Iron Depletion Improves Glycemic Control in Poorly Controlled Type 2 Diabetic Patients with Iron Overload and Negative Main HFE-Gene Mutations


Iron overload increases the risk of diabetes via mechanisms of abnormal glucose metabolism: insulin deficiency, insulin resistance, and/or hepatic dysfunction. Iron reduction upregulates glucose uptake and improves hepatocytes insulin receptor activity. This study was conducted to examine the effects of iron depletion—via controlled phlebotomy—on the hypoglycemic treatment in poorly controlled type 2 diabetes mellitus (T2DM) patients with non-genetic iron overload. Forty three patients with poorly controlled T2DM and iron overload were divided into 2 groups: iron depletion group and control group. Regular phlebotomy was performed for iron depletion group on monthly basis until serum ferritin reached 20 μg/L or less. Both groups were examined and compared for blood pressure, serum ferritin, lipid profile, HFE-gene, HbA1c, HOMA-IR and number of medicines used for diabetic control. The results had revealed that group differences of HbA1c (-2.64, 95% CI -3.23 to 2.04, p < 0.001) and HOMA-IR (-0.68, 95% CI -0.98 to -0.37, p < 0.001) showed significant decreases in iron depletion group at end of study. Significant decrease in the numbers of hypoglycemic medicines in iron depletion group was shown at end of study (p < 0.001); 66.7% of iron depletion group patients were receiving 1 or 2 medicines at end of studyversus none of the control group. Diastolic blood pressure (DBP), triglycerides and LDL-C decreased significantly while HDL-C levels showed significant rise after iron depletion. It can be concluded from the present study that iron depletion therapy is beneficial for improving the efficiency of glycemic control, DBP, and dyslipidemia in poorly controlled type 2 diabetics with iron over load.

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Mahmoud, A. , Elged, A. , Elgamal, R. and Hamada, A. (2015) Iron Depletion Improves Glycemic Control in Poorly Controlled Type 2 Diabetic Patients with Iron Overload and Negative Main HFE-Gene Mutations. Journal of Diabetes Mellitus, 5, 164-172. doi: 10.4236/jdm.2015.53020.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Shah, S.V. and Fonseca, V.A. (2011) Iron and Diabetes Revisited. Diabetes Care, 34, 1676-1677.
[2] Bowers, K., Yeung, E., Williams, M.A., Qi, L., Tobias, D.K., et al. (2011) A Prospective Study of Prepregnancy Dietary Iron Intake and Risk for Gestational Diabetes Mellitus. Diabetes Care, 34, 1557-1563.
[3] Swaminathan, S., Fonseca, V.A., Alam, M.G. and Shah, S.V. (2007) The Role of Iron in Diabetes and Its Complications. Diabetes Care, 30, 1926-1933.
[4] McClain, D.A., Abraham, D., Rogers, J., Brady, R., Gault, P., et al. (2006) High Prevalence of Abnormal Glucose Homeostasis Secondary to Decreased Insulin Secretion in Individuals with Hereditary Haemochromatosis. Diabetologia, 49, 1661-1669.
[5] Fernández-Real, J.M., López-Bermejo, A. and Ricart, W. (2002) Cross-Talk between Iron Metabolism and Diabetes. Diabetes, 51, 2348-2354.
[6] Jaruratanasirikul, S., Chareonmuang, R., Wongcharnchailert, M., Laosombat, V., Sangsupavanich, P. and Leetanaporn, K. (2008) Prevalence of Impaired Glucose Metabolism in Beta-Thalassemic Children Receiving Hypertransfusions with a Suboptimal Dosage of Iron-Chelating Therapy. European Journal of Pediatrics, 167, 873-876.
[7] Simcox, J.A. and McClain, D.A. (2013) Iron and Diabetes Risk. Cell Metabolism, 17, 329-341.
[8] Hirabara, S.M., Gorjao, R., Vinolo, M.A., Rodrigues, A.C., Nachbar, R.T. and Curi, R. (2012) Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions. Journal of Biomedical Science, 2012, 16 p.
[9] Gabrielsen, J.S., Gao, Y., Simcox, J.A., Huang, J., Thorup, D., et al. (2012) Adipocyte Iron Regulates Adiponectin and Insulin Sensitivity. Journal of Clinical Investigation, 122, 3529-3540.
[10] Blaslov, K., Bulum, T., Zibar, K. and Duvnjak, L. (2013) Relationship between Adiponectin Level, Insulin Sensitivity, and Metabolic Syndrome in Type 1 Diabetic Patients. International Journal of Endocrinology, 2013, 6 p.
[11] Qiu, C., Zhang, C., Gelaye, B., Enquobahrie, D.A., Frederick, I.O. and Williams, M.A. (2011) Gestational Diabetes Mellitus in Relation to Maternal Dietary Heme Iron and Nonheme Iron Intake. Diabetes Care, 34, 1564-1569.
[12] Fernández-Real, J.M., Penarroja, G., Castro, A., García-Bragado, F., Hernández-Aguado, I. and Ricart, W. (2002) Blood Letting in High-Ferritin Type 2 Diabetes: Effect on Insulin Sensitivity and β-Cell Function. Diabetes, 51, 1000-1004.
[13] Ascherio, A., Rimm, E.B., Giovannucci, E., Willett, W.C. and Stampfer, M.J. (2001) Blood Donations and Risk of Coronary Heart Disease in Men. Circulation, 103, 52-57.
[14] Montosi, G., Garuti, C., Martinelli, S. and Pietrangelo, A. (1998) Hepatic Stellate Cells Are Not Subjected to Oxidative Stress Iron-Induced Fibrogenesis in Rodents. Hepatology, 27, 1611-1622.
[15] Adams, P., Brissot, P. and Powell, L.W. (2000) EASL International Consensus Conference on Hemochromatosis. Journal of Hepatology, 33, 485-504.
[16] Cooksey, R.C., Jones, D., Gabrielsen, S., Huang, J., Simcox, J.A., et al. (2010) Dietary Iron Restriction or Iron Chelation Protects from Diabetes and Loss of Beta-Cell Function in the Obese (ob/ob lep-/-) Mouse. American Journal of Physiology-Endocrinology and Metabolism, 298, E1236-E1243.
[17] Houschyar, K.S., Ludtke, R., Dobos, G.J., Kalus, U., Broecker-Preuss, M., et al. (2012) Effects of Phlebotomy-Induced Reduction of Body Iron Stores on Metabolic Syndrome: Results from a Randomized Clinical Trial. BMC Medicine, 10, 54-62.
[18] Crowley, M.J., Holleman, R., Klamerus, M.L., Bosworth, H.B., Edelman, D. and Heisler, M. (2014) Factors Associated with Persistent Poorly Controlled Diabetes Mellitus: Clues to Improving Management in Patients with Resistant Poor Control. Chronic Illness, 10, 291-302.
[19] Adams, P., Brissot, P. and Powell, L.W. (2000) EASL International Consensus Conference on Haemochromatosis. Journal of Hepatology, 33, 485-504.
[20] Valenti, L., Fracanzani, A.L., Dongiovani, P., Bugianesi, E., Marchesini, G., et al. (2007) Iron Depletion by Phlebotomy Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease and Hyperferritinemia: Evidence from a Case-Control Study. The American Journal of Gastroenterology, 102, 1251-1258.
[21] Dongiovanni, P., Ruscica, M., Rametta, R., Recalcati, S., Steffani, L., et al. (2013) Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance. The American Journal of Pathology, 182, 2254-2263.
[22] Zacharski, L.R. (2010) Hemochromatosis, Iron Toxicity, and Disease. Journal of Internal Medicine, 268, 246-248.
[23] Raman, S.V., Winner 3rd, M.W., Tran, T., Velayutham, M., Simonetti, O.P., et al. (2008) In Vivo Atherosclerotic Plaque Characterization Using Magnetic Susceptibility Distinguishes Symptom-Producing Plaques. JACC: Cardiovascular Imaging, 1, 49-57.
[24] Valenti, L., Dongiovanni, P., Motta, B.M., Swinkels, D.W., Bonara, P., et al. (2011) Serum Hepcidin and Macrophage Iron Correlate with MCP-1 Release and Vascular Damage in Patients with Metabolic Syndrome Alterations. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 683-690.
[25] Zidek, W., Tenschert, W., Karoff, C. and Vetter, H. (1985) Tratment of Resistant Hypertension by Phlebotomy. Klinische Wochenschrift, 63, 762-764.
[26] Barenbrock, M., Spieker, C., Rahn, K.H. and Zidek, W. (1993) Therapeutic Efficiency of Phlebotomy in Posttransplant Hypertension Associated with Erythrocytosis. Clinical Nephrology, 40, 241-243.
[27] Ducluzeau, P.H., Fletcher, L.M., Vidal, H., Laville, M. and Tavaré, J.M. (2002) Molecular Mechanisms of Insulin-Stimulated Glucose Uptake in Adipocytes. Diabetes & Metabolism, 28, 85-92.
[28] Ware, W.R. (2013) Iron and Diabetes. Integrative Healthcare Practitioners, 76-81.
[29] Ahmed, U., Latham, P.S. and Oates, P.S. (2012) Interactions between Hepatic Iron and Lipid Metabolism with Possible Relevance to Steatohepatitis. World Journal of Gastroenterology, 18, 4651-4658.
[30] Fleming, D.J., Tucker, K.L., Jacques, P.F., Dallal, G.E., Wilson, P.W. and Wood, R.J. (2002) Dietary Factors Associated with the Risk of High Iron Stores in the Elderly Framingham Heart Study Cohort. The American Journal of Clinical Nutrition, 76, 1375-1384.
[31] Jehn, M., Clark, J.M. and Guallar, E. (2004) Serum Ferritin and Risk of the Metabolic Syndrome in U.S. Adults. Diabetes Care, 27, 2422-2428.
[32] Equitani, F., Fernández-Real, J.M., Menichella, G., Koch, M., Calvani, M., et al. (2008) Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations. Diabetes Care, 31, 3-8.
[33] Lamas, G.A., Goertz, C., Boineau, R., Mark, D.B., Rozema, T., et al. (2013) Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients with Previous Myocardial Infarction: The TACT Randomized Trial. JAMA, 309, 1241-1250.
[34] Boussageon, R., Supper, I., Bejan-Angoulvant, T., Kellou, N., Cucherat, M., Boissel, J.-P., et al. (2012) Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials. PLoS Medicine, 9, e1001204.
[35] Turnbull, F. and Zoungas, S. (2012) Intensive Glucose-Lowering Therapy in People with Type 2 Diabetes, What Do We Learn from a New Meta-Analysis of Randomized Controlled Trials? Evidence-Based Medicine, 17, 98-99.
[36] Manco, M. and Fernández-Real, J.M. (2012) Back to Past Leeches: Repeated Phlebotomies and Cardiovascular Risk. BMC Medicine, 10, 53.

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