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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 20  |  Issue : 2  |  Page : 111-119

Insulin resistance in patients with end-stage renal disease on hemodialysis: effect of short-term erythropoietin therapy


1 Department of Internal Medicine, Menoufia University Hospitals, Menoufia, Egypt
2 Department of Nephrology, Shibin El-Kom Teaching Hospital, Menoufia, Egypt

Date of Submission20-Jul-2019
Date of Acceptance21-Nov-2019
Date of Web Publication27-Apr-2020

Correspondence Address:
Mr. Islam S Shebl
Department of Nephrology, Shibin El-Kom Teaching Hospital, Menoufia, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_25_19

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  Abstract 


Background Insulin resistance (IR) is a characteristic feature of uremia. Both IR and metabolic syndrome are considered independent predictors for cardiovascular events and mortality in patients with chronic kidney disease. Few studies have shown a favorable effect of erythropoietin (EPO) in decreasing IR. We hypothesized that short-term treatment with EPO can lead to improvement of IR in patients with chronic kidney disease.
Patients and methods Patients were categorized into two groups: 20 hemodialysis patients (HDP) not receiving EPO (control) compared with other 40 HDP divided into two subgroups (20 diabetics and 20 nondiabetic), both receiving EPO (intervention group) all over the duration of the study, which extended for 6 months. All patients were subjected to history taking, full clinical examination, as well as laboratory investigations.
Results All baseline results of parameters of glycemic control showed significant stepwise increase from nondiabetic intervention group, to control group, and then to diabetic intervention group. homeostatic model assessment of insulin resistance (HOMA-IR) was 1.64±0.88, 6.14±0.46, and then 10.78±2.84, respectively. On comparing the results before and after EPO therapy in both intervention groups, there was a significant improvement in IR in both groups. HOMA-IR was 10.78±2.84 and 5.52±161 (P<0.001) before and after intervention, respectively, for diabetic patients, whereas it was 1.64±0.88 and 0.8±0.28 (P<0.001) before and after intervention, respectively, for nondiabetic patients. Glycated hemoglobin, fasting insulin level, as well as fasting and postprandial glucose measurements, all in both preintervension and postintervention settings were independent predictors for HOMA-IR after intervention in all 40 patients of both intervention groups.
Conclusion EPO treatment in HDPs is followed by improvement of IR in diabetic as well as nondiabetic patients with end-stage kidney disease and on hemodialysis.

Keywords: diabetes mellitus, end-stage renal disease, erythropoietin, hemodialysis, insulin resistance


How to cite this article:
Kasem HE, Shehab-Eldin WA, Shebl IS, Sonbol AA, Kamel MA. Insulin resistance in patients with end-stage renal disease on hemodialysis: effect of short-term erythropoietin therapy. J Egypt Soc Nephrol Transplant 2020;20:111-9

How to cite this URL:
Kasem HE, Shehab-Eldin WA, Shebl IS, Sonbol AA, Kamel MA. Insulin resistance in patients with end-stage renal disease on hemodialysis: effect of short-term erythropoietin therapy. J Egypt Soc Nephrol Transplant [serial online] 2020 [cited 2020 Dec 4];20:111-9. Available from: http://www.jesnt.eg.net/text.asp?2020/20/2/111/283243




  Introduction Top


Insulin resistance (IR) is a characteristic feature of uremia. As long as hyperinsulinemia is adequate to overcome IR, glucose tolerance remains normal [1]. In addition to abnormalities in carbohydrate metabolism, the IR syndrome is accompanied by an elevation in nonesterified fatty acid, abnormalities in visceral fat metabolism, elevated uric acid, endothelial dysfunction, and abnormalities in glucocorticoids leading to the development of atherosclerosis [2]. The influence of IR to cardiovascular risk is independent of age, BMI, concomitant hypertension and dyslipidemia, or C-reactive protein levels [3].

Numerous factors implicated in the etiology of IR include uremic toxins; chronic metabolic acidosis; intracellular ion homeostasis disequilibrium; quantitative disturbances of insulin receptor on adipocytes, skeletal muscles, and hepatocytes; cytokines produced by adipocytes (adipokines); chronic inflammation; and low physical activity [4]. Nevertheless, definitive evidence for the efficacy of some of these interventions in clinical outcomes, such as cardiovascular end points or mortality, is still lacking. However, management of IR of patients on hemodialysis is multifaceted [4]. Treatment of IR of patients with chronic kidney disease (CKD) can be achieved by hemodialysis, angiotensin-converting enzyme inhibitors, thiazolidinedione, treatment of calcium and phosphate disturbances, and recombinant human erythropoietin (EPO) [5].

Anemia is common among patients with end-stage kidney disease (ESKD). In addition to causing disabling symptoms, severe anemia may affect cardiovascular function of hemodialysis patients (HDP). Cardiovascular disease is a major cause of morbidity and mortality in patients on hemodialysis [6]. The present study is therefore conducted to assess IR of patients with CKD irrespective of diabetic status, to evaluate the effect of short-term human EPO therapy on IR.


  Patients and methods Top


Study design

This is a prospective case–control study that enrolled 60 patients with ESKD on regular hemodialysis. Group I was the study group (n=40), which consisted of patients (20 diabetics and 20 nondiabetics) with ESKD who were on regular hemodialysis and were given subcutaneous EPO in a dose of 80‒120 μg/kg/week. Before starting EPO, all patients received intravenous iron supplementation in a dose of 1000 mg to replenish deficient iron stores and continued on the intravenous iron therapy 100 mg/week thereafter. Group II was the control group (n=20), which included patients with ESKD on regular hemodialysis, but these cases did not receive EPO. IR was calculated by homeostatic model assessment of insulin resistance (HOMA-IR) because of its simplicity, where HOMA-IR = Glucose (in mg/dl) × insulin/405. Glucose in massing unit’s mg/dl.

The study was approved by the Ethics Committee of Faculty of Medicine, Menoufia University, and it was conducted during the period from February 2018 to September 2018.

Study population

All patients with end-stage renal diseases (either diabetic or nondiabetic) who were receiving regular hemodialysis were included in our study.

Patients with congestive heart failure or end-stage pulmonary disease and cancer were excluded from the study. Moreover, patients on drugs like corticosteroids, beta blockers, TZDs, biguanides, and ACE inhibitors were also excluded from the study.

All patients were subjected to informed consent, detailed history taking, full clinical examination, as well as laboratory investigations. Laboratory investigations included complete blood picture, serum electrolytes level (Na, K, Ca, and PO4), serum uric acid, serum urea, and creatinine levels, glycated hemoglobin (HbA1C), fasting and postprandial blood sugar, transferrin saturation, fasting insulin, and lipid profile.

Statistical analysis

Statistical analyses were performed using the SPSS software, version 22.0 (SPSS Inc., Chicago, Illinois, USA). Patient demographic and laboratory characteristics were presented as mean and SD for continuous variables and as proportions (percentages) for categorical variables. For continuous variables, comparison among the three population subgroups was done by one-way analysis of variance test, followed by post-hoc (Tukey) test whenever significant difference is found. Simple three-group comparisons were performed using χ2 test for categorical variables. Comparisons between results before and after EPO treatment for each population were done using paired samples t test. Pearson’s correlation was conducted between patients’ HOMA-IR and other study variables before and after intervention. Lastly, multivariate regression analysis was performed to assess the respective independent effects of several variables on postintervention HOMA-IR. The confidence interval was set to 95% and the margin of error accepted was set to 5%. So a P value lower than 0.05 was considered significant.


  Results Top


None of these patients’ demographic data and risk factors (age, sex, BMI, and duration of dialysis, as well as prevalence of diabetes mellitus and hypertension, presence of residual renal function, and positive virology) were significantly different between the study groups (P>0.05) ([Figure 1]). However, on comparing laboratory parameters, there was a statistically significant differences between study groups regarding baseline results with respect to hemoglobin (Hb), creatinine, transferrin saturation, and serum albumin before therapy (P<0.05). However, there is a statistically insignificant difference between the study groups regarding baseline cholesterol levels before therapy (P>0.05). Post-hoc analysis showed that there were highly statistically significant differences between group I (control) and group II (intervention nondiabetic) and between group I (controls) and group III (intervention diabetic) regarding Hb, creatinine, and transferrin (P<0.001). Additionally, there was a highly statistically significant difference between group I (Controls) and group III (intervention diabetic) only regarding serum albumin before therapy (P<0.001). Regarding baseline results of parameters of dialysis efficiency, none showed differences of statistical significance in the study groups (P>0.05). On the contrary, all baseline results of glycemic control parameters were significantly different between the study groups, and their post-hoc analysis results showed a stepwise increase from intervention nondiabetic group, to control group, to diabetic group in all the parameters, with highly significant differences in all pairwise comparisons (P<0.001) ([Table 1] and [Figure 1],[Figure 2],[Figure 3]).
Figure 1 Comparison between prelaboratory and postlaboratory findings in the intervention diabetic group.

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Table 1 Comparison between the studied groups regarding baseline study parameters

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Figure 2 Comparison between prelaboratory and postlaboratory findings in the intervention diabetic group.

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Figure 3 Comparison between baseline criteria of glycemic control in both control and intervention groups.

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On comparing the results before and after EPO therapy in intervention diabetic group, we found a significant improvement in almost all laboratory parameters, including Hb, transferrin saturation, serum albumin, cholesterol, uric acid, HbA1C, fasting and postprandial glucose levels, fasting insulin, and HOMA-IR (P<0.05). However, in intervention nondiabetic group, we found a significant improvement in almost all laboratory findings, including Hb, transferrin saturation, cholesterol, uric acid, HbA1C, fasting and postprandial glucose levels, fasting insulin, and HOMA-IR (P<0.05). Regarding serum urea measurements before and after dialysis, we found a significant increase in both sets of measurement after EPO therapy than before in nondiabetic patients, whereas in diabetic patients, the significant increase was found in postdialysis serum urea measurement ([Table 2] and [Table 3]).
Table 2 Comparison between laboratory findings before and after erythropoietin therapy in the intervention diabetic group

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Table 3 Comparison between laboratory findings before and after erythropoietin therapy in the intervention nondiabetic group

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On correlation analysis, both baseline and postintervention HOMA-IR was significantly correlated with baseline and postintervention measurements of HbA1C, fasting and postprandial glucose levels, and fasting insulin. Concerning each population separately, postintervention HOMA-IR in diabetic patients was significantly correlated with the previously mentioned parameters as well as duration of dialysis session. However, in nondiabetic patients, postintervention HOMA-IR was significantly correlated with only fasting and postprandial glucose levels ([Table 4] and [Table 5]).
Table 4 Correlation analyses between homeostatic model assessment of insulin resistance and rest of studied variables before intervention

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Table 5 Correlation analyses between homeostatic model assessment of insulin resistance and rest of studied variables after intervention

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  Discussion Top


IR is defined as reduced sensitivity of target organs to the biologic effect of insulin. Major functions of insulin include stimulation of glucose uptake by skeletal muscles, inhibition of hepatic glucose production, and inhibition of lipolysis in adipose tissues [7]. IR is often distinguished as either hepatic IR or peripheral IR. Hepatic IR refers to impaired suppression of hepatic glucose production, whereas peripheral IR refers to impaired skeletal muscles and adipose tissues response to insulin [8]. The most important causes of IR include genetic factors, obesity, physical inactivity, diet, medications, and aging. Other comorbid conditions that are strongly associated with IR are diabetes, hypertension, and hyperlipidemia [2].

IR is common to patients with ESKD and predicts subsequent cardiovascular events and mortality. IR results from a combination of genetic and environmental factors and contributes to type 2 diabetes mellitus, dyslipidemia, hypertension, central obesity, and cardiovascular disease [9]. IR, as potentially modifiable cardiovascular risk factor, is currently considered as a therapeutic target for patients with CKD undergoing hemodialysis. This is because of the nearly universal presence of IR and concomitant hyperinsulinemia in patients with diabetic and nondiabetic CKD [10]. The kidney plays a major role in the metabolism of insulin [11]. An estimated 30–80% of insulin in systemic circulation is removed by the kidney [12]. Insulin has a molecular weight of 6000 Da and is freely filtered by the kidney. Unfiltered insulin is also extracted from peritubular capillaries. Insulin is transported into the proximal tubules via carrier-mediated endocytosis and is metabolized into amino acids by lysosomes [13].

Approximately 60% of total renal clearance of insulin occurs by glomerular filtration and 40% by extraction from the peritubular vessels. As renal function is important to handling of insulin, it is unclear whether high fasting insulin indicates IR or decreased renal clearance in this population. As a result, these indices are derived to estimate IR from fasting insulin and glucose concentrations in the general population, such as HOMA-IR, which is calculated as fasting plasma glucose (mmol/l)×fasting plasma insulin (μIU/ml)/22.5 [14]. EPO is a glycoprotein hormone that primarily regulates red cell production. Recently, a growing body of evidence has demonstrated nonerythroid effects of EPO depending on the observation that the EPO receptor is expressed in several nonerythoid tissues including endothelium, heat, kidney, brain, adipose tissue, small bowel, uterus, and pancreatic beta-cells [15].

Indeed a series of studies have reported that EPO treatment can improve glucose tolerance, metabolic function, and inflammation in mouse models of diabetes and obesity [16]. The results of the present work showed a significant decrease in the mean values of fasting insulin levels as well as IR (calculated by HOMA-IR) in the studied group treated with EPO after 6 months; on the contrary, the control group showed insignificant changes. The results showed also a statistically significant improvement in Hb, cholesterol, HbA1C, glucose fasting and postprandial glucose in the studied group treated with EPO after 6 months.

Several previous studies showed a result that is concordant to ours. Osman and colleagues included 30 patients with ESKD in their study who were randomly assigned into two groups. EPO group consisted of 15 HDP (seven females and eight males, with mean age 47.8±9.3 years) treated with EPO therapy. Non-EPO group consisted of 15 (seven females and eight males, with mean age of 45.5±8.6 years) patients not treated with EPO. In addition to, the control group (six females, nine males, mean age 48.8±11 years) was not treated with EPO. They reported that the mean fasting insulin (11±4.2 mU/l) and HOMA-IR test (2.6±1.1) were significantly higher in patients with ESKD than control group (6.6±1.4 and 1.5±0.3 mU/l, respectively). There were significant decreases in HbA1C (5.6±1%), fasting insulin level (9.3±3.1 µU/ml), HOMA-IR (2.2±0.7), and serum leptin levels (17.4±8.7 ng/ml) and also significant increase in neuropeptide Y levels (113±9.9 pg/ml) after 3 months of rHuEpo therapy, in addition to further significant decreases in fasting insulin levels (7.1±2.1 µU/ml) and HOMA-IR (1.7±6) after 6 months in rHuEpo group. In contrast, there were significantly increases in HbA1C% (5.9±0.5%) and leptin levels (42.3±25.3 ng/ml) in No-rHuEpo group throughout the study [1].

Moreover, Nand and colleagues conducted a prospective case–control study. Adult patients of CKD (both diabetic and nondiabetic) were enrolled in the study and were randomly assigned into two groups. The study group consisted of 20 patients with ESKD (10 diabetics and 10 nondiabetics) who were on regular twice weekly hemodialysis and were given subcutaneous EPO (80–120 U/kg/weeks) after each session of dialysis. Control group included 10 patients with ESKD on regular hemodialysis but did not receive EPO. They reported that mean baseline fasting insulin levels and IR as reflected by HOMA-IR were similar in the two groups. HOMA-IR was 5.48±10.43 in the study group and 3.11±2.16 in the control group. The levels decreased significantly to 0.51±0.36 (P<0.001) in the study group and increased insignificantly to 3.84±4.08 (P>0.05) in the control group after 6 months [4].

Additionally, Khedr and colleagues conducted a study in which 59 HDP were studied. The patients were divided into two groups: 30 HDPs on regular EPO treatment (group I), and 29 HDPs not receiving EPO (group II); diabetic patients were not excluded. Full medical history and clinical examination, hematological parameters, lipid profile, serum albumin, parathyroid hormone, Kt/V, fasting glucose, and insulin levels were measured in all patients. HOMA-IR was used to compare IR. The results of this study showed that the mean insulin level of HD patients treated with EPO (group I) (17.5±10.6 μU/ml) was significantly lower than patients without EPO (group II) (28.8±7.7 μU/ml) (P<0.001). HOMA-IR levels in group I were significantly lower than in group II (3.8±2.97, 7.98±4.9, respectively, P<0.001). IR reflected by HOMA-IR levels among diabetic patients in group I was significantly lower than among diabetic patients in group II (3.9±3.2, 9.4±7.2, respectively, P<0.001). Moreover, HOMA-IR levels among nondiabetic patients in group I were significantly lower than among nondiabetic patients in group II (3.7±2.85, 6.9±1.43, respectively, P<0.01). We found a statistically significant negative correlation between duration of EPO treatment, fasting blood glucose, insulin levels, and IR (r=−0.62, −0.71, and −0.57, P<0.001) [17].

Rasic-Milutinovic and colleagues investigated the effects of 6-month duration treatment of EPO on IR and inflammatory parameters in 16 (six male/10 female) patients on maintenance HD with renal anemia (hemoglobin concentration ≤105 g/l). The control group consisted of 15 patients on HD with renal anemia, without EPO treatment. Further clinical and laboratory variables were observed: fasting blood glucose, insulin, albumin, iron, total iron binding capacity, transferrin saturation, ferritin, tumor necrosis factor-alpha (TNF-α), and interleukin-6. Independent predictors for a change of calculated IR index by HOMA-IR were identified by multivariate linear regression analysis.

They reported that there was a significant reduction of insulin levels and therefore significant lowering of HOMA-IR was registered for EPO-treated group. Improvement in anemia was observed [Hb, 93.90±17.34 vs. 116.40±21.03 g/l; P=0.01; hematocrit, 0.28 (0.24–0.31) vs. 0.33% (0.31–0.37); P=0.01] as well as a trend toward iron stores decrease [ferritin, 466.45 (174.40–886.90) vs. 279 µg/l (137.00–648.50); P=0.06]. A significant decrease of TNF-α [2.30 (1.48–2.95) vs. 1.65 pg/ml (0.11–1.96); P=0.01] and iterleukin-6 levels [8.32 (2.31–9.83) vs. 2.60 pg/ml (2.00–3.05); P=0.01] was presented. After adjustment for confounding variables (age, sex, and Kt/V), a model consisting of BMI, ferritin, and TNF-α accounted for 96% of the variance in HOMA-IR in EPO-treated patients [18].

In the study by Tuzcu and colleagues, three groups of patients were included: HDPs treated with EPO [EPO (+) group] or without EPO [EPO (−) group], and healthy controls. Anthropometrical parameters, lipid levels, fasting glucose, and insulin levels were measured in all patients. HOMA was used to compare insulin sensitivity. Analysis of variance, independent t test, and Pearson correlation were used for statistical analysis. The results of this study showed that the mean insulin level of control group (20.04±7.2 pmol/l) was significantly lower than EPO (+) group (P<0.04) and EPO (−) group (P<0.0001). HOMA (%B) levels in the EPO (+) group were significantly lower than in the EPO (−) group (106±42, 140±63, respectively, P<0.02). HOMA (%B) levels in the control group (66±17) were significantly lower than in the EPO (+) and EPO (−) group (P<0.005 and <0.0001, respectively). HOMA (%S) levels in the EPO (+) groups were significantly higher than in the EPO (−) group (91±40, 56±26, respectively; P<0.01). HOMA (%S) levels of control group (125±24) were significantly higher than EPO (+) and EPO (−) groups (P<0.02 and <0.0001, respectively). We found a positive correlation between duration of EPO treatment and insulin sensitivity (r=0.484, P<0.002) [19].

The site of IR in patients with renal disease is localized to skeletal muscle; suppression of hepatic glucose metabolism remained normal in studies in which it was assessed. A postreceptor defect has been recognized as the primary defect in patients with ESKD [20]. Studies suggest variable pancreatic beta-cell function in response to IR in ESKD, resulting in glucose intolerance in some patients. However, management of IR in patients on hemodialysis is multifaceted. Treatment of IR in patients with CKD can be achieved by hemodialysis, angiotensin-converting enzyme inhibitors, thiazolidinedione, and treatment of calcium and phosphate disturbances and recombinant human EPO [21].

IR results from a combination of genetic and environmental factors including infiltration of inflammatory cells into adipose tissue in animal models and is associated with IR in humans [22]. Among potential therapeutic approaches, the hormone EPO exerts anti-inflammatory effects in a variety of nonerythroid tissues in which the receptor for EPO is widely expressed [23]. Various observations suggested a relationship between EPO and diabetes. There is an increased prevalence of anemia with inadequate EPO response to diabetes [24], and treatment of anemia slows the progression of micro-vascular and macrovascular complications [25].

EPO reduced glucose levels in nondiabetic humans and reduced diet induced obesity and suppressed gluconeogenesis in rodents. However, EPO increases adipose tissue oxidative metabolism, and deletion of EPO in adipocytes results in obesity, and failure to reproduce this highlights potential genetic and environmental influences [26]. The results of present work showed a significant decrease in the mean values of HbA1C in the studied group after 6 months as compared with baseline; on the contrary, the control group showed insignificant changes as compared with baseline. Our study findings are in line with that of previous studies.

Ng and colleagues conducted a prospective study of patients with type 2 diabetes and CKD stage undergoing intravenous iron (group I) and/or erythropoiesis stimulating agents (ESA) (group II). Full blood profiles were determined over the study period. Glycemic control was monitored using HbA1C, seven-point daily glucose three times weekly, and continuous glucose monitoring. There were 15 patients in both group I and group II. Mean A1C (95% confidence interval) values fell in both groups [7.40% (6.60–8.19) to 6.96% (6.27–7.25), P<0.01, with intravenous iron and 7.31% (6.42–8.54) to 6.63% (6.03–7.36); P=0.013, ESA]. There was no change in mean blood glucose in group I [9.55 mmol/l (8.20–10.90) vs. 9.71 mmol/l (8.29–11.13); P=0.07] and in group II [8.72 mmol/l (7.31–10.12) vs. 8.78 mmol/l (7.47–9.99); P=0.61] over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment [27].HbA1C is the most widely accepted and used method of assessing chronic hyperglycemia in patients with diabetes. It is formed by irreversible binding of glucose to hemoglobin over the life span of the erythrocytes [28]. Treatment of anemia in ESKD using iron replacement therapy, an EPO, has resulted in significant improvements to quality of life and the correction of anemia without the need for blood transfusions [29].

In cases with chronic renal failure, renal anemia lowers the HbA1C values because the life span of erythrocytes is shortened. The HbA1C values are reported to be correlated with the life span of the erythrocytes in patients with diabetic nephropathy. It has also been reported that the values of HbA1C are underestimated in patients with diabetic nephropathy undergoing peritoneal dialysis or hemodialysis [30].

Furthermore, the HbA1C values of patients who were treated with EPO were lower than those patients who were not treated, as the life span of the erythrocytes is shortened [31].

This was not the case of Abdel-Aziz and colleagues, who studied HbA1C reliability in patients with diabetes on regular hemodialysis before and after EPO therapy. The study included 41 patients on regular hemodialysis who were EPO naive: 31 with diabetes mellitus and 10 nondiabetic controls. Baseline HbA1C and fasting blood glucose levels were measured and repeated after a 3-month course of EPO. He reported that HbA1C decreased significantly after EPO therapy (P=0.01) and was associated with a significant decline in fasting blood glucose levels (P=0.001), with a significant negative correlation with hemoglobin (r=−0.185, P=0.03). HbA1C showed significant correlation with fasting blood glucose in diabetic patients before EPO therapy (r=0.82, P<0.0001). This correlation was found to be independent of other laboratory parameters. No correlation was found between HbA1C and fasting blood glucose levels after 3 months of EPO treatment [32].


  Conclusion Top


EPO treatment in hemodialyzed patients with chronic renal failure is followed by improvement of IR in the studied group in the form of significant decline of HOMA-IR, HbA1C, and fasting blood glucose level; on the contrary, the control group showed insignificant changes. These results are obtained by studying the EPO therapy and the possible causes of IR in hemodialyzed patients. However, regular EPO therapy is advised in all HDPs because of its favorable effect on insulin sensitivity and appetite in addition to its role in treatment of anemia in these populations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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