnoses had a higher total number of claims per patient (34.37 vs. 29.99; P < 0.0001) and an increase in the per-patient total health care costs ($20,023 vs. $16,905; P < 0.0001). After hemochromatosis diagnosis, health care costs were 2%, 8%, 23%, and 43% higher for inpatient admissions, emergency department visits, outpatient visits, and pharmaceutical prescriptions, compared respectively with the 12 months before diagnosis. In the 12 months following the index date, hemochromatosis cases incurred $2,732 more in total unadjusted costs compared with controls. Compared with controls, cases had adjusted incident rate ratio (IRR) 1.26 (95% CI = 1.30-1.77) times the total number of claims (IRR = 1.40, 95% CI = 1.38-1.43) more outpatient visits and IRR = 1.10 (95% CI = 1.08-1.11) excess pharmaceutical claims. Compared with controls, cases had significantly higher adjusted mean health care costs for inpatient services ($6,484 vs. $7,854), outpatient services ($7,032 vs. $11,005), and pharmaceutical claims ($2,520 vs. $2,822; all P values < 0.05). The annual health care costs among type 2 diabetes, hypertension, arthritis, and chronic kidney disease (CKD) patients with hemochromatosis were $6,968, $7,424, $2,967, and $43,847, respectively, higher than type 2 diabetes, hypertension, arthritis, and CKD patients without hemochromatosis (P < 0.0001). CONCLUSIONS Hemochromatosis in the United States is associated with significant health care utilization and economic burdens driven by outpatient visits, pharmaceutical claims, and a high number of comorbidities DISCLOSURES: No outside funding supported this study. The authors have no relevant financial or other relationships to disclose. An abstract containing some of the results from this study was accepted for the American Association for the Study of Liver Diseases Meeting; November 9-13, 2018; San Francisco, CA.
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Affiliation(s)
- Mohamed I. Elsaid
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Tina John
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - You Li
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Sobha Koduru
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Saima Z. Ali
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Carolyn Catalano
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Navaneeth Narayanan
- Department of Pharmacy Practice, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey, Piscataway, and Division of Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Vinod K. Rustgi
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
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14
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Jiang L, Wang K, Lo K, Zhong Y, Yang A, Fang X, Akezhuoli H, Song Z, Chen L, An P, Xu M, Min J, Wang F. Sex-Specific Association of Circulating Ferritin Level and Risk of Type 2 Diabetes: A Dose-Response Meta-Analysis of Prospective Studies. J Clin Endocrinol Metab 2019; 104:4539-4551. [PMID: 31074789 DOI: 10.1210/jc.2019-00495] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022]
Abstract
CONTEXT Although the role of iron in the development of type 2 diabetes (T2D) has long been a concern, prospective studies directly linking body iron stores to T2D risk in a sex-dependent context have been inconsistent. OBJECTIVE A systematic meta-analysis was conducted to explore the sex-specific association of circulating ferritin with T2D risk. DATA SOURCES We searched PubMed, Web of Science, and EMBASE databases to identify available prospective studies through 1 August 2018. RESULTS Fifteen prospective studies comprising 77,352 participants and 18,404 patients with T2D, aged 20 to 80 years, and with ∼3 to 17 years of follow-up were identified. For each 100-μg/L increment in ferritin levels of overall participants, T2D risk increased by 22% (RR, 1.22; 95% CI, 1.14 to 1.31). Of note, major heterogeneities by sex were identified, with increased ferritin level having an apparently greater effect on T2D risk in women (RR, 1.53; 95% CI, 1.29 to 1.82) than in men (RR, 1.21; 95% CI, 1.15 to 1.27) after exclusion of a study with high heterogeneity (41,512 men and 6974 women for sex-specific analyses; P = 0.020 for sex difference). Further nonlinear analysis between circulating ferritin and T2D risk also showed sex-dimorphic association in that the T2D risk of women was twice as strong in magnitude as that of men at the same ferritin level. CONCLUSIONS Greater circulating ferritin levels were independently associated with increased T2D risk, which appeared stronger among women than men. Our findings provide prospective evidence for further testing of the utility of ferritin levels in predicting T2D risk in a sex-specific manner.
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Affiliation(s)
- Li Jiang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
- The First Affiliated Hospital, School of Public Health, Zhengzhou University, Zhengzhou, China
| | - Kai Wang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Kenneth Lo
- Departments of Cardiology and Endocrinology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Centre for Global Cardiometabolic Health, Department of Epidemiology, Brown University, Providence, Rhode Island
| | - Yueyang Zhong
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Aimin Yang
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Kong Kong SAR, China
| | - Xuexian Fang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Hailati Akezhuoli
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zijun Song
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Liyun Chen
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng An
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
| | - Mingqing Xu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
| | - Junxia Min
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fudi Wang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
- The First Affiliated Hospital, School of Public Health, Zhengzhou University, Zhengzhou, China
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15
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Luo Y, Bajoria R, Lai Y, Pan H, Li Q, Zhang Z, Yang P, Chatterjee R, Liang Y. Prevalence of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia. Diabetes Metab Syndr Obes 2019; 12:457-468. [PMID: 31114275 PMCID: PMC6489622 DOI: 10.2147/dmso.s194591] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/13/2019] [Indexed: 12/28/2022] Open
Abstract
Purpose: To determine the prevalence and underlying pathology of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia (NTDT). Patients and methods: In this study, we enrolled 211 patients aged 4-63 years with NTDT, including 79 β thalassemia intermedia patients, 114 Hb H disease patients and 18 Hb E/β thalassemia patients. All had oral glucose tolerance test, serum ferritin (SF), homeostasis model assessment (HOMA) and liver iron concentration (LIC) measurement. One hundred and twenty healthy age-matched controls were also used for the comparative purpose. Iron load was assessed by using SF and hepatic load by LIC using validated MRI techniques. Results: The 211 patients were divided into three groups according to their fasting and 2 hrs postprandial blood glucose levels: hypoglycemic, normal glucose tolerance (NGT) and hyperglycemic groups. In this study, 149 patients had NGT, 33 had hypoglycemia, 4 had diabetes and 25 had impaired glucose tolerance (IGT). None had impaired fasting glucose. There was a significant correlation between 2 hrs postprandial blood glucose levels and age, PINS120, HOMA-IR, alanine aminotransferase and LIC (P<0.05). Risk factors for IGT in NTDT patients were older age (≥24 years) and SF concentration of ≥2,500 ng/mL. Conclusion: Age ≥24 years and SF ≥2,500 ng/mL of NTDT patients were at a greater risk for impaired glucose tolerance.
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Affiliation(s)
- Yunchen Luo
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
| | - Rekha Bajoria
- Reproductive Medicine, Institute for Women’s Health, Haematology Unit, University College Hospitals and Royal Free Hospital, London, UK
| | - Yongrong Lai
- Department of Haematology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
| | - Hongfei Pan
- Department of Paediatrics, Affiliated Hospital of Youjiang Medical College for Nationality, Nanning, Guangxi, People’s Republic of China
| | - Qiaochuan Li
- Department of Haematology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
| | - Zhongming Zhang
- Department of Haematology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
| | - Pijian Yang
- Department of Geriatric Endocrinology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
| | - Ratna Chatterjee
- Reproductive Medicine, Institute for Women’s Health, Haematology Unit, University College Hospitals and Royal Free Hospital, London, UK
| | - Yuzhen Liang
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China
- Correspondence: Yuzhen Liang The Second Affiliated Hospital of Guangxi Medical University, No.166, University East Road, Xixiangtang District, Nanning, Guangxi, People’s Republic of ChinaTel +861 351 766 5676Email
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16
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Prion protein modulates glucose homeostasis by altering intracellular iron. Sci Rep 2018; 8:6556. [PMID: 29700330 PMCID: PMC5919926 DOI: 10.1038/s41598-018-24786-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 03/20/2018] [Indexed: 11/08/2022] Open
Abstract
The prion protein (PrPC), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrPC on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP-/-) were significantly lower than wild type (PrP+/+) controls. Silencing of PrPC in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrPC-dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP+/+ but not PrP-/- mice, indicating PrPC-mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron-overloaded PrP+/+ relative to PrP-/- mice, suggesting that PrPC-mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer's disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis.
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17
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Layoun A, Samba-Mondonga M, Fragoso G, Calvé A, Santos MM. MyD88 Adaptor Protein Is Required for Appropriate Hepcidin Induction in Response to Dietary Iron Overload in Mice. Front Physiol 2018; 9:159. [PMID: 29556203 PMCID: PMC5845127 DOI: 10.3389/fphys.2018.00159] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 02/16/2018] [Indexed: 12/21/2022] Open
Abstract
Iron homeostasis is tightly regulated to provide virtually all cells in the body, particularly red blood cells, with this essential element while defending against its toxicity. The peptide hormone hepcidin is central to the control of the amount of iron absorbed from the diet and iron recycling from macrophages. Previously, we have shown that hepcidin induction in macrophages following Toll-like receptor (TLR) stimulation depends on the presence of myeloid differentiation primary response gene 88 (MyD88). In this study, we analyzed the regulation of iron metabolism in MyD88−/− mice to further investigate MyD88 involvement in iron sensing and hepcidin induction. We show that mice lacking MyD88 accumulate significantly more iron in their livers than wild-type counterparts in response to dietary iron loading as they are unable to appropriately control hepcidin levels. The defect was associated with inappropriately low levels of Smad4 protein and Smad1/5/8 phosphorylation in liver samples found in the MyD88−/− mice compared to wild-type mice. In conclusion, our results reveal a previously unknown link between MyD88 and iron homeostasis, and provide new insights into the regulation of hepcidin through the iron-sensing pathway.
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Affiliation(s)
- Antonio Layoun
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.,Département de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Macha Samba-Mondonga
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.,Département de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Gabriela Fragoso
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
| | - Annie Calvé
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
| | - Manuela M Santos
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.,Département de Médecine, Université de Montréal, Montréal, QC, Canada
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18
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Gordeuk VR, Brannon PM. Ethnic and genetic factors of iron status in women of reproductive age. Am J Clin Nutr 2017; 106:1594S-1599S. [PMID: 29070555 PMCID: PMC5701719 DOI: 10.3945/ajcn.117.155853] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: African Americans are at increased risk of iron deficiency (ID) but also have higher serum ferritin (SF) concentrations than those of the general population. The Hemochromatosis and Iron Overload Screening (HEIRS) Study was a multicenter study of ethnically diverse participants that tested for the hemochromatosis (HFE) C282Y genotype and iron status.Objective: We sought to determine the prevalence and predictors of ID (SF concentration ≤15 μg/L) and elevated iron stores (SF concentration >300 μg/L) in HEIRS women of reproductive age (25-44 y).Design: The HEIRS Study was a cross-sectional study of iron status and HFE mutations in primary care patients at 5 centers in the United States and Canada. We analyzed data for women of reproductive age according to whether or not they were pregnant or breastfeeding at the time of the study.Results: ID was present in 12.5% of 20,080 nonpregnant and nonbreastfeeding women compared with 19.2% of 1962 pregnant or breastfeeding women (P < 0.001). Asian American ethnicity (OR ≤0.9; P ≤ 0.049) and HFE C282Y (OR ≤0.84; P ≤ 0.060) were independently associated with a decreased risk of ID in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women. Hispanic ethnicity (OR: 1.8; P < 0.001) and African American ethnicity (OR: 1.6; P < 0.001) were associated with an increased risk of ID in nonpregnant and nonbreastfeeding women. Elevated iron stores were shown in 1.7% of nonpregnant and nonbreastfeeding women compared with 0.7% of pregnant or breastfeeding women (P = 0.001). HFE C282Y homozygosity had the most marked independent association with elevated iron stores in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women (OR >49.0; P < 0.001), but African American ethnicity was also associated with increased iron stores in both groups of women (OR >2.0; P < 0.001). Asian American ethnicity (OR: 1.8; P = 0.001) and HFE C282Y heterozygosity (OR: 1.9; P = 0.003) were associated with increased iron stores in nonpregnant and nonbreastfeeding women.Conclusions: Both ID and elevated iron stores are present in women of reproductive age and are influenced by ethnicity and HFE C282Y. Efforts to optimize iron status should keep these findings in view. This study was registered at clinicaltrials.gov as NCT03276247.
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Affiliation(s)
- Victor R Gordeuk
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL;
| | - Patsy M Brannon
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, and,Office of Dietary Supplements, NIH, Bethesda, MD
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19
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Sahay M, Kalra S, Badani R, Bantwal G, Bhoraskar A, Das AK, Dhorepatil B, Ghosh S, Jeloka T, Khandelwal D, Latif ZA, Nadkar M, Pathan MF, Saboo B, Sahay R, Shimjee S, Shrestha D, Siyan A, Talukdar SH, Tiwaskar M, Unnikrishnan AG. Diabetes and Anemia: International Diabetes Federation (IDF) - Southeast Asian Region (SEAR) position statement. Diabetes Metab Syndr 2017; 11 Suppl 2:S685-S695. [PMID: 28483426 DOI: 10.1016/j.dsx.2017.04.026] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
Abstract
Anemia is often associated with diabetes mellitus and is known to intensify the risk of developing diabetes-related microvascular and macrovascular complications. There is paucity in understanding of co-existence of these conditions, especially in Southeast Asian countries. Iron and/or erythropoietin deficiencies are the major causes of anemia in diabetes, and diabetic kidney disease plays a key role. Patients with diabetes need to be screened for anemia along with other risk factors and anemia should be corrected appropriately to improve overall clinical outcomes. This position statement aims to provide a comprehensive overview and an algorithm for appropriate management of anemia in patients with diabetes.
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Affiliation(s)
| | | | | | | | | | - A K Das
- Pondicherry Institute of Medical Sciences, Puducherry, India
| | | | | | | | | | | | - Milind Nadkar
- Seth G.S. Medical College & KEM Hospital, Mumbai, India
| | | | - Banshi Saboo
- Dia Care - Diabetes Care and Hormone Clinic, Ambawadi, Ahmedabad, India
| | | | | | | | - Ali Siyan
- Maldivian Diabetes Society, Male, Maldives
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20
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Barton JC, Acton RT. Diabetes in HFE Hemochromatosis. J Diabetes Res 2017; 2017:9826930. [PMID: 28331855 PMCID: PMC5346371 DOI: 10.1155/2017/9826930] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 12/12/2016] [Accepted: 01/04/2017] [Indexed: 02/08/2023] Open
Abstract
Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.
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Affiliation(s)
- James C. Barton
- Southern Iron Disorders Center, Birmingham, AL 35209, USA
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ronald T. Acton
- Southern Iron Disorders Center, Birmingham, AL 35209, USA
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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21
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Rametta R, Dongiovanni P, Pelusi S, Francione P, Iuculano F, Borroni V, Fatta E, Castagna A, Girelli D, Fargion S, Valenti L. Hepcidin resistance in dysmetabolic iron overload. Liver Int 2016; 36:1540-8. [PMID: 26998752 DOI: 10.1111/liv.13124] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/12/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Dysmetabolic iron overload syndrome (DIOS) is a frequent condition predisposing to metabolic, cardiovascular and hepatic damage, whose pathogenesis remains poorly defined. Aim of this study was to characterize iron metabolism in DIOS. METHODS We evaluated 18 patients with DIOS, compared to 18 with nonalcoholic fatty liver and 23 healthy individuals with normal iron status, and 10 patients with hereditary haemochromatosis by a 24-h oral iron tolerance test with hepcidin measurement and iron metabolism modelling under normal iron stores. RESULTS Dysmetabolic iron overload syndrome patients had higher peak transferrin saturation and area under the-curve of transferrin saturation than subjects with normal iron status, but lower values than haemochromatosis patients (P < 0.05 for all). Conversely, they had higher peak circulating hepcidin levels and area under the curve of hepcidin than the other groups (P < 0.05 for all). This was independent age, sex, haemoglobin, ferritin, and transferrin saturation levels (P = 0.0002). Hepcidin increase in response to the rise in transferrin saturation (hepcidin release index) was not impaired in DIOS patients. Viceversa, the ability of the hepcidin spike to control the rise in transferrin saturation at the beginning of the test (hepcidin resistance index) was impaired in DIOS (P = 0.0002). In DIOS patients, the hepcidin resistance index was correlated with ferritin levels at diagnosis (P = 0.016). CONCLUSIONS Dysmetabolic iron overload syndrome is associated with a subtle impairment in the ability of the iron hormone hepcidin to restrain iron absorption following an iron challenge, suggesting a hepcidin resistance state. Further studies are required to better characterize the molecular mechanism underpinning this new iron metabolism alteration.
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Affiliation(s)
- Raffaela Rametta
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paolo Francione
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Federica Iuculano
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Vittorio Borroni
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Erika Fatta
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Annalisa Castagna
- Policlinico G.B. Rossi, Department of Medicine, Università di Verona, Verona, Italy
| | - Domenico Girelli
- Policlinico G.B. Rossi, Department of Medicine, Università di Verona, Verona, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. .,Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
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22
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Abstract
Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors-especially alcohol consumption-and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research.
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Affiliation(s)
- Lawrie W Powell
- Centre for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, The University of Queensland, Brisbane, Australia.
| | - Rebecca C Seckington
- Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Yves Deugnier
- University Hospital and University of Rennes 1, Rennes, France
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Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism 2016; 65:1026-37. [PMID: 26409295 DOI: 10.1016/j.metabol.2015.08.018] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/23/2015] [Accepted: 08/26/2015] [Indexed: 02/07/2023]
Abstract
UNLABELLED Epidemiological, familial, and twin studies indicate that non-alcoholic fatty liver disease, now the leading cause of liver damage in developed countries, has a strong heritability. The common I148M variant of PNPLA3 impairing hepatocellular lipid droplets remodeling is the major genetic determinant of hepatic fat content. The I148M variant has a strong impact on the full spectrum of liver damage related to fatty liver, encompassing non-alcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma, and influences the response to therapeutic approaches. Common variants in GCKR enhance de novo hepatic lipogenesis in response to glucose and liver inflammation. Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver. CONCLUSIONS These and other recent findings reviewed here indicate that impaired lipid handling by hepatocytes has a major role in the pathogenesis of non-alcoholic fatty liver disease by triggering inflammation, fibrogenesis, and carcinogenesis. These discoveries have provided potential novel biomarkers for clinical use and have revealed intriguing therapeutic targets.
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Affiliation(s)
- Paola Dongiovanni
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
| | - Luca Valenti
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation, Università degli Studi Milano, Milan, Italy.
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Abstract
Iron is an essential element for several metabolic pathways and physiological processes. The maintenance of iron homeostasis within the human body requires a dynamic and highly sophisticated interplay of several proteins, as states of iron deficiency or excess are both potentially deleterious to health. Among these is plasma transferrin, which is central to iron metabolism not only through iron transport between body tissues in a soluble nontoxic form but also through its protective scavenger role in sequestering free toxic iron. The transferrin saturation (TSAT), an index that takes into account both plasma iron and its main transport protein, is considered an important biochemical marker of body iron status. Its increasing use in many health systems is due to the increased availability of measurement methods, such as calorimetry, turbidimetry, nephelometry, and immunochemistry to estimate its value. However, despite its frequent use in clinical practice to detect states of iron deficiency or iron overload, careful attention should be paid to the inherent limitations of the test especially in certain settings such as inflammation in order to avoid misinterpretation and erroneous conclusions. Beyond its usual clinical use, an emerging body of evidence has linked TSAT levels to major clinical outcomes such as cardiovascular mortality. This has the potential to extend the utility of TSAT index to risk stratification and prognostication. However, most of the current evidence is mainly driven by observational studies where the risk of residual confounding cannot be fully eliminated. Indeed, future efforts are required to fully explore this capability in well-designed clinical trials or prospective large-scale cohorts.
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Affiliation(s)
- M E Elsayed
- Graduate Entry Medical School, University of Limerick, Limerick, Ireland; University Hospital Limerick, Limerick, Ireland
| | - M U Sharif
- Graduate Entry Medical School, University of Limerick, Limerick, Ireland; University Hospital Limerick, Limerick, Ireland
| | - A G Stack
- Graduate Entry Medical School, University of Limerick, Limerick, Ireland; University Hospital Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Limerick, Ireland.
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Barton JC, Barton JC, Adams PC, Acton RT. Risk Factors for Insulin Resistance, Metabolic Syndrome, and Diabetes in 248 HFE C282Y Homozygotes Identified by Population Screening in the HEIRS Study. Metab Syndr Relat Disord 2016; 14:94-101. [PMID: 26771691 DOI: 10.1089/met.2015.0123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We sought to identify risk factors for insulin resistance, metabolic syndrome (MetS), and diabetes mellitus in 248 non-Hispanic white HFE C282Y homozygotes identified by population screening. METHODS We analyzed observations obtained prospectively in a postscreening examination: age; sex; body mass index (BMI); systolic/diastolic blood pressure; metacarpophalangeal (MP) joint hypertrophy; hepatomegaly; complete blood counts; alanine/aspartate aminotransferase levels; elevated C-reactive protein (>0.5 mg/dL); transferrin saturation; serum ferritin; homeostasis model assessment-insulin resistance (HOMA-IR); and MetS. RESULTS Twenty-six participants (10.5%) had diabetes diagnoses. A significant trend across HOMA-IR quartiles was observed only for blood neutrophils. Logistic regression on HOMA-IR fourth quartile revealed positive associations: age (P = 0.0002); male sex (P = 0.0022); and BMI (P < 0.0001). HOMA-IR fourth quartile predicted MetS (P < 0.0001). Logistic regression on diabetes revealed positive associations: age (P = 0.0012); male sex (P = 0.0068); MP joint hypertrophy (P = 0.0167); neutrophils (P = 0.0342); and MetS (P = 0.0298). Serum ferritin did not predict HOMA-IR fourth quartile, MetS, or diabetes. CONCLUSIONS In screening C282Y homozygotes, age, male sex, and BMI predicted HOMA-IR fourth quartile. HOMA-IR fourth quartile alone predicted MetS. Diabetes was associated with greater age, male sex, MP joint hypertrophy, greater blood neutrophil counts, and MetS.
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Affiliation(s)
- James C Barton
- 1 Southern Iron Disorders Center , Birmingham, Alabama.,2 Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | | | - Paul C Adams
- 3 Department of Medicine, University of Western Ontario , London, Ontario, Canada
| | - Ronald T Acton
- 1 Southern Iron Disorders Center , Birmingham, Alabama.,4 Department of Microbiology, University of Alabama at Birmingham , Alabama
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26
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Kim S, Park SK, Ryoo JH, Choi JM, Hong HP, Park JH, Suh YJ, Byoun YS. Incidental risk for diabetes according to serum ferritin concentration in Korean men. Clin Chim Acta 2015; 451:165-9. [DOI: 10.1016/j.cca.2015.09.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 09/23/2015] [Accepted: 09/23/2015] [Indexed: 10/23/2022]
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Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk. DISEASE MARKERS 2015; 2015:818570. [PMID: 26543300 PMCID: PMC4620378 DOI: 10.1155/2015/818570] [Citation(s) in RCA: 207] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/20/2015] [Indexed: 01/09/2023]
Abstract
Gamma-glutamyltransferase (GGT) is a well-established serum marker for alcohol-related liver disease. However, GGT's predictive utility applies well beyond liver disease: elevated GGT is linked to increased risk to a multitude of diseases and conditions, including cardiovascular disease, diabetes, metabolic syndrome (MetS), and all-cause mortality. The literature from multiple population groups worldwide consistently shows strong predictive power for GGT, even across different gender and ethnic categories. Here, we examine the relationship of GGT to other serum markers such as serum ferritin (SF) levels, and we suggest a link to exposure to environmental and endogenous toxins, resulting in oxidative and nitrosative stress. We observe a general upward trend in population levels of GGT over time, particularly in the US and Korea. Since the late 1970s, both GGT and incident MetS and its related disorders have risen in virtual lockstep. GGT is an early predictive marker for atherosclerosis, heart failure, arterial stiffness and plaque, gestational diabetes, and various liver diseases, including viral hepatitis, other infectious diseases, and several life-threatening cancers. We review literature both from the medical sciences and from life insurance industries demonstrating that serum GGT is a superior marker for future disease risk, when compared against multiple other known mortality risk factors.
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Vetro C, Rosso R, Palmucci S, Russello M, Colletta G, Romeo MA, Ximenes B, Romano A, Palumbo GA, Di Raimondo F. Erythrocytapheresis is a valid and safe therapeutic option in dysmetabolic iron overload syndrome. J Clin Apher 2015; 31:443-7. [PMID: 26411360 DOI: 10.1002/jca.21434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 09/10/2015] [Indexed: 11/10/2022]
Abstract
Dysmetabolic iron overload syndrome is a rare event causing hepatic impairment with serious long-term side effects. Here, we describe a case of metabolic syndrome-related hepatic iron overload that showed a rapid, effective, and safe response to erythrocytapheresis. J. Clin. Apheresis 31:443-447, 2016. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Calogero Vetro
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy.
| | - Rosamaria Rosso
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Stefano Palmucci
- Radiodiagnostic and Radiotherapy Unit, University Hospital "Policlinico-Vittorio Emanuele", Catania, Catania, Italy
| | | | - Grazia Colletta
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Maria Anna Romeo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Benedetta Ximenes
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Alessandra Romano
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Giuseppe Alberto Palumbo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Francesco Di Raimondo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
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Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:460190. [PMID: 26273621 PMCID: PMC4530215 DOI: 10.1155/2015/460190] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 12/18/2014] [Indexed: 02/06/2023]
Abstract
Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation: patatin-like phospholipase domain-containing 3 (PNPLA3) I148M gene and transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis.
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30
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Ye K, Cao C, Lin X, O'Brien KO, Gu Z. Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption. BMC Genet 2015; 16:61. [PMID: 26054392 PMCID: PMC4460683 DOI: 10.1186/s12863-015-0223-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 06/01/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. RESULTS Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. CONCLUSIONS Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.
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Affiliation(s)
- Kaixiong Ye
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
| | - Chang Cao
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
| | - Xu Lin
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate University of the Chinese Academy of Sciences, Shanghai, China.
| | | | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
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31
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Park RJ, Moon JD. Low transferrin saturation is associated with impaired fasting glucose and insulin resistance in the South Korean adults: the 2010 Korean National Health and Nutrition Examination Survey. Diabet Med 2015; 32:673-8. [PMID: 25444086 DOI: 10.1111/dme.12643] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/25/2014] [Indexed: 12/12/2022]
Abstract
AIMS The associations of transferrin saturation with diabetes have not been well evaluated and conflicting results have been reported. The purpose of this study is to examine the association of iron indices (serum ferritin and transferrin saturation) with risk of impaired fasting glucose and insulin resistance. METHODS We conducted a cross-sectional study in 2413 individuals (1150 men and 1263 women) aged 20-50 years who participated in the 2010 Korean National Health and Nutrition Examination Survey. Participants were free of diabetes, malignancy, liver cirrhosis, chronic renal failure, anaemia, pregnancy and menopause. Fasting plasma glucose, insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as the outcomes. RESULTS Impaired fasting glucose was more prevalent in the highest compared with the lowest serum ferritin quartile among men (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.20-3.24) after adjustment for multiple covariates. Following the same adjustment, impaired fasting glucose was less prevalent in the highest compared with the lowest transferrin saturation quartile among men (OR, 0.45; 95% CI, 0.25-0.80) and women (OR, 0.33; 95% CI, 0.14-0.77). Moreover, a higher ferritin level was significantly associated with higher HOMA-IR after adjusting for confounders in men. Lower transferrin saturation was also significantly associated with higher insulin levels and HOMA-IR in both sexes. CONCLUSIONS Lower transferrin saturations were associated with an increased risk of impaired fasting glucose and insulin resistance among general South Korean population.
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Affiliation(s)
- R J Park
- Department of Occupational and Environmental Medicine, Gwangyang Sarang General Hospital, Gwangyang-si, Jeollanam-do, Republic of Korea; Department of Medicine, Graduate School of Chonnam National University, Gwangju, Republic of Korea
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32
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Zaloumis SG, Allen KJ, Bertalli NA, Turkovic L, Delatycki MB, Nicoll AJ, McLaren CE, English DR, Hopper JL, Giles GG, Anderson GJ, Olynyk JK, Powell LW, Gurrin LC. Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study. J Gastroenterol Hepatol 2015; 30:719-25. [PMID: 25311314 PMCID: PMC4782752 DOI: 10.1111/jgh.12804] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/25/2014] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study. METHODS HFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation. RESULTS At baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection). CONCLUSION No documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants.
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Affiliation(s)
- Sophie G. Zaloumis
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Katrina J. Allen
- Murdoch Childrens Research Institute, Victoria, Australia,Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia,Department of Gastroenterology, Royal Children's Hospital, Victoria, Australia
| | | | - Lidija Turkovic
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Martin B. Delatycki
- Murdoch Childrens Research Institute, Victoria, Australia,Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia,Austin Health, Heidelberg, Victoria, Australia
| | | | | | - Dallas R. English
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia,Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Graham G. Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia,Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
| | - Greg J. Anderson
- QIMR Berghofer Medical Research Institute and The University of Queensland, Brisbane, Australia
| | - John K. Olynyk
- Department of Gastroenterology, Fremantle Hospital, Fremantle, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Western Australian Institute of Medical Research, Perth, Australia
| | - Lawrie W. Powell
- QIMR Berghofer Medical Research Institute and The University of Queensland, Brisbane, Australia,The University of Queensland and the Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Lyle C. Gurrin
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
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Pretorius E, Bester J, Vermeulen N, Alummoottil S, Soma P, Buys AV, Kell DB. Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics. Cardiovasc Diabetol 2015; 14:30. [PMID: 25848817 PMCID: PMC4364097 DOI: 10.1186/s12933-015-0192-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/06/2015] [Indexed: 01/14/2023] Open
Abstract
We have noted in previous work, in a variety of inflammatory diseases, where iron dysregulation occurs, a strong tendency for erythrocytes to lose their normal discoid shape and to adopt a skewed morphology (as judged by their axial ratios in the light microscope and by their ultrastructure in the SEM). Similarly, the polymerization of fibrinogen, as induced in vitro by added thrombin, leads not to the common ‘spaghetti-like’ structures but to dense matted deposits. Type 2 diabetes is a known inflammatory disease. In the present work, we found that the axial ratio of the erythrocytes of poorly controlled (as suggested by increased HbA1c levels) type 2 diabetics was significantly increased, and that their fibrin morphologies were again highly aberrant. As judged by scanning electron microscopy and in the atomic force microscope, these could be reversed, to some degree, by the addition of the iron chelators deferoxamine (DFO) or deferasirox (DFX). As well as their demonstrated diagnostic significance, these morphological indicators may have prognostic value.
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Pretorius E, Kell DB. Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases. Integr Biol (Camb) 2014; 6:486-510. [PMID: 24714688 DOI: 10.1039/c4ib00025k] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Most non-communicable diseases involve inflammatory changes in one or more vascular systems, and there is considerable evidence that unliganded iron plays major roles in this. Most studies concentrate on biochemical changes, but there are important biophysical correlates. Here we summarize recent microscopy-based observations to the effect that iron can have major effects on erythrocyte morphology, on erythrocyte deformability and on both fibrinogen polymerization and the consequent structure of the fibrin clots formed, each of which contributes significantly and negatively to such diseases. We highlight in particular type 2 diabetes mellitus, ischemic thrombotic stroke, systemic lupus erythematosus, hereditary hemochromatosis and Alzheimer's disease, while recognizing that many other diseases have co-morbidities (and similar causes). Inflammatory biomarkers such as ferritin and fibrinogen are themselves inflammatory, creating a positive feedback that exacerbates disease progression. The biophysical correlates we describe may provide novel, inexpensive and useful biomarkers of the therapeutic benefits of successful treatments.
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Affiliation(s)
- Etheresia Pretorius
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag x323, Arcadia 0007, South Africa.
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35
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Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 2014; 6:748-73. [PMID: 24549403 DOI: 10.1039/c3mt00347g] [Citation(s) in RCA: 400] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
"Serum ferritin" presents a paradox, as the iron storage protein ferritin is not synthesised in serum yet is to be found there. Serum ferritin is also a well known inflammatory marker, but it is unclear whether serum ferritin reflects or causes inflammation, or whether it is involved in an inflammatory cycle. We argue here that serum ferritin arises from damaged cells, and is thus a marker of cellular damage. The protein in serum ferritin is considered benign, but it has lost (i.e. dumped) most of its normal complement of iron which when unliganded is highly toxic. The facts that serum ferritin levels can correlate with both disease and with body iron stores are thus expected on simple chemical kinetic grounds. Serum ferritin levels also correlate with other phenotypic readouts such as erythrocyte morphology. Overall, this systems approach serves to explain a number of apparent paradoxes of serum ferritin, including (i) why it correlates with biomarkers of cell damage, (ii) why it correlates with biomarkers of hydroxyl radical formation (and oxidative stress) and (iii) therefore why it correlates with the presence and/or severity of numerous diseases. This leads to suggestions for how one might exploit the corollaries of the recognition that serum ferritin levels mainly represent a consequence of cell stress and damage.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK.
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36
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Chang JS, Lin SM, Chao JCJ, Chen YC, Wang CM, Chou NH, Pan WH, Bai CH. Serum ferritin contributes to racial or geographic disparities in metabolic syndrome in Taiwan. Public Health Nutr 2014; 17:1498-506. [PMID: 23866264 PMCID: PMC10282300 DOI: 10.1017/s1368980013001596] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 04/17/2013] [Accepted: 05/08/2013] [Indexed: 11/07/2022]
Abstract
OBJECTIVES Asians and Pacific Islanders have higher circulating serum ferritin (SF) compared with Caucasians but the clinical significance of this is unclear. There is a higher prevalence of metabolic syndrome (MetS) in Taiwanese Indigenous than Han Chinese. Genetically, Indigenous are related to Austronesians and account for 2 % of Taiwan's population. We tested the hypothesis that accumulation of Fe in the body contributes to the ethnic/racial disparities in MetS in Taiwan. DESIGN A population-based, cross-sectional study. SETTING National Nutrition and Health Survey in Taiwan and Penghu Island. SUBJECTS A total of 2638 healthy adults aged ≥19 years. Three ethnic groups were included. RESULTS Han Chinese and Indigenous people had comparable levels of SF. Austronesia origin was independently associated with MetS (OR = 2·61, 95 % CI 2·02, 3·36). After multiple adjustments, the odds for MetS (OR = 2·49, 95 % CI 1·15, 5·28) was significantly higher among Indigenous people in the highest SF tertile compared with those in the lowest tertile. Hakka and Penghu Islanders yielded the lowest risks (OR = 1·08, 95 % CI 0·44, 2·65 and OR = 1·21, 95 % CI 0·52, 2·78, respectively). Indigenous people in the highest SF tertile had increased risk for abnormal levels of fasting glucose (OR = 2·34, 95 % CI 1·27, 4·29), TAG (OR = 1·94, 95 % CI 1·11, 3·39) and HDL-cholesterol (OR = 2·10, 95 % CI 1·18, 3·73) than those in the lowest SF tertile. CONCLUSIONS Our results raise the possibility that ethnic/racial differences in body Fe store susceptibility may contribute to racial and geographic disparities in MetS.
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Affiliation(s)
- Jung-Su Chang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Shiue-Ming Lin
- Department of Public Health, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei City, Taiwan 110, Republic of China
| | - Jane C-J Chao
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Yi-Chun Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Chi-Mei Wang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Ni-Hsin Chou
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Wen-Harn Pan
- Institute of Biomedical Science, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, Republic of China
| | - Chyi-Huey Bai
- Department of Public Health, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei City, Taiwan 110, Republic of China
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Orban E, Schwab S, Thorand B, Huth C. Association of iron indices and type 2 diabetes: a meta-analysis of observational studies. Diabetes Metab Res Rev 2014; 30:372-94. [PMID: 24327370 DOI: 10.1002/dmrr.2506] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 10/29/2013] [Accepted: 10/31/2013] [Indexed: 02/06/2023]
Abstract
The literature on the role of body iron status in the development of type 2 diabetes (T2D) in humans is inconsistent. We aimed to assess the association between iron indices and T2D by a meta-analysis of previously published studies. A systematic literature search was conducted in PubMed and EMBASE. Observational studies on the association of ferritin (when controlled for age and sex), transferrin saturation, soluble transferrin receptor and transferrin with T2D were included. Pooled association estimates were calculated using a random effects model. Forty-six eligible studies were identified. The pooled multivariable adjusted relative risks of T2D in the highest versus lowest quartile of ferritin levels were significantly elevated in both cross-sectional as well as prospective studies and after restriction to inflammation-adjusted studies [overall: 1.67 (95% CI 1.41-1.99)]. The mean difference indicated 43.54 ng/mL (95% CI 28.14-58.94) higher ferritin levels in type 2 diabetic individuals. The relative risk for a transferrin saturation ≥ 50% was 1.59 (95% CI 1.28-1.97), the mean difference was -1.92% [95% CI -2.99-(-0.85)]. Study-specific results of soluble transferrin receptor and transferrin levels were extremely heterogeneous. Ferritin and clinically elevated transferrin saturation were strongly associated with an increased risk of T2D, overall and in prospective studies. Ferritin was also significantly associated after multivariable adjustment including inflammation. Thus, the current evidence hints at a causal effect; however, publication bias and unmeasured confounding cannot be excluded.
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Gupta M, Palta A, Singh R, Lehl SS. Body iron stores in middle-aged North Indian patients with type 2 diabetes and obesity. J Midlife Health 2014; 5:72-7. [PMID: 24970985 PMCID: PMC4071648 DOI: 10.4103/0976-7800.133991] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Introduction: Evidence from various epidemiological and clinical studies suggests that iron overload is proinflammatory and proatherosclerotic. Excess body iron has been positively associated with insulin resistance, type 2 diabetes and obesity. Aim of the Study: To study the relationship of body iron stores with type 2 diabetes and obesity in middle aged North Indian population. Materials and Methods: The participant population consisted of four groups of randomly selected participants (between 40 and 65 years of age and postmenopausal women); Group A: Normal individuals (controls), Group B: Obese nondiabetic individuals, Group C: Lean diabetic patients, Group D: Obese diabetic patients. Blood was examined for hematological, biochemical estimations, C-reactive protein, and serum ferritin (SF). Observation and Results: A total of 197 participants were enrolled. The mean SF levels (ng/ml) among males were: Group A (n = 18) 148.56 ± 119.90; Group B (n = 25) 129.11 ± 94.77; Group C (n = 27) 127.96 ± 109.65 and Group D (n = 22) 148.36 ± 104.94. The mean SF levels (ng/ml) among females were: Group A (n = 23) 67.44 ± 37.59; Group B (n = 25) 59.62 ± 43.56; Group C (n = 24) 77.97 ± 91.46 and Group D (n = 33) 66.46 ± 86.05. No statistical difference was found among the groups in both the sexes. Conclusions: Our observation is in sharp contrast to the earlier studies published from the West stressing that iron stores are increased in obesity and diabetes. We conclude that SF may not be a strong risk factor in the pathogenesis of obesity and diabetes in middle aged North Indians.
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Affiliation(s)
- Monica Gupta
- Department of Medicine, Government Medical College and Hospital, Chandigarh, India
| | - Anshu Palta
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Ram Singh
- Department of Medicine, Government Medical College and Hospital, Chandigarh, India
| | - Sarabmeet Singh Lehl
- Department of Medicine, Government Medical College and Hospital, Chandigarh, India
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HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 µg/L. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:390-2. [PMID: 23862168 DOI: 10.1155/2013/493170] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Many patients referred for an elevated serum ferritin level <1000 µg⁄L are advised that they likely have iron overload and hemochromatosis. AIMS To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 µg⁄L to 1000 µg⁄L in Caucasian participants in a primary care, population-based study. METHODS The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation. RESULTS There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 µg⁄L to 1000 µg⁄L for women, 300 µg⁄L to 1000 µg⁄L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women. CONCLUSIONS Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.
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Pretorius E, Bester J, Vermeulen N, Lipinski B, Gericke GS, Kell DB. Profound morphological changes in the erythrocytes and fibrin networks of patients with hemochromatosis or with hyperferritinemia, and their normalization by iron chelators and other agents. PLoS One 2014; 9:e85271. [PMID: 24416376 PMCID: PMC3887013 DOI: 10.1371/journal.pone.0085271] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 11/25/2013] [Indexed: 12/22/2022] Open
Abstract
It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise.
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Affiliation(s)
- Etheresia Pretorius
- Department of Physiology, University of Pretoria, Arcadia, South Africa
- * E-mail:
| | - Janette Bester
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Natasha Vermeulen
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Boguslaw Lipinski
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | | | - Douglas B. Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, Lancs, United Kingdom
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Khan AR, Awan FR. Metals in the pathogenesis of type 2 diabetes. J Diabetes Metab Disord 2014; 13:16. [PMID: 24401367 PMCID: PMC3916582 DOI: 10.1186/2251-6581-13-16] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 12/30/2013] [Indexed: 12/15/2022]
Abstract
Minerals are one of the components of food, though they are not synthesized in the body but they are essential for optimal health. Several essential metals are required for the proper functioning of many enzymes, transcriptional factors and proteins important in various biochemical pathways. For example Zn, Mg and Mn are cofactors of hundreds of enzymes, and Zn is involved in the synthesis and secretion of insulin from the pancreatic beta-cells. Similarly, Cr enhances the insulin receptor activity on target tissues, especially in muscle cells. Insulin is the key hormone required to maintain the blood glucose level in normal range. In case of insulin deficiency or resistance, blood glucose concentration exceeds the upper limit of the normal range of 126 mg/dl. Persistent increase of blood serum glucose level leads to overt chronic hyperglycemia, which is a major clinical symptom of diabetes mellitus. Poor glycemic control and diabetes alters the levels of essential trace elements such as Zn, Mg, Mn, Cr, Fe etc. by increasing urinary excretion and their concomitant decrease in the blood. Hence, the main purpose of this review is to discuss the important roles of essential trace elements in normal homeostasis and physiological functioning. Moreover, perturbation of essential trace elements is also discussed in perspective of type 2 diabetes pathobiology.
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Affiliation(s)
| | - Fazli Rabbi Awan
- Diabetes and Cardio-Metabolic Disorder (D&C-MD) Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Jhang Road, Faisalabad, P,O, Box,577, Pakistan.
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Abstract
The common form of hereditary hemochromatosis is an autosomal recessive disorder most prevalent in Caucasians that results in excessive iron storage. The clinical manifestations of hemochromatosis are protean. HFE genotype, which determines the degree of iron overload and duration of disease have profound effects on disease expression. The prevalence of diabetes in this population has likely been underestimated because of studies that include a broad range of ethnicities and associating diabetes with allele frequency in spite of the decreased risk of diabetes in heterozygotes compared with homozygotes. Loss of insulin secretory capacity is likely the primary defect contributing to development of diabetes with insulin resistance playing a secondary role. Phlebotomy can ameliorate the defects in insulin secretion if initiated early. Screening a select population of individuals with type 2 diabetes may identify patients with hemochromatosis early and substantially impact individual clinical outcomes.
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Affiliation(s)
- T Creighton Mitchell
- Department of Medicine, Division of Endocrinology, University of Utah, 15 North 2030 East, Salt Lake City, UT, 84108, USA
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Dekker LH, Nicolaou M, van der A DL, Busschers WB, Brewster LM, Snijder MB, Stronks K, van Valkengoed IGM. Sex differences in the association between serum ferritin and fasting glucose in type 2 diabetes among South Asian Surinamese, African Surinamese, and ethnic Dutch: the population-based SUNSET study. Diabetes Care 2013; 36:965-71. [PMID: 23172974 PMCID: PMC3609507 DOI: 10.2337/dc12-1243] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Moderately elevated iron stores below the levels commonly associated with hemochromatosis have been implicated in the etiology of diabetes. Studies suggest that iron status (measured by serum ferritin) differs significantly according to sex, but inconsistent findings have been reported. Our aim is to test the association between serum ferritin and the prevalence of type 2 diabetes and fasting glucose concentrations in a population-based, multiethnic, cross-sectional study including men and women of African Surinamese, South Asian Surinamese, and ethnic Dutch origin. RESEARCH DESIGN AND METHODS We analyzed data on 508 ethnic Dutch, 597 African Surinamese, and 339 South Asian Surinamese aged 35-60 years. Type 2 diabetes was defined as a fasting plasma glucose level ≥7.0 mmol/L or a self-reported diagnosis. RESULTS Serum ferritin was positively associated with type 2 diabetes and fasting glucose, but differences in the associations according to sex were observed. Serum ferritin concentration was positively associated with type 2 diabetes among women in all ethnic groups (odds ratio [OR] ethnic Dutch: 1.07 [95% CI 1.01-1.13]; OR South Asian Surinamese: 1.05 [1.00-1.10]; OR African Surinamese: 1.05 [1.01-1.10]), but not among men. Serum ferritin was also more strongly associated with fasting glucose in women than in men. Moreover, the magnitude of sex differences in the association between serum ferritin and fasting glucose, but not type 2 diabetes, was more pronounced in the African Surinamese group than in the other ethnic groups (P for interaction ≤0.0001). CONCLUSIONS We found a positive association between serum ferritin and type 2 diabetes and fasting glucose in our multiethnic population, which appeared stronger among women than men. Further evaluation of the variation in sex differences between ethnic groups is warranted, particularly among the African Surinamese, to understand the mechanisms behind these sex differences.
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Affiliation(s)
- Louise H Dekker
- Department of Public Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of U.S. adults. Clin Nutr 2012; 32:1055-60. [PMID: 23312547 DOI: 10.1016/j.clnu.2012.11.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 11/19/2012] [Accepted: 11/26/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Iron overload is known to cause diabetes. However, the underlying mechanism is poorly understood. We therefore studied the association of different markers of iron metabolism, namely ferritin, erythrocyte protoporphyrin and transferrin saturation (TSAT, as defined by a percentage of transferrin that is saturated with iron) with pre-diabetes (preDM) in US adults without chronic kidney disease, anemia, and iron deficiency. METHODS Data on 2575 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 who were free of diabetes, chronic kidney disease, iron deficiency, and anemia were analyzed. Data on 3876 participants of the NHANES III (1988-1994) were used as replication. Homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level (HbA1C), fasting glucose, insulin, and preDM (defined as a fasting plasma glucose 100-125 mg/dl or an HBA1C value 5.7-6.4%) were measured as the outcomes. RESULTS Logistic regression analyses indicated independent associations of high ferritin (Ptrend = 0.028) and low TSAT (P(trend) = 0.029) with preDM after adjusting for sociodemographics, physical activity (active/sedementary), metabolic and inflammatory markers (triglycerides, total cholesterol, HDL cholesterol, mean arterial pressure, CRP, white cell count, and albumin), and liver enzymes (GGT, Alk phos, AST, and ALT). The NHANES III data showed similar associations. Combining the results showed a more significant association for high ferritin (P(meta) = 0.016) and low TSAT (P(meta) = 0.002). Moreover, TSAT was associated with HbA1C, fasting glucose, insulin, and HOMA-IR (P(meta) ≤ 0.001). CONCLUSIONS Higher ferritin and lower TSAT are associated with higher risk of preDM in a general population without confounding diseases. Further research is needed to examine the underlying mechanism of these two indices, especially TSAT, in the pathophysiology of preDM.
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Bao W, Rong Y, Rong S, Liu L. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med 2012; 10:119. [PMID: 23046549 PMCID: PMC3520769 DOI: 10.1186/1741-7015-10-119] [Citation(s) in RCA: 183] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Accepted: 10/10/2012] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Excess iron has been shown to induce diabetes in animal models. However, the results from human epidemiologic studies linking body iron stores and iron intake to the risk of type 2 diabetes mellitus (T2DM) are conflicting. In this study, we aimed to systematically evaluate the available evidence for associations between iron intake, body iron stores, and the risk of T2DM. METHODS A systematic search of the PubMed/MEDLINE and EMBASE databases to the end of 22 April 2012 was performed, and reference lists of retrieved articles were screened. Two reviewers independently evaluated the eligibility of inclusion and extracted the data. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS We reviewed 449 potentially relevant articles, and 11 prospective studies were included in the analysis. A meta-analysis of five studies gave a pooled RR for T2DM of 1.33 (95% CI 1.19 to 1.48; P<0.001) in individuals with the highest level of heme iron intake, compared with those with the lowest level. The pooled RR for T2DM for a daily increment of 1 mg of heme iron intake was 1.16 (1.09 to 1.23, P<0.001). Body iron stores, as measured by ferritin, soluble transferrin receptor (sTfR) and the sTfR:ferritin ratio, were significantly associated with the risk of T2DM. The pooled RRs for T2DM in individuals with the highest versus the lowest intake of ferritin levels was 1.70 (1.27-2.27, P<0.001) before adjustment for inflammatory markers and 1.63 (1.03-2.56, P = 0.036) after adjustment. We did not find any significant association of dietary intakes of total iron, non-heme, or supplemental iron intake with T2DM risk. CONCLUSION Higher heme iron intake and increased body iron stores were significantly associated with a greater risk of T2DM. Dietary total iron, non-heme iron, or supplemental iron intakes were not significantly associated with T2DM risk.
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Affiliation(s)
- Wei Bao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, P,R, China
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Kim MH, Bae YJ. Postmenopausal vegetarians' low serum ferritin level may reduce the risk for metabolic syndrome. Biol Trace Elem Res 2012; 149:34-41. [PMID: 22528775 DOI: 10.1007/s12011-012-9405-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Accepted: 03/26/2012] [Indexed: 11/24/2022]
Abstract
The present study was conducted to compare the serum ferritin status between the postmenopausal vegetarians and non-vegetarians and to identify the relation of serum ferritin with metabolic syndrome (MetS) risk factors in postmenopausal women. The two study groups consisted of postmenopausal vegetarians (n=59) who maintained a vegetarian diet for over 20 years and age-matched non-vegetarian controls (n=48). Anthropometric measurements, dietary intakes, serum metabolic syndrome-related parameters, and serum ferritin level between the two groups were compared. The vegetarians exhibited significantly lower weight (p<0.01), body mass index (BMI) (p<0.001), percentage of body fat (p<0.001), waist circumference (p<0.01), SBP (p<0.001), DBP (p<0.001), and fasting glucose (p<0.05). According to the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III criteria for MetS applying Korean guidelines for waist circumference, the prevalence of MetS was lower in vegetarians (33.9 %) than in non-vegetarians (47.9 %). Vegetarians had significantly lower serum level of ferritin (p<0.01) than non-vegetarians. In the correlation analysis, serum ferritin was positively related to fasting glucose (r=0.264, p<0.01), triglycerides (r=0.232, p<0.05), and the NCEP score (r=0.214, p<0.05) and negatively related to high-density lipoprotein-cholesterol (r=-0.225, p<0.05) after adjusting for BMI, lifestyle, and dietary factors (animal protein, animal fat, and dietary fiber intake). In conclusion, postmenopausal vegetarians had lower MetS presence and a lower serum ferritin level compared to non-vegetarians. Furthermore, vegetarians' low serum ferritin level may reduce the risk of MetS in postmenopausal women.
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Affiliation(s)
- Mi-Hyun Kim
- Department of Food and Nutrition, Kangwon National University, Samcheok 245-711, South Korea.
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Manco M, Fernandez-Real JM. Back to past leeches: repeated phlebotomies and cardiovascular risk. BMC Med 2012; 10:53. [PMID: 22647488 PMCID: PMC3409018 DOI: 10.1186/1741-7015-10-53] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 05/30/2012] [Indexed: 11/30/2022] Open
Abstract
In patients with metabolic syndrome, body iron overload exacerbates insulin resistance, impairment of glucose metabolism, endothelium dysfunction and coronary artery responses. Conversely, iron depletion is effective to ameliorate glucose metabolism and dysfunctional endothelium. Most of its effectiveness seems to occur through the amelioration of systemic and hepatic insulin resistance. In a study published by BMC Medicine, Michalsen et al. demonstrated a dramatic improvement of blood pressure, serum glucose and lipids after removing 550 to 800 ml of blood in subjects with metabolic syndrome. This effect was apparently independent of changes in insulin resistance, in contrast to previous cross-sectional and cohort studies investigating the association between iron overload, insulin resistance and cardiovascular disease. Despite drawbacks in the study design, its findings may lead the way to investigations aimed at exploring iron-dependent regulatory mechanisms of vascular tone in healthy individuals and patients with metabolic disease, thus providing a rationale for novel preventive and therapeutic strategies to counteract hypertension. Please see related article: http://www.biomedcentral.com/1741-7015/10/54.
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Affiliation(s)
- Melania Manco
- Bambino Gesù Children's Hospital and Research Institute, Research Unit for Multifactorial Disease, Rome, Italy.
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Kolberg JA, Gerwien RW, Watkins SM, Wuestehube LJ, Urdea M. Biomarkers in Type 2 diabetes: improving risk stratification with the PreDx ® Diabetes Risk Score. Expert Rev Mol Diagn 2012; 11:775-92. [PMID: 22022939 DOI: 10.1586/erm.11.63] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Type 2 diabetes is a chronic, debilitating and often deadly disease that has reached epidemic proportions. The onset of diabetes can be delayed or prevented in high-risk individuals by diet and lifestyle changes and medications, and hence a key element for addressing the diabetes epidemic is to identify those most at risk of developing diabetes so that preventative measures can be effectively focused. The PreDx(®) Diabetes Risk Score is a multimarker tool for assessing a patient's risk of developing diabetes within the next 5 years. Requiring a simple blood draw using standard sample collection and handling procedures, the PreDx Diabetes Risk Score is easily implemented in clinical practice and provides an assessment of diabetes risk that is superior to other measures, including fasting plasma glucose, glycated hemoglobin, measures of insulin resistance and other clinical measures. In this article, we provide an overview of the PreDx Diabetes Risk Score.
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Affiliation(s)
- Janice A Kolberg
- Tethys Bioscience, 5858 Horton Street, Suite 280, Emeryville, CA 94608, USA.
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Gan W, Guan Y, Wu Q, An P, Zhu J, Lu L, Jing L, Yu Y, Ruan S, Xie D, Makrides M, Gibson RA, Anderson GJ, Li H, Lin X, Wang F. Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. Am J Clin Nutr 2012; 95:626-32. [PMID: 22301935 DOI: 10.3945/ajcn.111.025684] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Transmembrane protease serine 6 (TMPRSS6) regulates iron homeostasis by inhibiting the expression of hepcidin. Multiple common variants in TMPRSS6 were significantly associated with serum iron in recent genome-wide association studies, but their effects in the Chinese remain to be elucidated. OBJECTIVE The objective was to determine whether the TMPRSS6 single nucleotide polymorphisms (SNPs) rs855791(V736A) and rs4820268(D521D) were associated with blood hemoglobin and plasma ferritin concentrations and risk of type 2 diabetes in Chinese individuals. DESIGN The SNPs rs855791(V736A) and rs4820268(D521D) in the TMPRSS6 gene were genotyped and tested for their associations with plasma iron and type 2 diabetes risk in 1574 unrelated Chinese Hans from Beijing. RESULTS The 2 TMPRSS6 SNPs rs855791(V736A) and rs4820268(D521D) were both significantly associated with plasma ferritin (P ≤ 0.0058), hemoglobin (P ≤ 0.0013), iron overload risk (P ≤ 0.0068), and type 2 diabetes risk (P ≤ 0.0314). None of the associations with hemoglobin or plasma ferritin remained significant (P ≥ 0.1229) when the 2 variants were both included in one linear regression model. A haplotype carrying both iron-lowering alleles from the 2 TMPRSS SNPs showed significant associations with lower hemoglobin (P = 0.0014), lower plasma ferritin (P = 0.0027), and a reduced risk of iron overload (P = 0.0017) and of type 2 diabetes (P = 0.0277). CONCLUSIONS These findings suggest that TMPRSS6 variants were significantly associated with plasma ferritin, hemoglobin, risk of iron overload, and type 2 diabetes in Chinese Hans. The type 2 diabetes risk conferred by the TMPRSS6 SNPs is possibly mediated by plasma ferritin.
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Affiliation(s)
- Wei Gan
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China
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