==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 1792168310.5144/0256-4947.2007.356asm-5-356Original ArticleAge- and body mass index-dependent relationship between correction of iron deficiency anemia and insulin resistance in non-diabetic premenopausal women Özdemir Ali *Sevinç Can *Selamet Umut *Kamacı Berna *Atalay Sacide † * Haydarpasa Numune Education and Research Hospital, Department of Internal Medicine, Istanbul, Turkey † Haydarpasa Numune Education and Research Hospital, Biochemical Laboratories, Istanbul, TurkeyCorrespondence and reprint requests: Ali Özdemir, MD, Halk Cad. Arif Hikmetpasa, Ap. No: 76 D: 3, Üsküdar, Istanbul, Turkey, T: +90(216) 391 56 65, F: +90(216) 346 05 82, alemoz2004@yahoo.comSep-Oct 2007 27 5 356 361 01 4 2007 Copyright © 2007, Annals of Saudi Medicine2007This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND No prospective studies have evaluated the effects of correction of iron deficiency anemia on insulin resistance in non-diabetic premenopausal women. We investigated this relationship in 54 non-diabetic premenopausal women with iron deficiency anemia. SUBJECTS AND METHODS All patients were treated with oral iron preparations. Insulin resistance was calculated with the Homeostasis Model Assessment formula. All patients were dichotomized by the median for age and BMI to assess how the relationship between iron deficiency anemia and insulin resistance was affected by age and BMI. RESULTS Although the fasting glucose levels did not change meaningfully, statistically significant decreases were found in fasting insulin levels following anemia treatment both in the younger age (<40 years) (P=0.040) women and in the low BMI (<27 kg/m2) (P=0.022) subgroups but not in the older age (≥40 years) and the high BMI (≥27 kg/m2) subgroups. Post-treatment fasting insulin levels were positively correlated both with BMI (r=0.386, P=0.004) and post-treatment hemoglobin levels (r=0.285, P=0.036). Regression analysis revealed that the factors affecting post-treatment insulin levels were BMI (P=0.001) and post-treatment hemoglobin levels (P=0.030). CONCLUSION Our results show that following the correction of iron deficiency anemia, insulin levels and HOMA scores decrease in younger and lean non-diabetic premenopausal women. ==== Body It is well known that complex interactions exist among insulin, insulin resistance, iron and anemia. A mutual relationship has been identified between insulin and iron metabolism. Insulin both stimulates the synthesis of ferritin and causes a rapid and marked stimulation of iron uptake of cells by redistributing transferin receptors from the intracellular compartment of the cell membrane to the cell surface. Regulation of iron uptake by insulin occurs in parallel with its effects on glucose transport.2 On the other hand, insulin action is also influenced by iron. Iron causes hyperinsulinemia and insulin resistance by inhibition of insulin internalization and actions.3 In fact, the initial and most common abnormality seen in conditions with iron overload is hepatic insulin resistance.4 In previous animal studies, it has been shown that glucose turnover increases in iron deficiency, and this increase is primarily due to enhanced peripheral insulin responsiveness.5–8 Interestingly, there are some reports indicating that low iron status increases insulin sensitivity in lacto-ovo vegetarians. In addition, phlebotomy is followed by decreases in serum glucose as well as by improvements in both beta-cell secretion and peripheral insulin action. 9,10 Insulin plays an important role in regulation of erythropoiesis both with its ability to boost activity of the transcription factor, hypoxia-inducible factor-1A (HIF-1A), and more directly as a growth factor influencing development of reticulocytes.11 On the other hand, some recent reports suggest that rising hemoglobin/ hematocrit (hemoglobin/hematocrit) levels are a component of insulin resistance syndrome, presumably due to the facilitative effect of insulin on erythropoietin synthesis.12–14 Conversely, in patients with chronic renal failure, anemia has been suggested to be responsible for the insulin resistance commonly seen in these patients. 15–18 Hyperinsulinemia and insulin resistance constitute a risk factor for atherosclerotic heart diseases.19 It is commonly accepted that premenopausal women carry less risk for cardiovascular diseases essentially due to the protective effect of intrinsic estrogen hormone.20 In premenopausal women, iron deficiency, which is usually caused by menstrual loss, is a very common health problem. Some animal and human studies indicate that iron deficiency increases glucose tolerance and insulin sensitivity. In that case, low iron status in premenopausal women may exert an independent and additional protective role besides hormonal status for atherosclerotic heart diseases. To the best of our knowledge, there have not been any prospective studies reporting the effects of correction of iron deficiency anemia on insulin resistance in non-diabetic premenopausal women. In this prospective study, we investigated how insulin resistance is affected by correction of anemia and how this relationship might be affected by anthropological parameters such as age and BMI. SUBJECTS AND METHODS We recruited 54 anemic premenopausal women (menstruating women of reproductive age) who had iron deficiency anemia due to menstrual loss (median age, 40 years; mean age, 36.28±10.64 years; range, 15 to 52 years) for this study. Serum ferritin values below the normal range and transferrin saturation below 15% were accepted as indicators of iron deficiency. Blood hemoglobin and hematocrit values below the normal range (≤12 g/dL and ≤35%, respectively) were accepted as indicators of anemia. All patients were treated with oral iron preparations (daily 225 mg ferroglycine sulfate), and the median duration of treatment was three months. Patients were excluded from the study if they had family histories of diabetes mellitus, repeatedly had fasting venous serum glucose levels >110 mg/dL or were previously placed on iron replacement treatments. Previous medications other than iron preparations that had already being used by the patients were continued. Informed consent was obtained from each subject after approval of the experimental protocol by the local human ethics committee. For each patient included in this study, hemoglobin, hematocrit, serum iron, transferrin saturation and serum ferritin were measured in 12-hour fasting blood both prior to the onset of iron replacement and 15 days after stopping iron treatment due to improvement of anemia. Both pre-treatment and post-treatment insulin and glucose levels were measured in three different venous serum samples taken within intervals of 5 minutes after 12 hours of fasting. Insulin level was measured with the ECLIA (ElectroChemiLuminescense ImmunoAssay) method using a Roche Modular Analytics E170 machine (Elecsys insulin kit No. 12017547). Insulin resistance (IR) was calculated according to the Homeostasis Model Assessment (HOMA) formula: HOMA-IR=fasting glucose (mmol/L)×fasting insulin (mU/L)/22.5. In all patients, we searched for the existence of a possible relationship between iron deficiency anemia and insulin resistance. All patients as a whole group were dichotomized by the median for age (<40 years, n=25 and ≥40 years, n=29) and BMI (<27 kg/m2, n=26 and ≥27 kg/m2, n=28) to assess how this relationship, if it existed, was affected by age and BMI. Statistical analysis was conducted using the Statistical Package for Social Sciences (SPSS, Inc, Chicago, IL, USA) for Windows 10.0 programs. Results were expressed as means±standard deviation. Comparisons between pre- and post-treatment levels were made by the paired T test. Simple (Pearson) correlation coefficients between HOMA-IR and measures of variables were calculated, and a multiple linear regression analysis was performed, considering HOMA-IR as a dependent variable and all others as explanatory variables. Since the levels of HOMA-IR strictly depended on fasting insulin and glucose concentration, we did not consider these parameters in the multiple regression analysis. Results were analyzed with 95% confidence intervals and probability levels less than 0.05 were considered significant. RESULTS The patients included in this study had a mean BMI of 26.84±5.95 kg/m2, a mean waist/hip ratio of 0.82±0.10 and mean age of 36.28±10.64 years. When all 54 patients were assessed as a whole, statistically significant decreases were found in fasting insulin levels and HOMA scores following the correction of iron deficiency anemia while pre-and post-treatment fasting glucose levels did not change meaningfully (Table 1). In the presence of anemia, neither fasting insulin levels nor HOMA scores were found to be significantly correlated with either hematological or iron parameters. After correction of the anemia, both fasting insulin levels and HOMA scores were found to be positively correlated with both BMI and post-treatment hemoglobin levels, with statistical significance. In the regression analysis, the factors affecting post-treatment insulin levels were found to be BMI (P=0.001) and post-treatment hemoglobin levels (P=0.030). When all the patients were dichotomized by the median for BMI into two subgroups as low (mean BMI, 21.90±2.62; range, 17 to 26 kg/m2) and high (mean BMI, 31.43±4,22; range, 27 to 44 kg/m2) subgroups, the high BMI subgroup consisted of older patients than the low BMI subgroup (42.50±5.51 and 29.58±10.82 years, P<0.001, respectively). Neither pre-treatment nor post-treatment levels of hemoglobin, hematocrit, serum iron, transferrin saturation, serum ferritin and fasting glucose differed significantly between the high and the low BMI subgorups. Also, pre-treatment fasting insulin levels and HOMA scores in the high and low BMI subgroups did not differ significantly from each other, but the mean post-treatment fasting insulin levels and HOMA scores were found to be significantly lower in the low BMI subgroup than in the high BMI subgroup (Table 2). The fasting glucose levels of the low and high BMI subgroups did not change meaningfully following iron treatment. After correction of the anemia, both insulin levels (from 9.18±7.35 to 6.29±2.82, P=0.022) and HOMA scores (from 2.13±1.89 to 1.43±0.67, P=0.032) in the low BMI subgroup decreased significantly, whereas decreases in insulin levels (from 10.64±5.79 to 9.39±3.65, P=0.150) and HOMA scores (from 2.64±1.71 to 2.26±0.93, P=0.145) in the high BMI subgroup were less evident and statistically insignificant. When all patients were dichotomized by the median for age into two subgroups as younger (mean age, 26.92±8.16; range, 15 to 39 years) and older (mean age 44.34±3.38; range, 40 to 52 years) age subgroups, the subjects in the older age subgroup also had a higher BMI (29.52±5.50 and 23.74±4.91 kg/m2, P<0.001). Neither pre-treatment nor post-treatment levels of hemoglobin, hematocrit, serum iron, transferrin saturation, serum ferritin, fasting glucose, serum insulin and HOMA scores differed significantly between the older and younger age subgroups (Table 3). Although statistically insignificant, post-treatment fasting glucose levels in the younger age subgroup had a tendency to fall (from 95.04±11.16 to 91.80±10.08, P=0.064), whereas post-treatment fasting glucose levels showed a tendency to rise in the older age subgroup (from 94.76±13.80 to 96.38±10.93, P=0.529). Fasting insulin levels and HOMA scores in the younger age subgroup decreased significantly after iron treatment (from 10.27±7.18 to 7.55±3.02, P=0.040 and from 2.47±1.93 to 1.74±0.79, P=0.032, respectively), but the decreases in these parameters in the older age subgroup were lesser and statistically insignificant (from 9.65±6.06 to 8.20±4.07, P=0.081 and from 2.33±1.71 to 1.97±1.00, P=0.146 respectively). DISCUSSION The most important result of this study is that the relationship between iron deficiency anemia and insulin levels (and HOMA scores, which are accepted as indicators of insulin resistance) seen in non-diabetic premenopausal women is multi-factorial. Our results show that some anthropological parameters such as age and BMI have an influence on the relationship between iron deficiency anemia and insulin levels. When all 54 patients were assessed as a whole, the results of this study differed from the results of animal and similar, but not identical, human studies, which reported that iron deficiency increases glucose tolerance and insulin sensitivity.5–9 According to our results, in general, following treatment of iron deficiency anemia, insulin levels and HOMA scores in premenopausal women decreased, with statistical significance. Our results showed that the decreases in insulin levels and HOMA scores actually occurred in patients of younger age and lower BMI. However, these parameters also showed a tendency to decrease rather than to increase in patients of older age and high BMI. To the best of our knowledge, there are no published human studies that assess the relationship between iron deficiency anemia and insulin resistance other than reports indicating that low iron status enhances insulin sensitivity in lacto-ovo vegetarians.9 Previously reported human studies investigating the relationship between anemia and insulin resistance usually consisted of patients with diagnoses of either thalassemia21–24 or aplastic anemia,25 and in general, subjects with these diagnoses are considered to have simultaneous iron overload. The relationship between iron overload and insulin resistance is well known.26 Patients with thalassemia and aplastic anemia have only the anemia factor as the common denominator with iron deficient patients, and therefore, it would be a mistake to consider these patients anemic, but at the same time iron overloaded patients are in the same category with iron deficient patients when evaluating insulin resistance. Our results also differ from the results of animal experiments showing that iron deficiency increases glucose tolerance primarily due to an increase in peripheral insulin responsiveness.5–8 Similar studies have also been done with chronic renal failure patients in whom insulin resistance is accompanied with many other factors, 15,17,27 and anemia has been suggested as the causal factor for insulin resistance in these patients. Moreover, it has been reported that insulin resistance is reduced or improved in these patients due to either the direct effect of erythropoietin treatment or the indirect effect of anemia correction.15,16,27 With respect to anemia, our results are similar to the results of the studies done with patients with chronic renal failure. However, our results indicate that neither low iron status itself nor the resultant anemia of iron deficiency are the causes of the higher insulin levels and HOMA scores. In this study, the results of the subgroup analysis for age and BMI suggest that the anthropological characteristics of a study population may affect the relationship between iron deficiency anemia and insulin resistance, so the contrary results found in this study could be due to the different anthropological characteristics of the study population. The reason for the different responses in means of insulin resistance to iron treatment exerted by the younger age/low BMI and the older age/high BMI subgroups is not clear given that subjects were of the same gender and had similar hormonal status. We speculate that patients of younger age and low BMI are more energetic and active following the treatment of anemia compared to patients of older age and higher BMI, and the expenditure of more energy might be an additional factor contributing to the reduction of insulin resistance. Also, the therapy duration of three months is not long enough to see the changes in the levels of insulin and HOMA scores in patients with older age and high BMI who already have established insulin resistance when compared with patients of younger age and low BMI. The results of these subgroup analyses indicate both the necessity of taking the anthropological characteristics of the study population into account while assessing the relationship between iron deficiency and insulin resistance, and the need for further studies with different population groups. On the other hand, there are some recent reports suggesting that the rising of hemoglobin/hematocrit values might be a component of the insulin resistance syndrome.12–14 In this study, we also found that there were statistically significant positive correlations between post-treatment hemoglobin levels and insulin levels as well as between post-treatment hemoglobin levels and HOMA scores. Also, regression analysis revealed that the factors affecting post-treatment insulin levels were BMI and post-treatment hemoglobin levels. These results of regression and correlation analyses provide support for the existence of a relationship between insulin resistance and hematological parameters. Therefore, when considering the treatment of iron deficiency anemia, targeting lower hemoglobin/hematocrit levels may be a suitable and a necessary action for patients of older age and higher BMI who already have established insulin resistance, and particularly for the patients in whom impaired glucose tolerance accompanies iron deficiency. We do not know the exact underlying mechanism that explains the significant decrease in fasting insulin levels and HOMA scores after the treatment of iron deficiency anemia in premenopausal women. Also, we do not know whether the decrease in insulin levels and HOMA scores following iron therapy is due to iron replacement itself or correction of the resultant anemia. Although there are some reports showing that insulin promotes the synthesis of erythropoietin by boosting the activity of HIF-1A, which functions physiologically as a detector of both hypoxia and iron-deficiency,11 and induces the synthesis of glucose transporters as well as glycolytic enzymes, it is not known whether diminished activity of HIF-1A following iron therapy affects the synthesis and secretion of insulin or not. Such a relationship, if it exists, could be responsible for the decrease in insulin levels and HOMA scores following iron replacement, so it is clear that this topic merits further investigation. Due to the role of insulin resistance and iron-dependent oxidative stress in the onset and progression of atherosclerosis, the relationship between iron deficiency and insulin resistance has importance. Despite some contrary reports,28,29 it has been shown that there is a link between iron status and the pathogenesis of atherosclerosis.30–35 Also, some evidence from previously published data show that the progression of an atherosclerotic plaque can be decelerated by reducing body iron stores with phlebotomy.31,36 When the results of our study are assessed in this perspective, it can be concluded that iron deficiency has a reducing effect on insulin levels in patients of younger age and lower BMI in whom atherosclerosis and its complications are expected to be less prevalent, whereas such an effect was not evident in patients of older age and higher BMI in whom atherosclerosis and its complications are expected to be more prevalent. This result is not compatible with the hypothesis that low iron status in premenopausal women may play an independent and additional protective role for atherosclerotic heart diseases. In conclusion, our results show that an age- and BMI-dependent relationship exists between iron deficiency anemia and insulin levels (and HOMA scores) in non-diabetic premenopausal women. When considering the treatment of iron deficiency anemia, targeting lower hemoglobin/hematocrit levels may be an appropriate and a necessary action for the patients of older age and higher BMI, particularly for patients in whom impaired glucose tolerance accompanies iron deficiency. Table 1 Pre- and post-treatment laboratory parameters of all patients. Pre-treatment Post-treatment P Hemoglobin (g/dL) 9.76±1.73 13.13±1.04 <0.001 Hematocrit (%) 30.26±4.25 39.11±2.92 <0.001 Iron (μg/dL) 20.94±15.14 83.80±27.09 <0.001 Ferritin (ng/mL) 5.56±4.07 33.40±23.76 <0.001 Transferrin saturation (%) 4.77±4.00 25.94±8.85 <0.001 Glucose (mg/dL) 94.89±12.50 94.26±10.70 0.693 Insulin (μIU/mL) 9.94±6.56 7.90±3.60 0.007 HOMA score 2.40±1.80 1.86±0.91 0.009 Table 2 Pre- and post-treatment laboratory parameters of low and high BMI subgroups. Lean BMI High BMI P Pre-treatment Hemoglobin (g/dL) 9.92±1.97 9.62±1.50 0.538 Hematocrit (%) 30.55±4.95 30.00±3.55 0.639 Iron (μg/dL) 19.58±15.79 22.21±14.67 0.527 Transferrin saturation (%) 4.58±3.92 4.94±4.15 0.747 Ferritin (ng/mL) 5.25±3.36 5.83±4.67 0.613 Fasting glucose (mg/dL) 92.15±8.52 97.43±15.08 0.123 Insulin (μIU/mL) 9.18±7.35 10.64±5.79 0.419 HOMA score 2.13±1.89 2.64±1.71 0.304 Post-treatment Hemoglobin (g/dL) 13.18±1.04 13.08±1.07 0.742 Hematocrit (%) 39.42±2.87 38.81±2.98 0.449 Iron (μg/dL) 80..85±26.96 86.54±27.42 0.446 Transferrin saturation (%) 24.97±7.76 26.85±9.81 0.442 Ferritin (ng/mL) 30.05±16.21 36.38±28.87 0.338 Fasting glucose (mg/dL) 91.85±9.31 96.50±11.56 0.111 Insulin (μIU/mL) 6.29±2.82 9.39±3.65 0.001 HOMA score 1.43±0.67 2.26±0.93 <0.001 Table 3 Pre- and post-treatment laboratory parameters of younger and older age subgroups. Younger age Older age P Pre-treatment Hemoglobin (g/dL) 10.08±1.80 9.49±1.66 0.217 Hematocrit (%) 31.25±4.40 29.41±3.99 0.114 Iron (μg/dL) 19.48±15.89 22.21±14.61 0.514 Transferrin saturation (%) 4.47±3.98 5.02±4.08 0.621 Ferritin (ng/mL) 5.28±3.08 5.79±4.79 0.656 Fasting glucose (mg/dL) 95.04±11.16 94.74±13.80 0.935 Insulin (μIU/mL) 10.27±7.20 9.65±6.08 0.734 HOMA score 2.47±1.93 2.33±1.71 0.776 Post-treatment Hemoglobin (g/dL) 13.18±0.87 13.08±1.19 0.717 Hematocrit (%) 39.32±2.45 38.92±3.30 0.623 Iron (μg/dL) 83.96±25.65 83.66±28.73 0.968 Transferrin saturation (%) 26.24±8.84 25.69±9.01 0.824 Ferritin (ng/mL) 27.85±12.06 37.98±29.67 0.123 Fasting glucose (mg/dL) 91.80±10.08 96.38±10.93 0.118 Insulin (μIU/mL) 7.55±3.02 8.20±4.07 0.516 HOMA score 1.74±0.79 1.97±1.00 0.355 ==== Refs REFERENCES 1 Davis RJ Corvera S Czech MP Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane J Biol Chem 1986 261 8708 8711 3013860 2 Tanner LI Lienhard GE Localization of transferrin receptors and insulin-like growth factor II receptors in vesicles from 3T3-L1 adipocytes that contain intracellular glucose transporters J Cell Biol 1989 108 1537 1545 2538483 3 Fernández-Real JM López-Bermejo A Ricart W Cross-Talk Between Iron Metabolism and Diabetes Diabetes 2002 51 2348 2354 12145144 4 Dandona P Hussain MAM Varghese Z Politis D Flynn DM Hoffbrand AV Insulin resistance and iron overload Ann Clin Biochem 1983 20 77 79 6342506 5 Borel MJ Beard JL Farrell PA Hepatic glucose production and insulin sensitivity and responsiveness in iron-deficient anemic rats Am J Physiol 1993 3 264 3 Pt 1 E380 90 8460685 6 Brooks GA Henderson SA Dallman PR Increased glucose dependence in resting, iron-deficient rats Am J Physiol 1987 10 253 4 Pt 1 E461 6 3661703 7 Henderson SA Dallman PR Brooks GA Glucose turnover and oxidation are increased in the iron-deficient anemic rat Am J Physiol 1986 4 250 4 Pt 1 E414 21 3963182 8 Klempa KL Willis WT Chengson R Dallman PR Brooks GA Iron deficiency decreases gluconeogenesis in isolated rat hepatocytes J Appl Physiol 1989 11 67 5 1868 72 2600020 9 Hua NW Stoohs RA Facchini FS Low iron status and enhanced insulin sensitivity in lacto-ovo vegetarians Br J Nutr 2001 10 86 4 515 9 11591239 10 Facchini FS Effect of phlebotomy on plasma glucose and insulin concentrations Diabetes Care 1998 21 2190 11 McCarty MF Hyperinsulinemia may boost both hematocrit and iron absorption by up-regulating activity of hypoxia-inducible factor-1alpha Med Hypotheses 2003 Nov-Dec 61 5–6 567 73 14592787 12 Barbieri M Ragno E Benvenuti E Zito GA Corsi A Ferrucci L New aspects of the insulin resistance syndrome: impact on haematological parameters Diabetologia 2001 10 44 10 1232 7 11692171 13 Choi KM Lee J Kim YH Kim KB Kim DL Kim SG Relation between insulin resistance and hematological parameters in elderly Koreans-Southwest Seoul (SWS) Study Diabetes Res Clin Pract 2003 6 60 3 205 12. 1 12757983 14 Zidek V Fucikova A Musilova A Bila V Kren V Pravenec M Hematocrit and hemoglobin values are negatively correlated with insulin resistance in spontaneous hypertension Folia Biol (Praha) 1999 45 6 247 51 10732721 15 Mak RH Metabolic effects of erythropoietin in patients on peritoneal dialysis Pediatr Nephrol 1998 10 12 8 660 5 9811391 16 Mak RH Effect of recombinant human erythropoietin on insulin, amino acid, and lipid metabolism in uremia J Pediatr 1996 7 129 1 97 104 8757568 17 Mak RH Correction of anemia by erythropoietin reverses insulin resistance and hyperinsulinemia in uremia Am J Physiol 1996 5 270 5 Pt 2 F839 44 8928846 18 Igaki N Takashima M Ohyama M Oh S Kida A Yanase K The beneficial effect of effecttive control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries Clin Exp Nephrol 2004 6 8 2 163 7 15235936 19 Yun KH Jeong MH Kim KH Hong YJ Park HW Kim JH The effect of insulin resistance on prognosis of non-diabetic patients who underwent percutaneous coronary intervention J Korean Med Sci 2006 4 21 2 212 6 16614503 20 Orshal JM Khalil RA Gender, sex hormones, and vascular tone Am J Physiol Regul Integr Comp Physiol 2004 2 286 2 R233 49 14707008 21 Khalifa AS Salem M Mounir E El-Tawil MM El-Sawy M Abd Al-Aziz MM Abnormal glucose tolerance in Egyptian beta-thalassemic patients: possible association with genotyping Pediatr Diabetes 2004 9 5 3 126 32 15450007 22 Messina MF Lombardo F Meo A Miceli M Wasniewska M Valenzise M Three-year prospective evaluation of glucose tolerance, betacell function and peripheral insulin sensitivity in non-diabetic patients with thalassemia major J Endocrinol Invest 2002 6 25 6 497 501 12109619 23 Pappas S Donohue SM Denver AE Mohamed-Ali V Goubet S Yudkin JS Glucose intolerance in thalassemia major is related to insulin resistance and hepatic dysfunction Metabolism 1996 5 45 5 652 7 8622611 24 Dmochowski K Finegood DT Francombe W Tyler B Zinman B Factors determining glucose tolerance in patients with thalassemia major J Clin Endocrinol Metab 1993 8 77 2 478 83 8345055 25 Wajnrajch MP Gertner JM Huma Z Popovic J Lin K Verlander PC Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry Pediatrics 2001 Appr 107 4 744 54 11335753 26 Vantyghem MC Girardot C Boulogne A Wemeau JL Iron overload and insulin resistance Presse Med 2005 11 5 34 19 Pt 1 1391 8 16292193 27 Spaia S Pangalos M Askepidis N Pazarloglou M Mavropoulou E Theodoridis S Efffect of short-term rHuEPO treatment on insulin resistance in haemodialysis patients Nephron 2000 4 84 4 320 5 10754408 28 Dabbagh AJ Shwaery GT Keaney JF Jr Frei B Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit Arterioscler Thromb Vasc Biol 1997 11 17 11 2638 45 9409237 29 Aslan M Kosecik M Horoz M Selek S Celik H Erel O Assessment of paraoxonase and arylesterase activities in patients with iron deficiency anemia Atherosclerosis 2006 5 6 [Epub ahead of print] 30 You SA Wang Q Ferritin in atherosclerosis Clin Chim Acta 2005 7 1 357 1 1 16 15963791 31 Qayyum R Schulman P Iron and atherosclerosis Clin Cardiol 2005 3 28 3 119 22 15813617 32 Minqin R Rajendran R Pan N Tan BK Ong WY Watt F The iron chelator desferrioxaamine inhibits atherosclerotic lesion developmment and decreases lesion iron concentrations in the cholesterol-fed rabbit Free Radic Biol Med 2005 5 1 38 9 1206 11 15808418 33 Sengoelge G Sunder-Plassmann G Horl WH Potential risk for infection and atherosclerosis due to iron therapy J Ren Nutr 2005 1 15 1 105 10 15648017 34 Kruszewski M The role of labile iron pool in cardiovascular diseases Acta Biochim Pol 2004 51 2 471 80 15218543 35 Yuan XM Li W The iron hypothesis of atherosclerosis and its clinical impact Ann Med 2003 35 8 578 91 14708968 36 Zheng H Cable R Spencer B Votto N Katz SD Iron stores and vascular function in voluntary blood donors Arterioscler Thromb Vasc Biol 2005 8 25 8 1577 83 15961703