Hostname: page-component-7c8c6479df-ph5wq Total loading time: 0 Render date: 2024-03-28T08:34:11.935Z Has data issue: false hasContentIssue false

Effects of magnesium supplementation on carotid intima–media thickness and metabolic profiles in diabetic haemodialysis patients: a randomised, double-blind, placebo-controlled trial

Published online by Cambridge University Press:  11 February 2019

Hamid Reza Talari
Affiliation:
Department of Radiology, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Mehrafrouz Zakizade
Affiliation:
Department of Radiology, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Alireza Soleimani
Affiliation:
Department of Internal Medicine, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Fereshteh Bahmani
Affiliation:
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Amir Ghaderi
Affiliation:
Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Naghmeh Mirhosseini
Affiliation:
School of Public Health, University of Saskatchewan, Saskatoon, SK S7N 2Z4, Canada
Masoumeh Eslahi
Affiliation:
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Mahtab Babadi
Affiliation:
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
Mohammad Ali Mansournia
Affiliation:
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran 1417653761, Iran
Zatollah Asemi*
Affiliation:
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, PO Box 87159-81151, Iran
*
*Corresponding author: Z. Asemi, email asemi_r@yahoo.com
Rights & Permissions [Opens in a new window]

Abstract

This study evaluated the effects of Mg administration on carotid intima–media thickness (CIMT), glycaemic control and markers of cardio-metabolic risk in diabetic haemodialysis (HD) patients. This randomised, double-blind, placebo-controlled clinical trial was conducted in fifty-four diabetic HD patients. Participants were randomly divided into two groups to take either 250 mg/d Mg as magnesium oxide (n 27) or placebo (n 27) for 24 weeks. Mg supplementation resulted in a significant reduction in mean (P<0·001) and maximum levels of left CIMT (P=0·02) and mean levels of right CIMT (P=0·004) compared with the placebo. In addition, taking Mg supplements significantly reduced serum insulin levels (β=–9·42 pmol/l; 95% CI –14·94, –3·90; P=0·001), homoeostasis model of assessment-insulin resistance (β=–0·56; 95 % CI –0·89, –0·24; P=0·001) and HbA1c (β=–0·74 %; 95 % CI –1·10, –0·39; P<0·001) and significantly increased the quantitative insulin sensitivity check index (β=0·008; 95 % CI 0·002, 0·01; P=0·002) compared with the placebo. In addition, Mg administration led to a significant reduction in serum total cholesterol (β=–0·30 mmol/l; 95% CI –0·56, –0·04; P=0·02), LDL-cholesterol (β=–0·29 mmol/l; 95% CI –0·52, –0·05; P=0·01), high-sensitivity C-reactive protein (hs-CRP) (P<0·001) and plasma malondialdehyde (MDA) (P=0·04) and a significant rise in plasma total antioxidant capacity (TAC) levels (P<0·001) compared with the placebo. Overall, we found that taking Mg for 24 weeks by diabetic HD patients significantly improved mean and maximum levels of left and mean levels of right CIMT, insulin metabolism, HbA1c, total cholesterol and LDL-cholesterol, hs-CRP, TAC and MDA levels.

Type
Full Papers
Copyright
© The Authors 2019 

Haemodialysis (HD) is getting remarkably involved in the treatment of patients with end-stage kidney diseases worldwide( Reference Couser, Remuzzi and Mendis 1 ). Recently, the ratio of diabetic patients receiving HD has been exceedingly increased. Carotid intima–media thickness (CIMT) is a severe complication in diabetic patients under HD. This complication is often combined with protein–energy wasting, inflammation and subsequently cardiovascular events (CVE)( Reference Nambi, Pedroza and Kao 2 , Reference Minoguchi, Yokoe and Tazaki 3 ). Diabetes mellitus is associated with an excess inflammatory status and accounts for one of the major cause of end-stage renal disease (ESRD)( Reference Sabatino, Regolisti and Cosola 4 ). The risk of CVE is the largest among diabetic patients compared with non-diabetics with ESRD( Reference Whaley-Connell and Sowers 5 ). It has been reported that patients under HD are susceptible to many risk parameters for cardiac events including insulin resistance, enhanced reactive oxygen species (ROS), reduced antioxidant defence, infection and comorbid conditions such as hypertension, exacerbation of inflammatory cytokines, which in turn influence the health-related quality of life in diabetic patients under HD( Reference Sohrabi, Eftekhari and Eskandari 6 Reference Yen, Lin and Lin-Tan 8 ).

Recent evidence has demonstrated that Mg supplementation significantly improved CIMT in patients undergoing HD( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ). Inflammatory cytokines also take part in the pathophysiology of diabetic nephropathy( Reference Lim and Tesch 10 , Reference Wu, Sytwu and Lin 11 ). Clinical evidence has reported that enhanced inflammatory markers are common in diabetic HD patients and may result in the progressive atherosclerosis( Reference Almeida, Lourenço and Fonseca 12 ). It has been demonstrated that Mg levels in diabetes HD subjects were significantly lower than those of healthy controls( Reference Silva, Fragoso and Silva 13 ), and lower Mg status is associated with enhanced atherosclerosis of the common carotid artery( Reference Tzanakis, Virvidakis and Tsomi 14 ). Previously studies have shown the beneficial effects of Mg supplementation on metabolic profiles and insulin resistance in patients with type 2 diabetes mellitus (T2DM)( Reference Barbagallo and Dominguez 15 , Reference Barbagallo and Dominguez 16 ) and CIMT in HD subjects( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ). In addition, Mg administration significantly improved glucose homoeostasis outcomes in diabetic subjects( Reference Paolisso, Scheen and D’Onofrio 17 ). A growing body of evidence derived from clinical trials shows that Mg administration improves insulin sensitivity and dyslipidaemia in diabetic and non-diabetic patients( Reference Rodriguez-Moran and Guerrero-Romero 18 Reference Chacko, Sul and Song 20 ). Unlike, another study failed to find any improvement in glycaemic control and metabolic profiles in response to ingesting Mg supplements( Reference Navarrete-Cortes, Ble-Castillo and Guerrero-Romero 21 ). Mg element is an essential co-factor in the enzymatic process of high-energy phosphate, acts as a Ca ion channel antagonist and secretion of prostacyclin and nitric oxide (NO); therefore, Mg is involved in the metabolic pathways that regulate glucose and lipid profiles( Reference Lopez Martinez, Sanchez Castilla and Garcia de Lorenzo y Mateos 22 Reference Sontia and Touyz 24 ).

To our knowledge, data from studies investigating the effects of Mg administration on CIMT, glycaemic control, lipid profiles, biomarkers of inflammation and oxidative stress in diabetic HD patients are limited. Therefore, this study was aimed to evaluate the effects of Mg supplementation on CIMT and metabolic profiles in diabetic HD subjects.

Methods

Trial design and participants

The present study, registered in the Iranian website for clinical trials (http://www.irct.ir, no. IRCT2017090133941N19), was a randomised, double-blind, placebo-controlled clinical trial which was done among fifty-four diabetic HD patients aged 18–80 years who were referred to the Yasrebi Clinic in Kashan, Iran, between December 2017 and June 2018. This intervention was conducted in accordance with the Declaration of Helsinki and informed consent was taken from all subjects. This investigation was approved by the ethics committee of Kashan University of Medical Sciences (KAUMS). Patients with inflammatory and malignant diseases, those taking Mg supplements, antioxidant and/or anti-inflammatory supplements within 3 months before enrolment in the study and subjects taking immunosuppressive agents were not included in the present study. Immunosuppressive agents might have different side effects such as dyslipidaemia, hyperglycaemia, liver and kidney injury among patients, so we excluded the subjects on immunosuppressive agents from the present study( Reference Velickovic-Radovanovic, Mikov and Catic-Djordjevic 25 ).

Study design

First, subjects were matched according to sex, BMI and age. Patients were requested to continue their routine physical activity and not to take any anti-inflammatory and antioxidant medications or supplements that might influence their nutritional status during the 24-week intervention. Consumption of Mg and placebos throughout the study was checked through assessing Mg levels by an enzymatic method. A 3-d food records and physical activity records were completed by all participants at weeks 0, 6, 12, 18 and 24 of the intervention. To obtain macro- and micro-nutrient intake of participants based on 3- d food diaries, Nutritionist IV software (First Databank) modified for Iranian foods was used.

Intervention

Patients were randomly divided into two groups to take either 250 mg/d Mg supplements as magnesium oxide (Twenty First Century Pharmaceutical Company) (n 27) or placebo (Barij Essence Pharmaceutical Company) (n 27) for 24 weeks.

Assessment of anthropometric measures

Body weight and height were quantified in an overnight fasting status using a digital scale (Seca) at baseline and after the 24-week intervention. BMI was calculated by weight and height measurements (weight (kg)/height (m2)).

Assessment of outcomes

CIMT was considered as primary outcome and glycaemic control, lipid profiles and biomarkers of inflammation and oxidative stress were considered as secondary outcomes. Measurement of the CIMT was conducted in patients at the 2- cm distance of the common carotid bifurcation, by the same sonographer, at baseline and after the 24-week intervention using a Doppler ultrasonography device (Samsung Madyson V20) with linear multi-frequencies of 7·5–10 MHz probe. The physician was blinded to any clinical information of the subjects.

A 10 ml fasting blood sample was collected at baseline and after the 24-week intervention at Kashan reference laboratory. Then the samples were stored at –80°C before analysis. Serum insulin and high-sensitivity C-reactive protein (hs-CRP) levels were quantified using an ELISA kit (DiaMetra and LDN) with inter- and intra-assay CV below 7 %. The homoeostasis model of assessment-insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were determined according to the standard formula( Reference Pisprasert, Ingram and Lopez-Davila 26 ). HbA1c values in whole blood were assessed by Glycomat kit (BiocodeHycel) using the method of exchange chromatography. Enzymatic kits (Pars Azmun) were used to quantify serum Mg, fasting plasma glucose (FPG), lipid profiles with inter- and intra-assay CV below 5 %. The plasma NO using Griess method( Reference Tatsch, Bochi and Pereira Rda 27 ), total antioxidant capacity (TAC) by the method of ferric reducing antioxidant power developed by Benzie & Strain( Reference Benzie and Strain 28 ), total glutathione (GSH) using the Beutler & Gelbart( Reference Beutler and Gelbart 29 ) method and malondialdehyde (MDA) concentrations by the thiobarbituric acid reactive substances spectrophotometric test( Reference Janero 30 ) were determined with inter- and intra-assay CV below 5 %.

The questions of subjective global assessment (SGA) questionnaire were also asked by the same person after 12 weeks of the intervention. Then the SGA classifications were converted to numerical equivalents( Reference Nursal, Noyan and Tarim 31 ).

Sample size

We used a randomised clinical trial sample size calculation formula where type I (α) and type II errors (β) were 0·05 and 0·20 (power=80 %), respectively. According to the previous trial( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ), we used 0·13 mm as the sd and 0·105 as the change in mean (d) of CIMT as a primary outcome. Based on the formula, we needed twenty-five participants in each group; after allowing for five dropouts in each group, the final sample size was thirty persons in each group. We used the standard deviation (0·13 mm) of the CIMT from the Mortazavi et al. ( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ) paper with study design similar to ours. For sample size calculation, the minimal clinically important effect size is also required which is determined by the researcher (it should not be derived from the literature)( Reference Mansournia and Altman 32 , Reference Nielsen, Bertelsen and Verhagen 33 ). In addition, we hypothesised that effect size of 0·105 mm of CIMT would result in a significant change in CIMT in diabetic HD patients. In a study by Mortazavi et al. ( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ), Mg supplementation for 6 months to HD patients significantly reduced CIMT by 0·08 mm. Also the standardised effect size equals 0·0105/0·13=0·8 which is considered as a large effect size according to Cohen( Reference Mansournia and Altman 32 ). With sd=0·13 participants in each group, we have at least 80 % power (probability) of detecting a difference equal to or >0·105 (if it really exists) as statistically significant at the 5 % level.

Randomisation

Randomisation assignment was conducted using computer-generated random numbers. Randomisation and allocation were concealed from the researchers and patients until the final analyses were completed. The randomised allocation sequence, enrolling participants and allocating them to interventions were conducted by a trained nutritionist at the dialysis clinic.

Statistical methods

The Kolmogorov–Smirnov test was done to determine the normality of data. To detect the differences in anthropometric measures and dietary intakes between two groups, independent-samples t test was used. Multiple linear regression models were used to assess treatment effects on study outcomes after adjusting for confounding parameters including age and BMI. The effect sizes were presented as the mean differences with 95 % CI. P<0·05 were considered statistically significant. All statistical analyses were done using the Statistical Package for Social Science version 18 (SPSS Inc.).

Results

Three patients in each group withdraw from the trial, due to personal reasons, and finally fifty-four patients (Mg (n 27) and placebo (n 27)) completed the study (Fig. 1). The compliance rate was high; more than 90 % of capsules were taken during the course of the trial in both groups. No side effects were reported following the consumption of Mg supplements in diabetic HD patients throughout the study.

Fig. 1 Summary of patient flow diagram.

Distribution of sex, mean age, height, baseline weight and BMI as well as their means after intervention and years of dialysis of study participants were not statistically different between the two groups (Table 1).

Table 1 General characteristics of study participants (Mean values and standard deviations; numbers and percentages)

* Obtained from independent t test.

Obtained from Pearson’s χ 2 test.

Based on the 3-d dietary records obtained throughout the treatment period, we found no significant change in dietary macro- and micro-nutrient intake (Table 2).

Table 2 Mean dietary intake of study participants at baseline, weeks 6, 12, 18 and 24 of the study (Mean values and standard deviations)

TDF, total dietary fibre.

* Obtained from independent t test.

After the 24-week intervention, Mg supplementation resulted in a significant reduction in mean (β=–0·04 mm; 95 % CI –0·06, –0·02; P<0·001) and maximum levels of left CIMT (β= –0·06 mm; 95 % CI –0·11, –0·009; P=0·02) and mean levels of right CIMT (β=–0·05 mm; 95 % CI –0·08, –0·01; P=0·004) compared with the placebo (Table 3). In addition, taking Mg significantly reduced serum insulin levels (β=–9·42 pmol/l; 95% CI –14·94, –3·90; P=0·001), HOMA-IR (β=–0·56; 95 % CI –0·89, –0·24; P=0·001) and HbA1c (β=–0·74 %; 95 % CI –1·10, –0·39; P<0·001) and significantly increased QUICKI (β=0·008; 95 % CI 0·002, 0·01; P=0·002) compared with placebo. In addition, Mg administration led to a significant reduction in serum total cholesterol (β=–0·30 mmol/l; 95% CI –0·56, –0·04; P=0·02), LDL-cholesterol (β=–0·29 mmol/l; 95% CI –0·52, −0·05; P=0·01), hs-CRP (β=–1·57 mg/l; 95 % CI –2·06, –1·08; P<0·001) and plasma MDA (β=–0·26 µmol/l; 95 % CI –0·53, –0·001; P=0·04), and a significant rise in plasma TAC levels (β=168·91 mmol/l; 95 % CI 113·92, 223·89; P<0·001) compared with the placebo. Mg supplementation did not change maximum levels of right CIMT and other metabolic parameters.

Table 3 Carotid intima–media thickness, metabolic profiles, biomarkers of inflammation and oxidative stress at study baseline and after the 24-week intervention in patients with diabetic haemodialysis that received either magnesium supplements or placebo (Mean values and standard deviations; β-coefficients and 95 % confidence intervals)

CIMT, carotid intima–media thickness; FPG, fasting plasma glucose; HOMA-IR, homoeostasis model of assessment-insulin resistance; QUICKI, quantitative insulin sensitivity check index; hs-CRP, high-sensitivity C-reactive protein; NO, nitric oxide; TAC, total antioxidant capacity; GSH, total glutathione; MDA, malondialdehyde; SGA, subjective global assessment; GFR, glomerular filtration rate.

* ‘Outcome measures’ refers to the change in values of measures of interest between baseline and week 24. β (difference in the mean outcome measures between treatment groups (Mg group=1 and placebo group=0)).

Obtained from multiple regression model (adjusted for baseline values of each biochemical variables, age and baseline BMI).

To convert Mg in mg/dl to mg/l, multiply by 10. To convert FPG in mg/dl to mmol/l, multiply by 0·0555. To convert insulin in μIU/ml to pmol/l, multiply by 6. To convert TAG in mg/dl to mmol/l, multiply by 0·0113. To convert cholesterol in mg/dl to mmol/l, multiply by 0·0259.

Discussion

In this study, we investigated the effects of Mg supplementation on CIMT and metabolic profiles in diabetic HD subjects. We found that taking Mg for 24 weeks by diabetic HD patients significantly improved mean and maximum levels of left and mean levels of right CIMT, insulin, HOMA-IR, QUICKI, HbA1c, total cholesterol and LDL-cholesterol, hs-CRP, TAC and MDA levels; however, it did not have any effect on maximum levels of right CIMT and other metabolic profiles. Earlier, hypomagnesaemia was reported in the majority of subjects undergoing HD( Reference Silva, Fragoso and Silva 13 ). Based on this finding, Mg may be an appropriate adjunct therapy for diabetic HD subjects. To our best knowledge, this study for the first time evaluated the effects of Mg supplementation on CIMT and metabolic profiles in diabetic HD patients. According to the inclusion criteria, the age range of study participants was broad (18–80 years old); however, in reality at analysis phase we did not have any subjects younger than 35 years old and the number of participants in the age category of <55 was very low and the majority of study population were older than 55 years old. So age range of study participants was 35–80 years in both groups. Number of participants younger than 55 was 4 in placebo group and 6 in Mg group. All our patients were diabetic and under HD, which can affect the markers of cardio-metabolic risk. However, at the onset of the study, all participants were matched according to sex, BMI and age to decrease potential confounding effects, and we believe that this fact has been considered in our finding interpretation.

Effects on carotid intima–media thickness

Diabetic HD is associated with some complications, including increased CIMT and other atherosclerotic events( Reference Nambi, Pedroza and Kao 2 , Reference Minoguchi, Yokoe and Tazaki 3 ). The current study supported that Mg for 24 weeks by diabetic HD patients significantly reduced mean and maximum levels of left, and mean levels of right CIMT, but did not affect maximum levels of right CIMT. Previous studies have documented that there is a difference between the left and right CIMT. It was reported that haemodynamic factors including peak velocity, resistivity index and pulsatility index and age, sex, metabolic profiles especially lipid concentrations, blood glucose levels and other risk factors would have different effects on the left and right CIMT( Reference Luo, Yang and Cao 34 ). In a study conducted by Luo et al. ( Reference Luo, Yang and Cao 34 ), left CIMT correlated better with blood biochemical indices, including total cholesterol, LDL-cholesterol and fasting glucose levels. In addition, Hileman et al. ( Reference Hileman, Turner and Funderburg 35 ) demonstrated that decreased markers of oxidative stress, inflammation and monocyte activation resulted in improved CIMT. Earlier, it was documented that Mg may play an active role in the development and regression of atherosclerotic damage in HD patients. It has been reported that atherosclerotic changes in the carotid arteries measured by ultrasonography reflect atherosclerosis of coronary arteries( Reference Fabbian, Cacici and Franceschini 36 ). A recent meta-analysis demonstrated the significant risk of cardiovascular events was associated with CIMT( Reference Lorenz, Markus and Bots 37 ). Data on the effects of Mg supplementation on CIMT in diabetic patients undergoing HD are limited. In a study conducted by Mortazavi et al. ( Reference Mortazavi, Moeinzadeh and Saadatnia 9 ), Mg at a dosage of 440 mg three times per week for 6 months significantly decreased CIMT in HD patients. Turgut et al. ( Reference Turgut, Kanbay and Metin 38 ) also found that Mg supplementation in HD subjects at a dosage of 610 mg/d for 2 months improved CIMT and atherosclerosis. Recent evidence has demonstrated large amounts of Ca deposited in the coronary system of HD patients. In ESRD patients, enhanced P, Ca and parathyroid hormone (PTH) levels are the leading causes in the initiation and the progression of Ca deposition. Mg is considered a PTH antagonist, and evidence indicates that lower Mg status is significantly correlated with CVD and CIMT. A significant impact of Mg administration on CIMT may be explained through reduction in PTH and amelioration endothelial function( Reference Blacher, Guerin and Pannier 39 Reference Ganesh, Stack and Levin 41 ).

Effects on glycaemic control

HD patients are vulnerable to insulin resistance and oxidative damage( Reference Simental-Mendia, Sahebkar and Rodriguez-Moran 42 , Reference Simental-Mendia, Simental-Mendia and Sahebkar 43 ). We found that consuming Mg supplements for 24 weeks by diabetic HD patients improved insulin, HOMA-IR, QUICKI, HbA1c but did not affect FPG. It has been demonstrated that Mg deficiency, via blockage of insulin metabolism, dependents of kinases and the triggering of the initial phase response are involved in the reduction of insulin sensitivity and then in the defect of glycaemic metabolism( Reference Simental-Mendia, Sahebkar and Rodriguez-Moran 42 ). Data documenting the impact of Mg administration on glycaemic control and lipid parameters in diabetic patients undergoing HD are scarce. Previous studies have demonstrated that Mg consumption is an attractive option for decreasing the risk of developing T2DM and ameliorating glucose metabolism( Reference Kim, Xun and Liu 44 , Reference Rumawas, McKeown and Rogers 45 ). Also, in a meta-analysis conducted by Simental-Mendia et al. ( Reference Simental-Mendia, Sahebkar and Rodriguez-Moran 42 ), Mg supplementation significantly improved HOMA-IR and FPG in both diabetic and non-diabetic subjects. However, another study showed that Mg administration did not have any beneficial effect on improving HbA1c( Reference Gerich 46 ). This finding can be explained by the document showing that HbA1c is an indicator of overall glycaemia over the preceding 4 months; so it is possible that HbA1c may not impact on glycaemic metabolism of short-time duration( Reference Gerich 46 ). Improved glucose homoeostasis parameters are believed to prevent malnutrition and atherosclerosis syndrome, the latter being one of the most important phenomenon in diabetic subjects under HD treatment. The favourable effects of Mg on glycaemic control may be due to the stimulated regulation of ATP-sensitive K channels and voltage-dependent Ca channel, which are implicated in the physiological insulin secretion( Reference Kowluru, Chen and Modrick 47 ).

Effects on lipid profiles

Patients with HD are susceptible to dyslipidaemia( Reference Simental-Mendia, Simental-Mendia and Sahebkar 43 ). We found that consuming Mg supplements for 24 weeks by diabetic HD patients reduced total cholesterol and LDL-cholesterol levels but did not affect other lipid profiles. Despite the non-pharmacological adjunct therapies, we still face the challenge of the epidemic growth of dyslipidaemia and CVD. Several finding have indirectly evaluated the impact of Mg intake on improving lipid parameters( Reference Jamilian, Samimi and Faraneh 48 , Reference Solati, Ouspid and Hosseini 49 ). We have previously reported that Mg supplementation at a dosage of 250 mg/d for 6 weeks by subjects with gestational diabetes improved few lipid profiles( Reference Jamilian, Samimi and Faraneh 48 ). Solati et al. ( Reference Solati, Ouspid and Hosseini 49 ) showed that Mg supplementation (300 mg/d) for 3 months to patients with T2DM significantly reduced LDL-cholesterol levels. However, in a meta-analysis by Simental-Mendia et al. ( Reference Simental-Mendia, Simental-Mendia and Sahebkar 43 ), Mg administration had no significant effects on lipid profiles in both diabetic and non-diabetic subjects. The beneficial actions of Mg on lipid profiles may be due to increased cholesterol esterification mediated by higher lecithin–cholesterol acyltransferase activity( Reference Gueux, Rayssiguier and Piot 50 , Reference Sales, Santos and Cintra 51 ).

Effects on biomarkers of inflammation and oxidative stress

A significant proportion of subjects with diabetes ultimately develop diabetic nephropathy( Reference Dronavalli, Duka and Bakris 52 ). Dialysis causes some relevant changes in the function of the immune system, monocyte-derived dendritic cells and in the release of various pro-inflammatory parameters and oxidative stress increase( Reference DeAngelis, Reis and Ricklin 53 , Reference Choi, Woo and Kim 54 ). We found that diabetic patients undergoing HD who were supplemented with Mg for 24 weeks had significantly reduced serum hs-CRP and plasma MDA and enhanced TAC levels but did not improve plasma NO and GSH levels, when compared with patients who received placebo. Some studies demonstrated that Mg supplementation had beneficial impacts on oxidative stress and inflammation in patients without diabetic HD. In accordance to these results, Mg supplementation ameliorated inflammation and oxidative stress in the metabolic syndrome( Reference Song, Ridker and Manson 55 ). Also, Mg administration (320 mg/d) among adults for 7 weeks significantly reduced hs-CRP( Reference Nielsen, Johnson and Zeng 56 ). In another study, after Mg intake at a dosage of 250 mg/d for 12 weeks, the median values of hs-CRP were significantly decreased and the plasma TAC levels were enhanced in patients with diabetic foot ulcer( Reference Razzaghi, Pidar and Momen-Heravi 57 ). However, Mg supplementation did not affect metabolic profiles in diabetic subjects with normomagnesaemia( Reference Navarrete-Cortes, Ble-Castillo and Guerrero-Romero 21 ). Anti-inflammatory impacts of Mg intake may be due to the effects of its antagonism to Ca channels, inhibition of N-methyl-d-aspartate receptors and the inactivation of NF-κB( Reference Aneiros, Philipp and Lis 58 , Reference Mazur, Maier and Rock 59 ). As well as, Mg supplementation may enhance TAC levels through decreasing ROS production and increasing glutathione-peroxidase activity( Reference Liu, Guo and Wang 60 , Reference Boujelben, Ghorbel and Vincent 61 ).

This study had few limitations. In the present study, we could not evaluate the effects of Mg intake on gene expression of insulin and inflammation signalling pathway and the role of polymorphisms in gene candidates in diabetic HD subjects. In addition, further studies are needed with bigger sample size to confirm our findings. Also, we were not able to assess the levels of calcification of the right and left carotid arteries, PTH and vitamin D at baseline and after the 24-week Mg supplementation, due to the lack of enough funding. In the present study, we were not able to determine whether Mg supplementation improves HD state. However, Mg intake might play an indirect role in HD state due to its effect on improved glycaemic control and other metabolic profiles. In the present study, despite a significant reduction in insulin concentrations, HbA1c levels and HOMA-IR, we did not find any significant effect on FPG following Mg supplementation. Consistent with our findings, in a study conducted by ELDerawi et al. ( Reference ELDerawi, Naser and Taleb 62 ), Mg supplementation (250 mg/d of elemental Mg) for 3 months to patients with T2DM significantly reduced insulin, HbA1c levels and HOMA-IR but did not affect fasting glucose. Moreover, Yokota et al. ( Reference Yokota, Kato and Lister 63 ) reported a significant reduction in insulin levels and HOMA-IR but not in fasting glucose and HbA1c after Mg supplementation for 30 d in patients with T2DM. In addition, a 3-month oral administration of magnesium oxide significantly decreased HbA1c and HOMA-IR but did not affect fasting glucose in pre-diabetic and obese patients with stage 2 and 3 chronic kidney disease( Reference Toprak, Kurt and Sari 64 ). There are also controversial findings; Guerrero-Romero et al. ( Reference Guerrero-Romero, Tamez-Perez and Gonzalez-Gonzalez 19 ) demonstrated that the intake of 50 ml magnesium chloride for 16 weeks significantly improved HOMA-IR, fasting glucose and HbA1c in patients with T2DM. The absence of beneficial effects of Mg supplementation on FPG may be ascribed to the failure in effectively increasing intracellular Mg. Higher doses of Mg or longer duration of supplementation might be required to let intracellular Mg increase. It is also important to note that serum Mg levels do not thoroughly reflect dietary or supplemental Mg intake. Although serum Mg levels are dependent on dietary intake, intestinal absorption, and kidney function, urinary Mg excretion and intracellular Mg levels are better indicators than serum Mg concentrations and are more sensitive to oral supplementation than serum Mg concentrations. Overall, there are different parameters including participants’ characteristics like kidney function, higher doses of Mg or longer intervention which can provide appropriate intracellular levels of Mg necessary for lowering FPG. However, we were not able to assess intracellular Mg concentrations in the present study. Perhaps if the dose or duration of Mg had been increased, the results of FPG would have been significant. Nonetheless, we believe that further studies with more prolonged use of Mg in doses that are higher than usual are required to establish its routine or selective administration in diabetic patients under HD to control their FPG levels.

Conclusions

Overall, we found that taking Mg for 24 weeks by diabetic HD patients significantly improved mean and maximum levels of left and mean levels of right CIMT, insulin, HOMA-IR, QUICKI, HbA1c, total cholesterol and LDL-cholesterol, hs-CRP, TAC and MDA levels; however, it did not have any effect on maximum levels of right CIMT and other metabolic profiles.

Acknowledgements

The authors would like to thank the staff of Akhavan Clinic (Kashan, Iran) for their assistance in this project.

The present study was supported by a grant from the Vice-chancellor for Research, KAUMS, and Iran.

Z. A. contributed in conception, design, statistical analysis and manuscript drafting. H. R. T., M. Z., A. S., F. B., A. G., N. M., M. E., M. B. and M. A. M. contributed in data collection and manuscript drafting.

The authors declare that there are no conflicts of interest.

References

1. Couser, WG, Remuzzi, G, Mendis, S, et al. (2011) The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int 80, 12581270.Google Scholar
2. Nambi, V, Pedroza, C & Kao, LS (2012) Carotid intima–media thickness and cardiovascular events. Lancet 379, 20282030.Google Scholar
3. Minoguchi, K, Yokoe, T, Tazaki, T, et al. (2005) Increased carotid intima–media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 172, 625630.Google Scholar
4. Sabatino, A, Regolisti, G, Cosola, C, et al. (2017) Intestinal microbiota in type 2 diabetes and chronic kidney disease. Curr Diab Rep 17, 16.Google Scholar
5. Whaley-Connell, A & Sowers, JR (2017) Insulin resistance in kidney disease: is there a distinct role separate from that of diabetes or obesity? Cardiorenal Med 8, 4149.Google Scholar
6. Sohrabi, Z, Eftekhari, MH, Eskandari, MH, et al. (2015) Malnutrition-inflammation score and quality of life in hemodialysis patients: is there any correlation? Nephrourol Mon 7, e27445.Google Scholar
7. Jakuszewski, P, Czerwienska, B, Chudek, J, et al. (2009) Which components of malnutrition–inflammation–atherosclerosis syndrome are more common in haemodialysis patients with diabetic nephropathy? Nephrology (Carlton) 14, 643649.Google Scholar
8. Yen, TH, Lin, JL, Lin-Tan, DT, et al. (2009) Cardiothoracic ratio, inflammation, malnutrition, and mortality in diabetes patients on maintenance hemodialysis. Am J Med Sci 337, 421428.Google Scholar
9. Mortazavi, M, Moeinzadeh, F, Saadatnia, M, et al. (2013) Effect of magnesium supplementation on carotid intima–media thickness and flow-mediated dilatation among hemodialysis patients: a double-blind, randomized, placebo-controlled trial. Eur Neurol 69, 309316.Google Scholar
10. Lim, AK & Tesch, GH (2012) Inflammation in diabetic nephropathy. Mediators Inflamm 2012, 146154.Google Scholar
11. Wu, CC, Sytwu, HK & Lin, YF (2012) Cytokines in diabetic nephropathy. Adv Clin Chem 56, 5574.Google Scholar
12. Almeida, A, Lourenço, O & Fonseca, A (2015) Haemodialysis in diabetic patients modulates inflammatory cytokine profile and T cell activation status. Scand J Immunol 82, 135141.Google Scholar
13. Silva, AP, Fragoso, A, Silva, C, et al. (2014) Magnesium and mortality in patients with diabetes and early chronic kidney disease. J Diabetes Metab 5, 2.Google Scholar
14. Tzanakis, I, Virvidakis, K, Tsomi, A, et al. (2004) Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients. Magnes Res 17, 102108.Google Scholar
15. Barbagallo, M & Dominguez, LJ (2015) Magnesium and type 2 diabetes. World J Diabetes 6, 11521157.Google Scholar
16. Barbagallo, M & Dominguez, LJ (2007) Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys 458, 4047.Google Scholar
17. Paolisso, G, Scheen, A, D’Onofrio, F, et al. (1990) Magnesium and glucose homeostasis. Diabetologia 33, 511514.Google Scholar
18. Rodriguez-Moran, M & Guerrero-Romero, F (2003) Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 26, 11471152.Google Scholar
19. Guerrero-Romero, F, Tamez-Perez, HE, Gonzalez-Gonzalez, G, et al. (2004) Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab 30, 253258.Google Scholar
20. Chacko, SA, Sul, J, Song, Y, et al. (2011) Magnesium supplementation, metabolic and inflammatory markers, and global genomic and proteomic profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals. Am J Clin Nutr 93, 463473.Google Scholar
21. Navarrete-Cortes, A, Ble-Castillo, JL, Guerrero-Romero, F, et al. (2014) No effect of magnesium supplementation on metabolic control and insulin sensitivity in type 2 diabetic patients with normomagnesemia. Magnes Res 27, 4856.Google Scholar
22. Lopez Martinez, J, Sanchez Castilla, M, Garcia de Lorenzo y Mateos, A, et al. (1997) Magnesium: metabolism and requirements. Nutr Hosp 12, 414.Google Scholar
23. Paolisso, G & Barbagallo, M (1997) Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Am J Hypertens 10, 346355.Google Scholar
24. Sontia, B & Touyz, RM (2007) Role of magnesium in hypertension. Arch Biochem Biophys 458, 3339.Google Scholar
25. Velickovic-Radovanovic, R, Mikov, M, Catic-Djordjevic, A, et al. (2012) Tacrolimus as a part of immunosuppressive treatment in kidney transplantation patients: sex differences. Gend Med 9, 471480.Google Scholar
26. Pisprasert, V, Ingram, KH, Lopez-Davila, MF, et al. (2013) Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans. Diabetes Care 36, 845853.Google Scholar
27. Tatsch, E, Bochi, GV, Pereira Rda, S, et al. (2011) A simple and inexpensive automated technique for measurement of serum nitrite/nitrate. Clin Biochem 44, 348350.Google Scholar
28. Benzie, IF & Strain, JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239, 7076.Google Scholar
29. Beutler, E & Gelbart, T (1985) Plasma glutathione in health and in patients with malignant disease. J Lab Clin Med 105, 581584.Google Scholar
30. Janero, DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9, 515540.Google Scholar
31. Nursal, TZ, Noyan, T, Tarim, A, et al. (2005) A new weighted scoring system for subjective global assessment. Nutrition 21, 666671.Google Scholar
32. Mansournia, MA & Altman, DG (2018) Invited commentary: methodological issues in the design and analysis of randomised trials. Br J Sports Med 52, 553555.Google Scholar
33. Nielsen, RO, Bertelsen, ML, Verhagen, E, et al. (2017) When is a study result important for athletes, clinicians and team coaches/staff? Br J Sports Med 51, 14541455.Google Scholar
34. Luo, X, Yang, Y, Cao, T, et al. (2011) Differences in left and right carotid intima–media thickness and the associated risk factors. Clin Radiol 66, 393398.Google Scholar
35. Hileman, CO, Turner, R, Funderburg, NT, et al. (2016) Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV. AIDS 30, 6573.Google Scholar
36. Fabbian, F, Cacici, G, Franceschini, L, et al. (2007) The relationship between carotid and coronary atherosclerotic damage in dialysis patients. Int J Artif Organs 30, 315320.Google Scholar
37. Lorenz, MW, Markus, HS, Bots, ML, et al. (2007) Prediction of clinical cardiovascular events with carotid intima–media thickness: a systematic review and meta-analysis. Circulation 115, 459467.Google Scholar
38. Turgut, F, Kanbay, M, Metin, MR, et al. (2008) Magnesium supplementation helps to improve carotid intima media thickness in patients on hemodialysis. Int Urol Nephrol 40, 10751082.Google Scholar
39. Blacher, J, Guerin, AP, Pannier, B, et al. (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38, 938942.Google Scholar
40. Block, GA, Hulbert-Shearon, TE, Levin, NW, et al. (1998) Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31, 607617.Google Scholar
41. Ganesh, SK, Stack, AG, Levin, NW, et al. (2001) Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 12, 21312138.Google Scholar
42. Simental-Mendia, LE, Sahebkar, A, Rodriguez-Moran, M, et al. (2016) A systematic review and meta-analysis of randomized controlled trials on the effects of magnesium supplementation on insulin sensitivity and glucose control. Pharmacol Res 111, 272282.Google Scholar
43. Simental-Mendia, LE, Simental-Mendia, M, Sahebkar, A, et al. (2017) Effect of magnesium supplementation on lipid profile: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 73, 525536.Google Scholar
44. Kim, DJ, Xun, P, Liu, K, et al. (2010) Magnesium intake in relation to systemic inflammation, insulin resistance, and the incidence of diabetes. Diabetes Care 33, 26042610.Google Scholar
45. Rumawas, ME, McKeown, NM, Rogers, G, et al. (2006) Magnesium intake is related to improved insulin homeostasis in the Framingham offspring cohort. J Am Coll Nutr 25, 486492.Google Scholar
46. Gerich, JE (2003) Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med 163, 13061316.Google Scholar
47. Kowluru, A, Chen, HQ, Modrick, LM, et al. (2001) Activation of acetyl-CoA carboxylase by a glutamate- and magnesium-sensitive protein phosphatase in the islet beta-cell. Diabetes 50, 15801587.Google Scholar
48. Jamilian, M, Samimi, M, Faraneh, AE, et al. (2017) Magnesium supplementation affects gene expression related to insulin and lipid in patients with gestational diabetes. Magnesium Res 30, 7179.Google Scholar
49. Solati, M, Ouspid, E, Hosseini, S, et al. (2014) Oral magnesium supplementation in type II diabetic patients. Med J Islam Repub Iran 28, 67.Google Scholar
50. Gueux, E, Rayssiguier, Y, Piot, MC, et al. (1984) Reduction of plasma lecithin--cholesterol acyltransferase activity by acute magnesium deficiency in the rat. J Nutr 114, 14791483.Google Scholar
51. Sales, CH, Santos, AR, Cintra, DE, et al. (2014) Magnesium-deficient high-fat diet: effects on adiposity, lipid profile and insulin sensitivity in growing rats. Clin Nutr 33, 879888.Google Scholar
52. Dronavalli, S, Duka, I & Bakris, GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 4, 444452.Google Scholar
53. DeAngelis, RA, Reis, ES, Ricklin, D, et al. (2012) Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis. Immunobiology 217, 10971105.Google Scholar
54. Choi, HM, Woo, YS, Kim, MG, et al. (2011) Altered monocyte-derived dendritic cell function in patients on hemodialysis: a culprit for underlying impaired immune responses. Clin Exp Nephrol 15, 546553.Google Scholar
55. Song, Y, Ridker, PM, Manson, JE, et al. (2005) Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 28, 14381444.Google Scholar
56. Nielsen, FH, Johnson, LK & Zeng, H (2010) Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep. Magnes Res 23, 158168.Google Scholar
57. Razzaghi, R, Pidar, F, Momen-Heravi, M, et al. (2018) Magnesium supplementation and the effects on wound healing and metabolic status in patients with diabetic foot ulcer: a randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res 181, 207215.Google Scholar
58. Aneiros, E, Philipp, S, Lis, A, et al. (2005) Modulation of Ca2+ signaling by Na+/Ca2+ exchangers in mast cells. J Immunol 174, 119130.Google Scholar
59. Mazur, A, Maier, JA, Rock, E, et al. (2007) Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys 458, 4856.Google Scholar
60. Liu, YX, Guo, YM & Wang, Z (2007) Effect of magnesium on reactive oxygen species production in the thigh muscles of broiler chickens. Br Poult Sci 48, 8489.Google Scholar
61. Boujelben, M, Ghorbel, F, Vincent, C, et al. (2006) Lipid peroxidation and HSP72/73 expression in rat following cadmium chloride administration: interactions of magnesium supplementation. Exp Toxicol Pathol 57, 437443.Google Scholar
62. ELDerawi, W, Naser, IA, Taleb, MH, et al. (2018) The effects of oral magnesium supplementation on glycemic response among type 2 diabetes patients. Nutrients 11, 44.Google Scholar
63. Yokota, K, Kato, M, Lister, F, et al. (2004) Clinical efficacy of magnesium supplementation in patients with type 2 diabetes. J Am Coll Nutr 23, 506s509s.Google Scholar
64. Toprak, O, Kurt, H, Sari, Y, et al. (2017) Magnesium replacement improves the metabolic profile in obese and pre-diabetic patients with mild-to-moderate chronic kidney disease: a 3-month, randomised, double-blind, placebo-controlled study. Kidney Blood Press Res 42, 3342.Google Scholar
Figure 0

Fig. 1 Summary of patient flow diagram.

Figure 1

Table 1 General characteristics of study participants (Mean values and standard deviations; numbers and percentages)

Figure 2

Table 2 Mean dietary intake of study participants at baseline, weeks 6, 12, 18 and 24 of the study (Mean values and standard deviations)

Figure 3

Table 3 Carotid intima–media thickness, metabolic profiles, biomarkers of inflammation and oxidative stress at study baseline and after the 24-week intervention in patients with diabetic haemodialysis that received either magnesium supplements or placebo (Mean values and standard deviations; β-coefficients and 95 % confidence intervals)