|Year : 2014 | Volume
| Issue : 4 | Page : 808-813
|Effect of deferoxamine therapy on insulin resistance in end-stage renal disease patients with iron overload
Alsayed Ahmed Alnahal1, Magdy Tahan2, Aymen Fathy3, Tamer Fathy3
1 Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Radiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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|Date of Web Publication||24-Jun-2014|
| Abstract|| |
Cardiovascular diseases are a common cause of morbidity and mortality in subjects on regular hemodialysis. Insulin resistance is associated with increased cardiovascular diseases. Elevated serum ferritin is linked to insulin resistance. The aim of this work is to study the effect of desferoxamine therapy on some of the cardiovascular risk factors such as fasting insulin, B-cell function, insulin resistance, glucose, HbA1c%, lipid profile, blood pressure and carotid intima media thickness (CAIMT). Our study included ten subjects on regular hemodialysis with elevated serum ferritin. We measured the fasting serum glucose, HbA1c%, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), fasting lipid profile, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and complete blood count (CBC). Statistically significant decreases in fasting serum insulin, B-cell function, glucose, HbA1c% and HOMA-IR were noted after deferoxamine therapy. No statistically significant difference was seen with regard to lipid profile, blood pressure and CAIMT. Iron overload increases insulin resistance and cardiovascular risk in hemodialysis subjects. Correction of anemia by iron therapy should keep target ferritin as per guidelines. Further studies are needed to determine the safest ferritin level among hemodialysis subjects.
|How to cite this article:|
Alnahal AA, Tahan M, Fathy A, Fathy T. Effect of deferoxamine therapy on insulin resistance in end-stage renal disease patients with iron overload. Saudi J Kidney Dis Transpl 2014;25:808-13
|How to cite this URL:|
Alnahal AA, Tahan M, Fathy A, Fathy T. Effect of deferoxamine therapy on insulin resistance in end-stage renal disease patients with iron overload. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Feb 19];25:808-13. Available from: http://www.sjkdt.org/text.asp?2014/25/4/808/135025
| Introduction|| |
Insulin resistance describes a condition that is characterized by decreased tissue sensitivity to the action of insulin, leading to a compensatory increase in insulin secretion. It is associated with a two-fold increase in the relative risk for atherosclerotic cardiovascular disease  and a five-fold increase in the risk for developing diabetes. 
Insulin resistance occurs in almost all uremic subjects and is largely responsible for the abnormal glucose metabolism seen in these people. Different factors contribute to insulin resistance in end-stage renal disease patients, e.g., uremic toxins, elevated parathormone, calcium and phosphorus. Insulin resistance secondary to uremic toxins improves by dialysis. 
Iron is both an essential mineral nutrient and an environmental toxin.  Age- and sex-related increase in iron stores have been implicated in the pathogenesis of several common diseases including atherosclerosis and diabetes.  Iron is a catalyst of free radical stress, and it has been suggested that free radicals and lipid per-oxidation play a part in the etiology of dia-betes  and in the pathogenesis of atheromatous plaques. 
| Aim of the Study|| |
Our aim is to study the effect of defero-xamine therapy on some of the metabolic car-diovasular risk factors parameters like fasting insulin, fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), HbA1c%, fasting lipid profile and carotid intima media thickness (CAIMT) among hemo-dialysis subjects with iron overload.
| Subjects and Methods|| |
This work was carried out in the Internal Medicine, Medical Biochemistry and Diagnostic Radiology Departments of Faculty of Medicine, Zagazig University, during the period from April 2009 to September 2010.
The present study included ten known end-stage renal failure patients on regular hemo-dialysis for less than one year before the study (six males and four females). Their ages ranged from 42 years to 61 years, with mean values ± SD of 48.4 ± 6.6 years. All of them were diabetic (their fasting blood glucose level ranged from 6.8-8 mmol/L, with mean values ± SD of 7.28 ± 0.39 mmol/L) and non-obese [their (body mass index) BMI] ranged from 22.58 to 25, with mean values ± SD of 23.93 ± 0.71). They had no family history of diabetes mel-litus. All these patients had serum ferritin levels >1000 µg/mL secondary to frequent blood transfusion, receiving iron i.v. before; none of them had any history suggestive of primary hemochromatosis. Patients' characteristics are shown in the [Table 1].
All study patients were subjected to the following:
- Full history and thorough clinical examination. We excluded subjects with previous history of ischemic cardiovascular diseases, uncontrolled dyslipidemia, history of chronic liver disease, other inflammatory conditions, evidence of peripheral vascular diseases or alcohol dependence. All patients in the study were receiving erthythropioe-tein in titrated doses to maintain hemoglobin between 11 and 12 g/dL. Four of them were receiving a single antihyperten-sive drug and two of them were on two drugs. Four patients were receiving anti-hyperlipdemia treatment. Duration of diabetes mellitus was five to eight years among these patients. Five patients were receiving oral hypoglycemic drugs (glipizide) and two were on insulin; three patients on a diet regimen. Viral markers of HCV, HBV and HIV were negative. All patients were on three regular sessions of dialysis per week using a polysulfone dialyzer.
- Routine investigations: (to verify the inclusion and the exclusion criteria of our subjects of the study included) Complete blood picture, total protein and serum albumin, alanine transferase (ALT) and aspartate transferase (AST), serum crea-tinine, blood urea and serum uric acid, erythrocyte sedimentation rate, C-reactive protein (CRP), fasting and two hours postprandial blood glucose, resting 12-lead elec-trocardiographic tracing, pelviabdominal ultrasonography and full fasting lipid profile. Serum ferritin level was performed every month during the study. 
- Special investigations:
- Measurement of fasting insulin by radio-immunoassay (μU/mL) was carried out by an insulin kit produced by Sorin Biomedica, Diagnostic Division 13040 SALUGGIA (VERVELLI), Italy. 
- Measurement of insulin resistance by homeostasis model assessment (HOMA) index was carried out using the following formula: HOMA index = fasting insulin (μU/mL) × fasting plasma glucose (mmol/L)/22.5.
- Measurement of beta cell function (index of insulin secretion also by HOMA) using: Beta-cell function% = (fasting insulin × 20)/(fasting plasma glucose - 3.5).  Subjects were categorized as insulin resistant if their HOMA was greater than 2. 
- Ultrasonographic measurement of carotid intima-median thickness (CAIMT). 
- Dose of desferoxamine: 5 mg/kg for the last hour of hemodialysis once/week, ob-servaion during treatment for any complication.  They received iron chelating agents for six months or until the serum ferritin level reached 800 ng/mL, the recommended level for patients on hemodialysis according to the KDOQI guidelines. 
- Anthropometric measures:
- Calculation of the BMI: BMI, also called Quetelet's index, was derived by dividing weight by the square of height. 
After an overnight fasting, 7 mL venous blood samples were collected using dry syringes and each blood sample was immediately transferred to sterile tubes with the reagents appropriate to the specific tests.
| Statistical Analysis|| |
The statistical analyses were performed using SPSS 14.0. Differences in means between groups were analyzed with Student's t-test (paired t test). P-values less than 0.05 were considered statistically significant.
| Results|| |
The results and statistical comparison of various parameters of end-stage renal disease patients before and after deferoxamine is given in [Table 2]. There was a statistically significant decrease in the mean values ± SD of fasting serum insulin (uU/mL), glucose (mmol/L), HOMA-IR (%), HbA1C (%), B-cell function (%) and serum ferritin (ng/mL) in comparison with subjects before and after deferoxamine therapy, while no statistically significant difference was seen with regard to SBP (mm Hg), DBP (mm Hg), cholesterol (mg/dL), triglyce-ride (mg/dL), HDL-C (mg/dL), LDL-C (mg/dL) and CAIMT (mm) before and after defero-xamine therapy.
|Table 2: Changes in the parameters before and after deferoxamine therapy.|
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| Discussion|| |
In our study, there was a statistically significant decrease in the mean value ± SD of B-cell function %, fasting serum insulin and HOMA-IR after deferoxamine as compared with chronic renal failure subjects with hyper-ferritinemia. Our finding is consistent with that of Rasic-Milutinovic et al, who found an improvement of insulin resistance in non-diabetic subjects with end-stage renal disease after ery-thropoietin therapy through reduction in iron stores.  Further explanation for this may be the improvement of the decreased B-cell function secondary to insulin resistance produced by elevated serum ferritin. Insulin is an anabolic hormone and it increases iron absorption and increased ferritin level, with subsequent deposition in B-cell, which further destroys B-cell and decreases its function in frank dia-betics.  This means further failure of B-cell function secondary to hyperglycemia and hyperferritinemia. These results are in agreement with those of MacDonald et al.  Their in vitro studies had shown that H-ferritin mRNA is four- to eight-fold higher in rat islets treated with 20 mmol/L glucose than in islets treated with 1 mmol/L glucose. Cavallo-Perin et al  reported that insulin sensitivity, which correlated closely with iron overload (r = -0.70), was reduced by 40% in thalassemia patients. Hepatic extraction and metabolism of insulin is reduced with increasing iron stores, leading to peripheral hyperinsulinemia.  These results were supported by another study by Jehn et al,  who found that the elevated iron stores were positively associated with insulin resistance and with the prevalence of the metabolic syndrome.
Both Zidek et al  and Barenbrock et al  found that blood letting, a means of reducing iron stores, is used in the treatment of resistant hypertension and in post-transplant hypertension associated with erythrocytosis. It is a fact that more than 50% of patients with essential hypertension are insulin resistant, and this subset of patients are at greatest cardiovascular risk.  No statistically significant difference with regard to systolic and diastolic blood presssure before and after deferoxamine therapy was seen in our study as blood pressure was under control by regular follow-up and adjustment of dry body weight in our patients. Similarly, no statistically significant difference was seen regarding fasting lipid profile before and after deferoxamine therapy.
Both fasting glucose and HbA1c significantly decreased after deferoxamine therapy in con-sistance with the findings of Redmon et al.  They reported that subcutaneous deferoxamine caused an improvement in glycated hemoglobin in nine patients. Ferritin has been shown to predict HbA1c independently of glucose, probably reflecting increased oxidative stress,  possibly due to improved insulin sensitivity.
There was no statistically significant difference with regard to CAIMT before and after deferoxamine therapy. In subjects with hemo-chromatosis, medium-sized arteries are characterized by an eccentric hypertrophy and decreased distensibility that are partially reversible after iron depletion.  Possibly due to the short duration of therapy, and possible associated atherosclerosis of long duration, no statistically significant change in lipid profile and blood pressure was seen in our study.
Ishizaka et al found that Ang II increased ferritin protein expression in endothelial and adventitial cells, which was associated with occasional iron deposits in the adventitia, and Ang II can promote oxidative stress and lipid peroxidation. They also showed that chronic administration of deferoxamine partially blunted Ang II-induced expression of HO-1, ferri-tin and MCP-1 and subsequent lipid peroxi-dation.  No change in BMI was seen in our subjects, possibly because they were on a diet regime from the renal side and the diabetic side.
We can conclude that iron overload may be deleterious even for those on regular hemo-dialysis. Therefore, we should keep the ferritin levels to <800 ng/mL as per the guidelines. Iron overload leads to uncontrolled fasting blood glucose, increased insulin resistance, uncontrolled blood pressure and decreased iron storage, resulting in improved insulin resistance and improved in diabetic control; however, it has no effect on CAIMT, which may be due to iron overload detected early in our subjects. Also, treatment was given for a short duration (3-6 months) (short period to reveal an effect on atherosclerosis), although there was a small decrease of CAIMT that was not statistically significant. There was no further progression in CAIMT.
Further studies with a larger number of subjects and longer duration of follow-up are needed to study the effect of optimizing ferritin levels on insulin resistance, lipid peroxidation and CAIMT.
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Alsayed Ahmed Alnahal
Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig
[Table 1], [Table 2]
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