Cited by 176Iron Metabolism and DisordersHemoglobinopathies and Related DisordersTrace Elements in Health

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Potential Role of Increased Iron Stores in Diabetes

Wilson, James G., Maher, Joseph F., Lindquist, Jennifer Hoff, Grambow, Steven C., Crook, Errol D.·2003·The American Journal of the Medical Sciences

DOI 10.1097/00000441-200306000-00004

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Abstract

Diabetes mellitus (DM) is an important risk factor for the development of cardiovascular disease. Extensive clinical, epidemiologic, and basic studies suggest that excessive tissue iron stores may contribute to the occurrence and complications of DM. Secondary diabetes occurs in inherited pathologic iron overload syndromes of European- and African-derived populations and is an established complication of transfusional iron overload. Epidemiologic studies have repeatedly shown positive correlation between levels of serum ferritin and those of fasting glucose, insulin, and glycosylated hemoglobin. Iron reduction therapy in hereditary hemochromatosis and transfusional iron overload is associated with improved glucose tolerance and reduced incidence of secondary diabetes. Trials of iron reduction therapy in diabetes mellitus, although limited and inconclusive, have shown clinical improvement in some patients. The current article reviews evidence suggesting that tissue iron contributes to DM and its complications and presents preliminary data that emphasize the potential importance of iron overload in DM of African Americans.

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“In addition, iron overload may contribute initially to insulin resistance and subsequently to decreased insulin secretion and ultimately result in diabetes.(18) This is confirmed by the evidence of reduced hyperinsulinemia in the presence of iron depletion.”
Background
Relationship between Serum Ferritin Levels and Sarcopenia in Korean Females Aged 60 Years and Older Using the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV-2, 3), 2008–2009
Kim, T. H., Hwang, H., & Kim, S.-H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090105 · Cited by 39
“Under oxidative stress, elevated serum ferritin may promote abnormal insulin secretion by pancreatic b-cells and impairment of insulin extraction by the liver [17,18].”
Background
Iron Overload Protects from Obesity by Ferroptosis
Wan, M., Jia, L., Xiong, Q., & Du, H. (2021) · Foods · doi:10.3390/foods10081787 · Cited by 36
“Moreover, the insulin receptor is a critical component of insulin signal transduction, and its malfunction is thought to be the fundamental cause of T2DM [17].”
BackgroundInfluential
Elevated serum tumor necrosis factor alpha and ferritin may contribute to the insulin resistance found in HCV positive Egyptian patients
Elsammak, M., Refai, W., Elsawaf, A., Abdel-Fattah, I., Elatti, E. A., & Ghazal, A. A. E. R. (2005) · Current Medical Research and Opinion · doi:10.1185/030079905x38141 · Cited by 35
Diabetes mellitus concurrent with hepatic haemosiderosis in two macaws (Ara severa, Ara militaris)
Gancz, A. Y., Wellehan, J. F. X., Boutette, J., Malka, S., Lee, S. E., Smith, D. A., & Taylor, M. (2007) · Avian Pathology · doi:10.1080/03079450701466093 · Cited by 35
“In humans, EIS is strongly associated with DM (Wilson et al., 2003; Platis et al., 2004).”
Background
Evaluation of trace elements and oxidative stress levels in the liver and kidney of streptozotocin-induced experimental diabetic rat model
Özçelik, D., Tunçdemi̇r, M., Öztürk, M., & Uzun, H. (2011) · General Physiology and Biophysics · doi:10.4149/gpb_2011_04_356 · Cited by 34
Key Nutrients for Optimal Blood Glucose Control and Mental Health in Individuals with Diabetes: A Review of the Evidence
Basiri, R., Seidu, B., & Cheskin, L. J. (2023) · Nutrients · doi:10.3390/nu15183929 · Cited by 34
“Excessive iron intake has consistently been found to increase ferritin, insulin resistance, and glycosylated hemoglobin, and may also increase diabetes complications [186].”
Background
Glucose abnormalities in non‐alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload
Lecube, A., Hernández, C., & Simó, R. (2009) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.972 · Cited by 33
Gastrointestinal Complications of Diabetes Mellitus
Ebert, E. C. (2005) · Disease-a-Month · doi:10.1016/j.disamonth.2005.11.002 · Cited by 33
Glucose metabolism after normalization of markers of iron overload by venesection in subjects with hereditary hemochromatosis
Hatunic, M., Finucane, F. M., Norris, S., Pacini, G., & Nolan, J. J. (2010) · Metabolism · doi:10.1016/j.metabol.2010.06.005 · Cited by 33
“Studies have shown that iron deposition in muscle decreases glucose uptake because of muscle damage and affects insulin synthesis and secretion in the pancreas [30].”
Background
Active-Site Environment of Copper-Bound Human Amylin Relevant to Type 2 Diabetes
Seal, M., & Dey, S. G. (2017) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.7b02266 · Cited by 32
Mineral Elements Content of Selected Kenyan Antidiabetic Medicinal Plants
Arika, W. M., & Ogola, P. E. (2015) · Advanced Techniques in Biology & Medicine · doi:10.4172/2379-1764.1000160 · Cited by 31
“Iron interferes with insulin inhibition of glucose production by the liver [35].”
Background
Sex Differences in the Association Between Serum Ferritin and Fasting Glucose in Type 2 Diabetes Among South Asian Surinamese, African Surinamese, and Ethnic Dutch
Dekker, L. H., Nicolaou, M., van der A, D. L., Busschers, W. B., Brewster, L. M., Snijder, M. B., Stronks, K., & van Valkengoed, I. G. M. (2012) · Diabetes Care · doi:10.2337/dc12-1243 · Cited by 30
Serum ferritin level is higher in male adolescents with obesity: results from the Korean National Health and Nutrition Examination Survey 2010
Jeon, Y. J., Jung, I. A., Kim, S. H., Cho, W. K., Jeong, S. H., Cho, K. S., Park, S. H., Jung, M. H., & Suh, B. (2013) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2013.18.3.141 · Cited by 30
Serum ferritin levels and the development of metabolic syndrome and its components: a 6.5-year follow-up study
Hämäläinen, P., Saltevo, J. T., Kautiainen, H., Mäntyselkä, P. T., & Vanhala, M. J. (2014) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-6-114 · Cited by 29
“Elevated body iron stores could promote oxidative stress, and in this manner affect the pathogenesis of insulin resistance [4-6].”
Background
Metabolic syndrome: A review of emerging markers and management
Singh, B. K., Arora, S., Goswami, B., & Mallika, V. (2009) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2009.04.012 · Cited by 29
Relationship between Serum Ferritin Levels and Dyslipidemia in Korean Adolescents
Kim, Y., Kim, D., Roh, Y. K., Ju, S.-Y., Yoon, Y.-J., Nam, G. E., Nam, H.-Y., Choi, J.-S., Lee, J.-E., Sang, J.-E., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153167 · Cited by 29
“In addition, iron is a transition metal capable of causing oxidative stress-induced tissue damage by catalyzing the conversion of hydrogen peroxide to free radicals that attack cellular membranes, proteins, and DNA [1,8,12,33], leading to derangements in glucose homeostasis such as insulin resistance and pancreatic β-…”
Background
High serum ferritin levels are associated with metabolic risk factors in non‐obese Korean young adults: Korean National Health and Nutrition Examination Survey (KNHANES) IV
Yoo, K., Ko, S., Park, J., Ahn, Y., Yim, H. W., Lee, W., & Park, Y. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04248.x · Cited by 28
Serum ferritin concentration in gestational diabetes mellitus and risk of subsequent development of early postpartum diabetes mellitus
Sharifi, F., Ziaee, V., Feizy, Mousavinasab, S. N. A. D., Anjomshoaa, & Mokhtari, M. (2010) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmsott.s15049 · Cited by 39
“Whether this association is independent of BMI is not clear.(1,2,14,17) Few data regarding the correlation of ferritin levels and body fat during pregnancy have been reported.”
Prevalence, Characteristics, and Prognostic Significance of HFE Gene Mutations in Type 2 Diabetes
Davis, T. M. E., Beilby, J. P., Davis, W. A., Olynyk, J. K., Jeffrey, G. P., Rossi, E., Boyder, C., & Bruce, D. G. (2008) · Diabetes Care · doi:10.2337/dc08-0248 · Cited by 27
“Hyperglycemia, and other effects of excess tissue iron including oxidant stress, angiogenesis and fibrosis (4-6), could promote the development of complications such as nephropathy (7,8).”
Serum Ferritin Levels Are Positively Associated With Metabolically Obese Normal Weight
Kim, J. W., Kim, D., Roh, Y. K., Ju, S.-Y., Nam, H.-Y., Nam, G. E., Kim, D.-W., Lee, S.-H., Lee, C.-W., Han, K., et al. (2015) · Medicine · doi:10.1097/md.0000000000002335 · Cited by 29
“hyperinsulinemia in the early phase of insulin resistance, and it inhibits the production of insulin as a more advanced phase is entered.(14,15) Iron acts as a catalyst for more reactive hydroxyl radicals and as an oxidative stress at multiple cellular targets.”
Background
Comparative Study of Serum Copper, Iron, Magnesium, and Zinc in Type 2 Diabetes-Associated Proteinuria
Khan, F. A., Al‐Jameil, N., Arjumand, S., Khan, M. F., Tabassum, H., Alenzi, N., Hijazy, S. M., Alenzi, S., Subaie, S., & Fatima, S. (2015) · Biological Trace Element Research · doi:10.1007/s12011-015-0379-3 · Cited by 28
Genome-wide admixture and association study of serum iron, ferritin, transferrin saturation and total iron binding capacity in African Americans
Li, J., Lange, L. A., Duan, Q., Lu, Y., Singleton, A., Zonderman, A. B., Evans, M. K., Li, Y., Taylor, H. A., Willis, M. S., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu454 · Cited by 26
“Genetic factors could affect iron metabolism through gastrointestinal absorption, transport, tissue uptake, storage or remobilization from tissue stores, and thus could have a large impact on the variation of these iron-related measures (2,3).”
BackgroundSelf-citation
Adipose Tissue Transferrin and Insulin Resistance
McClain, D. A., Sharma, N., Jain, S., HARRISON, A. V., Salaye, L., Comeau, M. E., Langefeld, C. D., Lorenzo, F., & Das, S. K. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00770 · Cited by 28
A Prospective Study of Magnesium and Iron Intake and Pancreatic Cancer in Men
Kesavan, Y., Giovannucci, E. L., Fuchs, C. S., & Michaud, D. S. (2009) · American Journal of Epidemiology · doi:10.1093/aje/kwp373 · Cited by 26
“Iron may also be related to insulin resistance since direct iron deposition in b-cells in the pancreas can impair insulin secretion (50).”
Background
Telomere length and elevated iron: The influence of phenotype and HFE genotype
Mainous, A. G., Wright, R. U., Hulihan, M., Twal, W. O., McLaren, C. E., Díaz, V. A., McLaren, G. D., Argraves, W. S., & Grant, A. M. (2013) · American Journal of Hematology · doi:10.1002/ajh.23438 · Cited by 26
“These variables may be in the causal pathway between elevated iron and telomere length [37,53,54].”
Plasma ferritin, C-reactive protein, and risk of incident type 2 diabetes in Singapore Chinese men and women
Wang, Y., Koh, W., Yuan, J., & Pan, A. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.04.012 · Cited by 25
Update on Diabetes Mellitus
Korc, M. (2004) · Disease Markers · doi:10.1155/2004/945073 · Cited by 25
“It has been suggested that increased iron stores in general may lead to an increased propensity to T2DM [47], and that both chronic pancreatitis and pancreatic cancer may be associated with a significant”
Serum Levels of Visfatin and Possible Interaction with Iron Parameters in Gestational Diabetes Mellitus
Kaygusuz, İ., Gümüş, İ. İ., Yılmaz, S., Simavlı, S. A., Uysal, S., Derbent, A. U., Gözdemir, E., & Kafalı, H. C. (2013) · Gynecologic and Obstetric Investigation · doi:10.1159/000348560 · Cited by 25
Higher serum ferritin level and lower femur neck strength in women at the stage of bone loss (≥ 45 years of age): The Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV)
Ahn, S. H., Lee, S., Kim, H., Lee, S. H., Kim, B., & Koh, J. (2016) · Endocrine Research · doi:10.3109/07435800.2016.1155600 · Cited by 23
“Iron is a catalyst for the formation of hydroxyl radicals, which are powerful oxidants that attack cellular membrane lipids, proteins, and nucleic acids, resulting in tissue damage (36,37) and contributing to the pathogenesis of various diseases, such as insulin resistance (38).”
Background
Relevance of the ability of fructose 1,6-bis(phosphate) to sequester ferrous but not ferric ions
Bajić, A., Zakrzewska, J., Gođevac, D. M., Anđjus, P. R., Jones, D. R., Spasić, M. B., & Spasojević, I. (2010) · Carbohydrate Research · doi:10.1016/j.carres.2010.12.008 · Cited by 23
The Impact of Obesity and Insulin Resistance on Iron and Red Blood Cell Parameters: A Single Center, Cross-Sectional Study
Altunoğlu, E., Müderrisoğlu, C., Erdenen, F., Ülgen, E., & Ar, M. C. (2013) · Turkish Journal of Hematology · doi:10.4274/tjh.2012.0187 · Cited by 22
“In addition, iron is a potent pro-oxidant that increases cellular oxidative stress, causing inhibition of insulin internalization and action, which results in hyperinsulinemia, IR, and abnormal β-cell function through iron toxicity [16,20,21,22,23,24,25].”
Background
Association of maternal iron deficiency anemia with the risk of gestational diabetes mellitus: a meta-analysis
Tiongco, R. E., Arceo, E. S., Clemente, B., & Pineda-Cortel, M. R. (2018) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-018-4932-0 · Cited by 25
The relationship between serum ferritin and metabolic syndrome in healthy Korean men
Ryoo, J., Kim, M., Lee, D., & Shin, J. (2011) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1211 · Cited by 22
“Others have suggested that iron deposition in pancreatic β-cells may also impair insulin secretion in more advanced states of iron overload [21].”
Background
Association between Serum Ferritin and Circulating Oxidized Low-density Lipoprotein Levels in Patients with Type 2 Diabetes
Ikeda, Y., Suehiro, T., Yamanaka, S., Kumon, Y., Takata, H., Inada, S., Ogami, N., Osaki, F., Inoue, M., Arii, K., et al. (2006) · Endocrine Journal · doi:10.1507/endocrj.k06-010 · Cited by 22
“There are some reports suggesting a significant influence of tissue iron excess on the development of diabetic nephropathy and vascular dysfunction [22, 23].”
Background
Association between Serum Ferritin and Osteocalcin as a Potential Mechanism Explaining the Iron-Induced Insulin Resistance
Juanola‐Falgarona, M., Fernández‐Cao, J. C., Salas‐Salvadó, J., Martínez‐González, M. Á., Estruch, R., Fiol, M., Arija, V., Bulló, M., & for the PREDIMED Study Investigators (2013) · PLoS ONE · doi:10.1371/journal.pone.0076433 · Cited by 21
“Iron deposition in the muscle decreases glucose uptake due to muscle damage [18] and it has additionally been suggested that iron deposition in pancreatic b-cells impairs insulin secretion in more advanced states of iron overload [19].”
Background
Mitochondrial response to oxidative and nitrosative stress in early stages of diabetes
Noriega‐Cisneros, R., Cortés‐Rojo, C., Manzo‐Ávalos, S., Clemente‐Guerrero, M., Calderón‐Cortés, E., Salgado‐Garciglia, R., Montoya-Pérez, R. D. C., Boldogh, I. R., & Saavedra‐Molina, A. (2013) · Mitochondrion · doi:10.1016/j.mito.2013.05.012 · Cited by 21
“It has been suggested that this phenomenon may be implicated in the development of diabetes (Kell, 2009; Wilson et al., 2003).”
Background
Study of the correlation between serum ferritin levels and the aggregation of metabolic disorders in non-diabetic elderly patients
Li, B., Lin, W. G., Lin, N., Dong, X., & Liu, L. (2014) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2014.1668 · Cited by 21
“association between iron protein and inflammation has been confirmed by many studies and numerous scholars consider that ferritin may be an inflammatory factor (5,9,14,15).”
BackgroundInfluential
Hemochromatosis
Adams, P. C. (2004) · Clinics in Liver Disease · doi:10.1016/j.cld.2004.06.002 · Cited by 20
Cluster and Factor Analysis of Elements in Serum and Urine of Diabetic Patients with Peripheral Neuropathy and Healthy People
Guo, W., Zhou, Q., Jia, Y., & Xu, J. (2019) · Biological Trace Element Research · doi:10.1007/s12011-019-01747-x · Cited by 21

Authors: Wilson, J. G., Maher, J. F., Lindquist, J. H., Grambow, S. C., & Crook, E. D.
Affiliations: University of Mississippi Medical Center (US)
Durham VA Medical Center (US)
Duke Medical Center (US)
Wayne State University (US)
Corresponding author: Wilson, James G.
ORCID: Wilson, James G.
Maher, Joseph F.
Grambow, Steven C.
Venue: The American Journal of the Medical Sciences
Publisher: Elsevier BV
Published: 2003-06
Volume: 325
Issue: 6
Pages: 332-339
ISSN: 0002-9629 (ISSN-L)
DOI: 10.1097/00000441-200306000-00004
OpenAlex: W2015938505
Cited by: 176
References: 63
Citations by year: 2025: 4 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 10 · 2015: 12 · 2014: 15 · 2013: 17 · 2012: 9
FWCI: 4.31
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The American Journal of the Medical Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords: diabetes mellitus, iron overload, serum ferritin, hereditary hemochromatosis, transfusional iron overload, secondary diabetes, African Americans, cardiovascular risk, glucose tolerance, HbA1c
MeSH terms: Animals, Black or African American, Clinical Trials as Topic, Diabetes Mellitus, Humans, Iron, Iron Overload, White People

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Potential Role of Increased Iron Stores in Diabetes

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