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Journal of the American College of Nutrition, Vol. 23, No. 3, 272-279 (2004)
Published by the American College of Nutrition

Original Research

The Impact of Vitamins and/or Mineral Supplementation on Blood Pressure in Type 2 Diabetes

Maryam Sadat Farvid, PhD, Mahmoud Jalali, PhD, Fereydoun Siassi, PhD, Navid Saadat, MD and Mostafa Hosseini, PhD

Department of Nutrition and Biochemistry (M.S.F., M.J., F.S.), Tehran, IRAN
Department of Epidemiology and Biostatistics (M.H.), Tehran, IRAN
School of Public Health, Tehran University of Medical Sciences, Endocrine Research Center, Shaheed Beheshti University of Medical Sciences (N.S.), Tehran, IRAN

Address reprint requests to: Maryam Sadat Farvid, PhD, Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran IRAN. E-mail: farvidm{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: The present study designed to assess the effect of Mg+Zn, vitamin C+E, and combination of these micronutrients on blood pressure in type 2 diabetic patients.

Materials and Methods: In a randomized, double-blind, placebo controlled clinical trial, 69 type 2 diabetic patients were randomly divided into four groups, each group receiving one of the following daily supplement for three months; group M: 200 mg Mg and 30 mg Zn (n = 16), group V: 200 mg vitamin C and 150 mg vitamin E (n = 18), group MV: minerals plus vitamins (n = 17), group P: placebo (n = 18). Blood pressure was measured at the beginning and at the end of the trial. Treatment effects were analyzed by general linear modeling.

Results: Results indicate that after three months of supplementation levels of systolic, diastolic and mean blood pressure decreased significantly in the MV group by 8 mmHg (122 ± 16 vs. 130 ± 19 mmHg), 6 mmHg (77 ± 9 vs. 83 ± 11 mmHg), and 7 mmHg (92 ± 9 vs. 99 ± 13 mmHg), respectively (p < 0.05). Also combination of vitamin and mineral supplementation had significantly effects in increasing serum potassium (p < 0.05) and in decreasing serum malondialdehyde (p < 0.05). There was no significant change in the levels of these parameters in the other three groups.

Conclusion: The results of the present study indicated that in type 2 diabetic patients a combination of vitamins and minerals, rather than vitamin C and E or Mg and Zn, might decrease blood pressure.

Key words: vitamin C, vitamin E, magnesium, zinc, blood pressure


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The prevalence of hypertension in patients with type 2 diabetes has been reported to be about 70% or roughly twice that of the general adult population [1–2]. Hypertension is well recognized as a risk factor for the macro-vascular complications of diabetes [3] and is also associated with diabetic nephropathy [4,5] and retinopathy [5]. Thus in order to reduce the risk of macro- and micro-vascular complications in diabetes, blood pressure should be effectively controlled. The pharmacological treatment of hypertension has attendant risks due to its adverse effects [6,7]. Therefore, the non-pharmacological treatment of hypertension has recently been attracting increasing interest. Epidemiological studies have demonstrated that low dietary intakes and plasma concentrations of antioxidants are associated with enhanced risk of hypertension [8,9]. However, the results of clinical studies on the effects of antioxidant supplementation in normotensives and hypertensives have been inconclusive [10–15]. In addition, a number of epidemiological studies have demonstrated a relationship between low dietary intake of Mg and blood pressure [16]. However, intervention studies with Mg therapy in hypertensives and normotensives have led to conflicting results [17–20].

Because of the known synergistic action between vitamin E and vitamin C [21], vitamin E and Zn [22,23] and vitamin E and Mg [24,25], a further important question is whether a combination of these micronutrients provides a better protection against hypertension. Thus the present study was designed to assess the effects of long term supplementation with Mg and Zn, vitamin E and C and a combination of these micronutrients on blood pressure levels in type 2 diabetic patients.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
A randomized double blind placebo controlled clinical trial was conducted on 76 type 2 diabetic patients, 30–69 years old and having diabetes for at least one year and with normotensive or borderline hypertensive. The sample size was chosen to provide adequate power (80%) to detect changes of 8 mmHg or higher in SBP and 5 mmHg or higher in DBP with a {alpha}-error of 5%. The number of patients in each group was calculated as 18.

Data on dietary habits, body mass index (BMI), medical history, smoking addiction, medication and dietary supplements were obtained from personal interviews. All subjects had to meet the following criteria to be included in the study: not taking vitamin and/or mineral supplements, thyroid hormones, estrogens, progesterone, diuretics or ß-blockers, having normal renal and hepatic function, no history of myocardial infarction and in females, not being pregnant.

The subjects were fully informed of the purpose, procedures and hazards of the trial and were free to leave the trial at any time. Written informed consent was obtained from all participants. The research protocol was approved by the Ethics Committee on Human Experimentation of Tehran University of Medical Sciences.

Dosage levels of vitamin C and Mg were lower than used in previous studies, which were estimated to be attainable through diet without any side effects, especially for magnesium as excessive gas and bloating, loose stools and diarrhea as reported by other studies. Zn dose was used as tolerable upper intake level (40 mg/day). Since the mean daily intake of Zn in our diabetic patients was 8.3 mg, we increased the level of intakes near to tolerable upper intake levels by giving 30 mg per day Zn supplementation.

Diabetic patients were stratified by gender and randomly assigned to one of the four treatment groups using block randomization procedure. Depending upon the treatment groups, each subject received two capsules per day for a period of three months. Each capsule contained one of the following preparations and hence determined the corresponding groups: Group M: Zn sulfate and Mg oxide (providing 15 mg Zn and 100 mg Mg); Group V: vitamin C (100 mg) and vitamin E (75 mg); Group MV: both of the above mineral and vitamin supplements; Group P: lactose (placebo). The supplement and placebo capsules looked identical and were specially prepared for this study by Darou-Pakhsh Co and were stored at 20–25° C.

After 12 to 14 hours overnight fasting, between 8 and 10 a.m. and before taking any oral hypoglycemic agent(s), 20 mL blood and urine samples were collected from each subject at the beginning and at the end of the three month trial. Blood and urine samples were collected in trace element free tubes. Aliquots of serum and urine were transferred to polystyrene tubes which were immediately stored at –70° C until analysis. Plasma ascorbic acid was measured with a colorimetric method with intra-assay CV of 4.6% and inter-assay CV of 5.2% [26], serum {alpha}-tocopherol was determined by High Performance Liquid Chromatography with intra-assay CV of 1.69% and inter-assay CV of 2.17% [27], and lipid-standardized {alpha}-tocopherol (LS-{alpha}-TOH) was calculated as serum {alpha}-tocopherol concentration expressed per mg triglyceride plus cholesterol (µg/mg). Zn and Mg were measured in serum and urine sample by colorimetric methods using commercials kits (Randox, UK; and Pars-Azmoon, Iran, respectively). Serum and urinary excretion of sodium and potassium were determined by flame photometry. Urine creatinine (Cr) was measured using Jaffe reaction [28], and all urine results were expressed in relation to creatinine excretion. Serum malondialdehyde (MDA) was determined by a colorimetric method with an interassay coefficient variation less than 2% [29].

The systolic and diastolic blood pressure (SBP and DBP) (5 minutes seated rest, mean of two readings) was measured at baseline and after three months’ supplementation. Mean arterial pressure (MAP) was calculated using following formula: (SBP+2DBP)/3 [30].

Nutrients intakes were estimated using two 24-hour dietaries recall questionnaire at the beginning and at the end of the three months trial and analyzed by Food Processor software. The subjects were asked not to alter their usual diets and physical activity throughout the study, and any changes in their medication were avoided whenever possible. Compliance with the supplementation was checked by capsule counts at weeks 6 and 12 and also confirmed through measurement of changes in the serum and/or urine levels of Mg, Zn, vitamin C and E. To enhance compliance, individual sessions with skilled counselor were conducted at following visits (six weeks and three months). Also, phone contacts between counseling sessions were made. Subjects who did not use more than 10 percent of capsules were excluded from the statistical analysis.

Statistical Analysis
All values are expressed as mean ± SD. Kolmogorov-Smirnov normality tests were performed on independent and dependent variables before further statistical analysis, and all variables were normally distributed. Differences between four groups were determined by one-way analysis of variance (ANOVA) for continuous data and the Chi square test for group data. Post hoc comparisons were performed with Tukey test. Adjustment for differences in baselines covariates and changes in variables during the study were performed by analysis of covariance using general linear models. Correlations among numerical continuous variables were analyzed using Pearson r correlation coefficients. A value of p < 0.05 was considered to be statistically significant. All data were analyzed using SPSS software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
During the follow up five patients withdrew, and two were excluded from statistical analysis because they interrupted trial treatment or changed their medication. As shown in Table 1, at the beginning of the study, the groups were similar with respect to the age, gender, duration of diabetes, body mass index (BMI), smoking, daily intake of vitamin C and E, Mg and Zn. There were no significant changes in BMI, physical activity, dietary intake or medication during the study period.


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  		Table 1. Demographic, Anthropometric and Biological Data for the Four Study Groups before Supplementation

 
At the beginning of the study, the groups were similar based upon plasma vitamin C and serum levels of vitamin E, Mg and Zn, and urinary levels of minerals (Table 2). After three months of supplementation, plasma vitamin C, serum levels of vitamin E and LS-{alpha}-TOH increased significantly in group V and MV as compared with baseline and group P and M. Serum and urinary levels of Zn increased significantly in group M (15.1% and 74.4%, respectively) and MV (19.9% and 44.5%, respectively). In spite of 2% and 5.4% increment in serum Mg in M and MV groups, respectively, and 15.6% and 13.3% increment in urine Mg in M and MV groups, respectively, the changes were not statistically significant.


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  		Table 2. Mean and SD Levels of Vitamins and Minerals in Type 2 Diabetic Patients before and after Three Months’ Supplementation

 
Table 3 shows the mean ± SD of systolic, diastolic and mean blood pressure at baseline. ANOVA showed no statistically significant difference(s) between groups. After three months of supplementation, significant decreases in MV group by 8 mmHg for systolic blood pressure (122 ± 16 vs. 130 ± 19 mmHg, p < 0.05), by 6 mmHg for diastolic blood pressure (77 ± 9 vs. 83 ± 11 mmHg, p < 0.05) and by 7 mmHg for mean arterial pressure (92 ± 9 vs. 99 ± 13 mmHg, p < 0.05) were observed from baseline and also when compared to the group P. There were no significant changes in the other three groups (Figs 1Go–3).


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  		Table 3. Baseline Levels of Systolic, Diastolic and Mean Blood Pressure in Type 2 Diabetic Patients

 


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  		Fig. 1. Levels of systolic blood pressure (SBP) before and after three months’ vitamin and/or mineral supplementation in Type 2 diabetic patients. *p < 0.05 compared with baseline and group P.

 


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  		Fig. 2. Levels of diastolic blood pressure (DBP) before and after three months’ vitamin and/or mineral supplementation in Type 2 diabetic patients. *p < 0.05 compared with baseline and group P.

 


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  		Fig. 3. Levels of mean arterial pressure (MAP) before and after three months’ vitamin and mineral supplementation in type 2 diabetic patients. *p < 0.05 compared with baseline and group P.

 
In general linear modeling there was a significant (p < 0.05) effect of vitamin and mineral supplementation to increase serum potassium and to decrease serum sodium/potassium ratio (Table 4). Despite no significant changes in serum sodium in studied groups, a positive correlation between the decrease in serum sodium and the reduction in systolic blood pressure has been demonstrated in group MV (Fig. 4).


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  		Table 4. Serum and Urine Sodium and Potassium Before and After 3 Months Vitamin and Mineral Supplementation in Type 2 Diabetic Patients

 


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  		Fig. 4. Correlation between change in systolic blood pressure (SBP) and change in serum sodium in group MV after three months’ supplementation.

 
Three months’ vitamin and mineral supplementation produced a significant reduction in mean value of MDA in group MV using general linear modeling (p < 0.05, Fig. 5). There were no significant changes in the other three groups.



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  		Fig. 5. Levels of malondialdehide (MDA) before and after three months’ vitamin and/or mineral supplementation in type 2 diabetic patients. *p < 0.05 compared with baseline and group P.

 

   DISCUSSION
 
The prevalence of hypertension in patients with type 2 diabetes has been reported to be about 70% or roughly twice that of the general adult population [1, 2]. Hypertension is well recognized as a risk factor for the macro-vascular complications of diabetes [3] and is also associated with diabetic nephropathy [4,5] and retinopathy [5]. Cardiovascular complications are the commonest cause of excess mortality in type 2 diabetes, and, of the acknowledged contributory factors that promote the development of such complications, hypertension is of particular importance in this condition [31]. The SHEP study has clearly shown twice the absolute risk reduction in cardiovascular events following tight blood pressure control in type 2 diabetic subjects than in non-diabetics [32]. Data from the UKPDS show that tight blood pressure control in a cohort of newly diagnosed subjects with type 2 diabetes is effective in reducing micro-vascular complication [33], and blood pressure reduction will slow the progression of diabetic nephropathy [34].

Our data show that a combination of vitamin C and E, Mg and Zn supplementation for at least three months can reduce systolic, diastolic and mean blood pressure. Neither vitamin nor mineral supplementation had any significant effect on these parameters.

It has been shown that blood pressure is sensitive to alteration of weight, dietary changes and physical activity [35], but these variables did not change in any studied group.

It seems that these micronutrients act synergistically, and hence a combination of these micronutrients provides a better effect. The ability of ascorbic acid to reduce {alpha}-tocopheroxyl radical to generate {alpha}-tocopherol and possibly to inhibit oxidation induced by {alpha}-tocopheroxyl radical has been demonstrated in many in vitro and in vivo studies [21,36]. Also, synergistic action between vitamin E and Mg has been shown previously [24,25]. Increased oxygen free radical production lowers the intracellular Mg concentration [37], and, in light of such evidence, vitamin E administration might also regulate the intracellular Mg concentration [25]. A synergistic effect of vitamin C, E and Zn could be expected based on the different environments where they act. Vitamin C acts in the hydrophilic milieu scavenging reactive oxygen spices [36]; Zn, located in the interphase of the bilayer, will prevent iron or copper binding to the membrane and {alpha}-tocopherol, in the hydrophobic domains of the bilayer, will inhibit the lipid oxidation free radical chain reaction [22]. In the present study, these interactions have been confirmed by significant decrease in MDA in group MV.

The specific biologic mechanisms for the beneficial effects of combinations of these micronutrients on blood pressure have not been fully established. Several data indicate that intracellular magnesium may play a key role in modulating vascular tone and hypertension [38], and using both magnesium and vitamin E supplementation [25] may increase intracellular magnesium and therefore decrease blood pressure. Because we did not measure intracellular magnesium, we cannot be sure that this is actually the case.

A negative association between serum potassium and both SBP and DBP has been reported [39,40], and 6.84 and 2.93 mmHg decreases in SBP and DBP, respectively, for each milligram per deciliter increase in serum potassium were previously demonstrated [39]. Also a highly significant negative correlation was reported between serum sodium and both SBP and DBP [41]. Therefore, it seems that the effects of combinations of vitamin and mineral supplementation in changing of serum potassium and sodium may be a reason for blood pressure reduction in group MV. The hypotensive action of vitamin C may result from its influence on Na+K+-ATPase [42], and also Mg is known to be an important cofactor for the activation of Na+K+-ATPase, playing a decisive role in the regulation of intracellular sodium concentration and vascular tone [43]. A Mg deficient state could induce vascular changes that are probably related to the reduction in membrane Na+K+-ATPase activity, consequently increasing the intracellular sodium concentration [44]. Thus, magnesium supplementation could avert these abnormalities by decreasing the intracellular sodium and, as a consequence, reduce blood pressure. Because we did not measure intracellular potassium and sodium, and activity of Na+K+-ATPase, we cannot be sure this is actually the case and requires further investigation.

Although Mg supplementation resulted in a small overall reduction in blood pressure, there was an apparent dose-dependent effect of Mg, specifically reductions of 4.3 mmHg systolic blood pressure and of 2.3 mmHg diastolic blood pressure for each 10 mmol/day (240 mg) increase in Mg dose. Studies indicate a greater efficacy that Mg supplementation may have at higher doses, and administrated small doses of Mg (10–15 mmol/day) failed to demonstrate significant effects [45]. Therefore, the lack of effect of magnesium in group M may be linked to the low doses used.

Since, in the present study, a small reduction in blood pressure was observed, and based on the HOPE study even a modest reduction in blood pressure led to a very significant reduction in cardiovascular events in patients unselected for blood pressure with high risk including diabetes mellitus [46], benefits may be observed by lowering blood pressure, even when it may appear to be normal in these patients.

This study does have limitations. Our data were obtained by measuring manual blood pressure; clearly, other studies are needed to confirm our findings by 24-hour ambulatory blood pressure measurement. Also, our patients were normotensive or mild hypertensive, the hypotensive effects of vitamin and mineral combination need to be confirmed in hypertensive diabetic patients too.

In conclusion, the results of the present study indicated that in type 2 diabetic patients, a combination of vitamins and minerals rather than vitamin C and E, or Mg and Zn, decrease blood pressure. Further studies are needed to clarify the cellular mechanism(s) of this effect.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
This work was supported by a grant from Research Undersecretary of Tehran University of Medical Sciences. We are indebted to the patients for their cooperation.

Received June 7, 2003. Accepted February 12, 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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