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Journal of Diabetes 6 (2014) 369–377
O R I G I N A L A RT I C L E
Association between magnesium concentration and HbA1c in children and adolescents with type 1 diabetes mellitus Assimina GALLI-TSINOPOULOU,1 Ioanna MAGGANA,1 Ioannis KYRGIOS,1 Konstantina MOUZAKI,1 Maria G. GRAMMATIKOPOULOU,2 Charilaos STYLIANOU,1 and Kyriaki KARAVANAKI3 1
4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, 2Department of Human Nutrition and Dietetics, Alexander Technological Educational Institute, Thessaloniki, and 32nd Department of Pediatrics, Faculty of Medicine, University of Athens, “P&A Kyriakou” Children’s Hospital, Athens, Greece
Correspondence Assimina Galli-Tsinopoulou, 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 564 03 Thessaloniki, Greece. Tel./Fax: +30 2310 991537 Email: [email protected] Received 25 June 2013; revised 14 December 2013; accepted 25 December 2013. doi: 10.1111/1753-0407.12118
Abstract Background: Magnesium levels may be decreased in patients with type 1 diabetes mellitus (T1DM), influencing disease control. Relevant studies concern mainly adults and there are few data from the pediatric population. The aim of the present study was to evaluate magnesium levels and examine their possible association with glycemic control in youths with T1DM. Methods: In all, 138 children and adolescents with T1DM aged between 1.9 and 20.3 years were recruited to the study. Using a cross-sectional design, we measured anthropometric parameters, HbA1c, serum magnesium, ionized and total calcium, phosphorus, potassium, sodium, and urinary albumin (UA). Estimated glomerular filtration rate (eGFR), based on serum creatinine concentrations, was also calculated. Results: Lower levels of magnesium were found in subjects with poor versus good glycemic control (0.79 ± 0.09 vs 0.82 ± 0.09 mmol/L, respectively; P = 0.002). Serum magnesium levels were negatively correlated with HbA1c (P < 0.001) and positively correlated with UA, calcium, phosphorus, and potassium levels (P < 0.05). After adjustment for confounding factors, only magnesium levels remained significantly associated with HbA1c (adjusted r2 = 0.172; P = 0.004). The odds ratio for poor glycemic control, indicated by HbA1c >7.5%, between the highest and lowest magnesium concentration quartiles was 0.190 and amounted to a decrease of 1.7% in the HbA1c level. Conclusions: The present study shows that low serum magnesium levels in children and adolescents with T1DM are associated with an increased risk of poor glycemic control, potentially contributing to the early development of cardiovascular complications. Keywords: children and adolescents, glycemic control, hypomagnesemia, magnesium, type 1 diabetes mellitus.
Significant findings of the study: The relationship between magnesium status and diabetes control begins in childhood. Hypomagnesemia in youths with type 1 diabetes mellitus (T1DM) is associated with an increased risk of poor glycemic control. What this study adds: New quantitative data on the relationship between serum magnesium levels and glycemic control in youth with T1DM. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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electrolytes in the glycemic regulation of diabetes in childhood and adolescence.
Introduction Magnesium is the second most abundant intracellular cation after potassium; it is obtained from the diet and is present in high amounts in a variety of unprocessed foods, including nuts, legumes, and vegetables; in contrast, meat, fish, and dairy products have a relatively low magnesium content.1 Although clinically evident magnesium deficiency is uncommon in otherwise healthy subjects, it may result from renal dysfunction, endocrine causes, gastrointestinal losses, or inadequate intake. Magnesium deficit may also coexist with deficiencies of other dietary elements, such as vitamins, calcium, and potassium, particularly in cases of malnutrition. It may manifest as anorexia, nausea, muscle weakness, ataxia, tetany, convulsions, mental confusion, and irritability, typically within 1–3 months after beginning a magnesium-free diet.1 What is interesting is that it has been known from relatively early on that a low dietary intake or a deficiency of magnesium is associated with cardiac arrhythmias, hypertension, coronary vasospasm, atherogenesis, ischemic heart disease, and sudden death.2 Recently, a significant inverse association was found between dietary magnesium intake or serum magnesium concentrations and risk of total cardiovascular events,3 whereas low serum magnesium levels have been shown previously to predict cardiovascular and all-cause mortality in a population-based study during follow-up as well.4 Moreover, serum magnesium levels have been inversely and independently associated with the intima– media thickness of common carotid artery in adolescents with type 1 diabetes mellitus (T1DM), which is a well-accepted early marker of atherosclerosis.5 In addition, low serum magnesium concentrations were shown to be associated with a high prevalence of premature ventricular complexes in patients with type 2 diabetes mellitus (T2DM) in a dose-dependent manner.6 All these data suggest that there may be a direct link between magnesium status, diabetes, and cardiovascular disease. Hypomagnesemia is common in patients with both T1DM and T2DM, especially in poorly controlled and chronically treated patients.7 However, to our knowledge, little research has addressed the relationship between serum magnesium levels and diabetes in youth. Although most studies have demonstrated lower magnesium concentrations in youngsters with T1DM,8–11 data concerning the association between magnesium and glycemic control remains obscure. In the present study we measured serum magnesium levels, along with levels of other electrolytes, in children and adolescents with T1DM to investigate the possible involvement of these 370
Methods Study design and subjects In all, 138 children and adolescents with T1DM aged between 1.9 and 20.3 years (61 children, 77 adolescents; 72 boys, 66 girls) who were followed-up in the Outpatient Unit of the 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, were enrolled in the present cross-sectional study. All subjects were treated with insulin given by either multiple daily injections (n = 119) or continuous subcutaneous infusion (n = 19) and were included in the study if they were 3 months. Exclusion criteria included the presence of acute disease or chronic conditions that could influence magnesium homeostasis. In addition, none of the children or adolescents had hypertension, diabetic retinopathy, or nephropathy. The study was approved by the Scientific Ethics Committee of the Faculty of Medicine, Aristotle University of Thessaloniki. Informed written consent was also obtained from the parents and/or guardians of all the study subjects who underwent clinical and laboratory investigations. Data collection Weight (SECA 711; Seca, Hamburg, Germany) and height (HARPENDEN stadiometer; Veeder-Root, Elizabethtown, NC, USA) were measured (in kg and m, respectively) and body mass index (BMI) was calculated as weight divided by height squared. All subjects underwent complete physical examination and were classified as prepubertal or pubertal using Marshall and Tanner staging.12,13 After overnight fasting, blood samples were collected from all subjects for measurement of serum levels of magnesium, ionized calcium, total calcium, phosphorus, potassium, sodium, and creatinine using standard methods and an Olympus AU-400 clinical chemistry analyzer (Olympus, Hamburg, Germany). Estimated glomerular filtration rate (eGFR), based on serum creatinine concentrations, was also calculated using the updated Schwartz formula after an agedependent adaptation for k.14 In addition, we collected data on total daily magnesium intake by all subjects, in line with the method used previously for the determination of nutritional status in a group of diabetic and healthy children and adolescents;15 specifically, we recorded dietary habits over 3 continuous days and analyzed these data using the US Department of Agriculture
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(USDA) 19 HealtheTec SR computer program (Nutrient Data Laboratory, Human Nutrition Research Center, USDA, Beltsville, MD, USA) and compared them against the dietary reference intakes (DRI) for the appropriate age and gender.16 Glycemic control was estimated for each patient through HbA1c, measured with a DCA 2000 analyzer (Bayer, Elkhart, IN, USA). In addition, each subject gave a random morning urine specimen for the determination of urinary albumin (UA), which was also measured using the DCA 2000 analyzer (Bayer).
Kruskal–Wallis tests where appropriate. Analysis of covariance (ANCOVA) was used to analyze data after controlling for potential covariates. Categorical variables were compared using the Chi-squared test and correlations were calculated with Spearman’s correlation coefficients. Logistic regression analysis was performed to investigate the association between magnesium concentration quartiles and poor glycemic control (HbA1c >7.5%) before and after adjustment for potential confounding factors. All tests were two-sided and the level for statistical significance was set at P < 0.05.
Groups and definition of cut-off points To define “glycemic control”, we used standard international criteria.17 Based on HbA1c levels, subjects were divided into two groups: (i) those with good glycemic control (normoglycemic group), defined as HbA1c levels ≤7.5%; and (ii) those with poor glycemic control, defined as HbA1c levels >7.5%. Moreover, to examine the association between demographics, clinical or laboratory measurements, and magnesium, subjects were divided into four groups (quartiles) based on magnesium serum concentrations as follows: quartile (Q) 1, serum magnesium 0.85 mmol/L. Statistical analysis Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). Data are presented as frequencies and percentages for categorical variables and as the mean ± SD for continuous variables. All continuous variables were tested for normal distribution by the Kolmogorov–Smirnov or Shapiro–Wilk test, and the significance of differences between groups was tested with an unpaired t-test and/or Mann–Whitney U-test or one-way analysis of variance (ANOVA) and/or
Table 1
Results Baseline data The mean age of the study population was 11.5 years, whereas the mean duration of diabetes was 4.1 years (Table 1). Serum magnesium levels of subjects varied from 0.51 to 2.11 mmol/L, with a mean value of 0.80 mmol/L. Overall, the mean daily dietary intake of magnesium was 181.1 mg/day, without differences between children and adolescents, in accordance with the recommended dietary allowance.15,16 Pubertal subjects had significantly higher HbA1c (8.3 ± 2.0 vs 7.7 ± 1.5%; P = 0.02), UA (30.9 ± 50.6 vs 13.5 ± 16.2 mg/L; P = 0.003) and eGFR (138.8 ± 28.3 vs 123.3 ±17.0 mL/ min per 1.73 m2; P < 0.001) levels than prepubertal subjects, but there were no significant differences in pubertal versus prepubertal subjects in terms of serum magnesium (0.80 ± 0.08 vs 0.80 ± 0.11 mmol/L, respectively; P = 0.571) or total and ionized calcium, phosphorus, potassium, and sodium levels (data not shown). Finally, no gender differences were detected in any of the parameters studied, including magnesium concentrations, except for eGFR, which was higher in boys than in girls (140.5 ± 27.3 vs 122.6 ±18.7 mL/min per 1.73 m2, respectively; P < 0.001).
Baseline data and comparisons between those with poor and good glycemic control Glycemic control
Age (years) Duration of diabetes (years) HbA1c (%) BMI (kg/m2) Magnesium (mmol/L) UA (mg/L) eGFR (mL/min per 1.73 m2)
Total sample (n = 138)
Poor (n = 73)
Good (n = 65)
P-value
11.5 ± 3.9 4.1 ± 3.4 8.0 ± 1.8 19.5 ± 3.8 0.80 ± 0.09 23.2 ± 40.1 132.0 ± 25.1
12.1 ± 4.0 4.5 ± 3.6 9.2 ± 1.7 19.9 ± 4.0 0.79 ± 0.09 30.5 ± 51.3 131.5 ± 23.8
10.8 ± 3.6 3.7 ± 3.1 6.7 ± 0.6 18.9 ± 3.5 0.82 ± 0.09 15.1 ± 18.9 132.4 ± 26.7
0.025 0.294 7.5% (%)
OR (95% CI)
P-value
OR (95% CI)
P-value
137 34 32 37 34
72 24 19 17 12
0.607 – 0.609 0.354 0.227
0.002 – 0.341 0.038 0.004
0.594 – 0.468 0.360 0.190
0.002 – 0.162 0.046 0.002
(52.6%) (70.6%) (59.4%) (45.9%) (35.3%)
(0.441, 0.836) (0.219, 1.690) (0.133, 0.945) (0.082, 0.630)
(0.426, 0.829) (0.161, 1.355) (0.131, 0.984) (0.065, 0.558)
Quartile (Q) 1, serum magnesium 0.85 mmol/L. UA, urinary albumin; OR, odds ratios; CI, confidence interval.
probability of poor glycemic control. The regression model was performed on the basis of the univariate correlations between HbA1c and other clinical or biochemical parameters (data not shown). When age, gender, serum magnesium, and UA levels were included in the model, only the association between serum magnesium and HbA1c remained significant (adjusted r2 = 0.172; P = 0.004). The odds ratio (OR) of detecting an HbA1c value >7.5% was 0.227 (unadjusted model) or 0.190 (adjusted model) for Q4 compared with Q1; this amounts to a significant decrease of approximately 1.7% in the HbA1c level (unstandardized β-value) between the highest and lowest serum magnesium quartiles. Discussion In the present study we measured serum magnesium levels, as well as other clinical and biochemical parameters, in children and adolescents with T1DM. There were 34 subjects (25% of the whole sample) who had serum magnesium concentrations 7.5%, between the highest and lowest serum magnesium quartiles was 0.190,
amounting to a decrease of 1.7% in the level of HbA1c. All these findings confirm that hypomagnesemia may be present and aggravate diabetes, even in the younger age groups, thus suggesting an additional mechanism that may contribute, at least in part, to the early development of complications. It is well established that circulating magnesium levels tend to decrease in adults with either T1DM or T2DM, especially in poorly controlled patients with a long duration of diabetes,20–30 independent of residual insulin secretory status.31 Moreover, previous studies have reported significantly lower total serum or plasma magnesium levels in children with known or newly diagnosed insulindependent diabetes mellitus (IDDM) compared with their healthy peers,8–11 although conflicting results have been published as well.32–35 Furthermore, children with IDDM retained a significantly greater percentage of magnesium than controls during a magnesium tolerance test, thus confirming lower magnesium levels.8 Nevertheless, it is of note that Husmann et al. indicated that only the ionized (i.e. active) form of magnesium and not total plasma levels of magnesium differed significantly in pediatric patients with newly diagnosed IDDM,36 although this was not confirmed in a later study.37 Serum levels of ionized magnesium were also found to be significantly reduced in T2DM patients compared with control subjects.38 In addition, when erythrocyte or platelet magnesium concentrations were determined for subjects with T1DM or T2DM and compared with those in healthy controls, significantly reduced levels were reported by a few,8,25,39,40 but not all,10,26,28,41 studies. In addition, magnesium levels have been found to differ in muscle, but not in mononuclear or polymorphonuclear cells.10,26,28,29 Although there is a lack of agreement regarding the cause of lower magnesium levels in diabetes, it has been suggested that inadequate magnesium intake, hypermagnesuria, or gastrointestinal disorders could be reason-
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Summary of mechanisms associating low magnesium status with diabetes
Mechanisms through which hypomagnesemia influences carbohydrate metabolism • Impaired insulin-mediated glucose uptake in target-cells because • Impaired glucose-induced insulin secretion by β-cells due to several intracellular phosphorylation reactions of the insulin competitive inhibition of calcium influx by magnesium signaling cascade are magnesium dependent concentration Mechanisms for the development of diabetic microvascular changes • Changes in vascular smooth muscle tone • Impaired platelet aggregation • Imbalance between prostacyclin–thromboxane synthesis • Increased blood arginase activity • Excessive production of reactive oxygen and nitrogen species
able explanations. In addition, it has been reported that young subjects with T2DM consume significantly less magnesium than those with T1DM.42 What strengthens this view is that hypomagnesemia in diabetes often coexists with other electrolyte disorders, such as hypokalemia and hypocalcemia.43 Indeed, another finding of the present study was that significant reductions in serum calcium, phosphorus, and potassium levels were observed in parallel with reductions in magnesium levels. However, the subjects in the present study were found to have a normal magnesium intake. Conversely, insulin deficiency may explain the increased urinary magnesium excretion, because insulin has been recognized to stimulate magnesium conservation in the loop of Henle and distal tubule.44 Moreover, uncontrolled hyperglycemia and hyperglycuria may increase magnesium excretion through osmotic diuresis, leading to a vicious circle.44 Actually, McNair et al. reported the occurrence of a definite hypermagnesuria in 55% of 215 outpatients with IDDM.18 Increased magnesium urinary excretion with a male predominance has also been reported in children and adolescents with T1DM compared with their healthy peers,8,34,45,46 as well as in adult patients with diabetes;26,27,29,35 however, inconsistent findings have also been published.28 As far as the relationship between magnesium status and glycemic control is concerned, incompatible results exist on this topic in youth with T1DM. Fort and Lifshitz described a negative correlation between magnesium levels and HbA1c,11 whereas others have reported that there is no relationship between hypomagnesemia and disease control,10,37 possibly because of good glycemic regulation or the small number of participants in these studies. Our findings are in agreement with previous studies that have reported a relationship between hypomagnesemia and poor glycemic control in adults with diabetes.21–24,26,28,30,38,40,41,47 Furthermore, a significant negative correlation between HbA1c and magnesium concentrations was detected when serum ionized magnesium were determined38 or when measurements were made separately in muscle, mononuclear cells, and platelets, whereas no association was found between 374
HbA1c levels and magnesium levels in erythrocytes.28,40 However, the role of magnesium administration in glycemic control remains controversial;48 it has been shown that oral or intravenous supplementation of magnesium in T1DM patients results in increased levels of magnesium in erythrocytes or skeletal muscle and decreased insulin requirements, but has no effect on metabolic control.49,50 Similar findings have been reported by studies in T2DM patients.51,52 The molecular mechanisms by which hypomagnesemia influences carbohydrate metabolism have been described in part (Table 4).53 In this context, magnesium deficit could also be associated with the development of chronic complications of diabetes, especially retinopathy, nephropathy, or neuropathy. Indeed, the relationship between metabolic control and impaired magnesium balance was corroborated when studies showed that insulin-treated T2DM or T1DM patients with severe background or proliferative retinopathy demonstrated lower plasma, serum or erythrocyte magnesium levels than those with no or mild background retinopathy;24,54–57 however, other studies failed to reveal a significant association between the severity of retinopathy and plasma magnesium concentrations in patients with T1DM or T2DM.27,58 Lower magnesium levels have also been detected previously in most,38,40 but not all,33,47 adult patients with T1DM or T2DM and micro- or macroalbuminuria compared with those without albuminuria. Analogous results have been reported for analyses of erythrocyte and intraplatelet magnesium concentrations.40,59 In addition, target serum magnesium levels for patients with diabetes of between 0.82 and 1.03 mmol/L have been suggested, because, in a previous study,19 T2DM patients who had serum magnesium levels within this range had the lowest deterioration of renal function and the best glycemic control. Erythrocyte magnesium content has also been shown to be lower in T1DM patients with polyneuropathy,60 and magnesium supplementation has been reported to improve nerve conduction and reduce the incidence of polyneuropathy, at least in young patients with a short duration of diabetes and early neurological signs.60,61 Together, these data suggest that hypomagnesemia may be an
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important risk factor for the development of diabetic micro- and macrovascular disease. However, the precise mechanism involved in the development of diabetic microvascular changes is not fully elucidated (Table 4).62–67 The cross-sectional design and the relatively small sample size of the present study may be considered limitations. In addition, because magnesium is an intracellular cation, its serum concentration may not accurately reflect total body magnesium status. However, in a recently published systematic review, it was concluded that serum and/or plasma magnesium concentrations appear to be useful biomarkers of magnesium status.68 In conclusion, the present study has shown that low serum magnesium levels in children and adolescents with T1DM are associated with an increased risk of poor glycemic control, potentially contributing to the early development of cardiovascular complications. These data indicate that the relationship between magnesium status and diabetes control begins in childhood. Intervention studies are needed to further elucidate whether restoration of magnesium balance, through the consumption of foods with a high magnesium content, or even via medication, could improve disease control and prevent potential longitudinal complications.
Acknowledgements The authors thank all the children and adolescents who participated in the study, as well as their parents and/or guardians.
Disclosure The authors declare no conflict of interests.
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56. Ceriello A, Giugliano D, Dello Russo P, Passariello N. Hypomagnesemia in relation to diabetic retinopathy. Diabetes Care. 1982; 5: 558–9. 57. McNair P, Christiansen C, Madsbad S et al. Hypomagnesemia, a risk factor in diabetic retinopathy. Diabetes. 1978; 27: 1075–7. 58. Corrêa ZM, Freitas AM, Marcon IM. Risk factors related to the severity of diabetic retinopathy. Arq Bras Oftalmol. 2003; 66: 739–43. 59. Shahid SM, Mahboob T. Electrolytes and Na+–K+ATPase: Potential risk factors for the development of diabetic nephropathy. Pak J Pharm Sci. 2008; 21: 172–9. 60. Engelen W, Bouten A, De Leeuw I, De Block C. Are low magnesium levels in type 1 diabetes associated with electromyographical signs of polyneuropathy? Magnes Res. 2000; 13: 197–203. 61. De Leeuw I, Engelen W, De Block C, Van Gaal L. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004; 17: 109–14. 62. Barbagallo M, Dominguez LJ, Resnick LM. Magnesium metabolism in hypertension and type 2 diabetes mellitus. Am J Ther. 2007; 14: 375–85.
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63. Zhou Q, Zhou Y, Liu W, Kummerow FA. Low magnesium stimulated prostacyclin generation in cultured human endothelial cells. Magnes Res. 2008; 21: 177– 84. 64. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 1993; 21: 1024–9. 65. Nadler JL, Malayan S, Luong H, Shaw S, Natarajan RD, Rude RK. Intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus. Diabetes Care. 1992; 15: 835–41. 66. Bjelakovic G, Sokolovic D, Ljiljana S et al. Arginase activity and magnesium levels in blood of children with diabetes mellitus. J Basic Clin Physiol Pharmacol. 2009; 20: 319–34. 67. Ankush RD, Suryakar AN, Ankush NR. Hypomagnesaemia in type-2 diabetes mellitus patients: A study on the status of oxidative and nitrosative stress. Indian J Clin Biochem. 2009; 24: 184–9. 68. Witkowski M, Hubert J, Mazur A. Methods of assessment of magnesium status in humans: A systematic review. Magnes Res. 2011; 24: 163–80.
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Journal of Diabetes 6 (2014) 369–377
O R I G I N A L A RT I C L E
Association between magnesium concentration and HbA1c in children and adolescents with type 1 diabetes mellitus Assimina GALLI-TSINOPOULOU,1 Ioanna MAGGANA,1 Ioannis KYRGIOS,1 Konstantina MOUZAKI,1 Maria G. GRAMMATIKOPOULOU,2 Charilaos STYLIANOU,1 and Kyriaki KARAVANAKI3 1
4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, 2Department of Human Nutrition and Dietetics, Alexander Technological Educational Institute, Thessaloniki, and 32nd Department of Pediatrics, Faculty of Medicine, University of Athens, “P&A Kyriakou” Children’s Hospital, Athens, Greece
Correspondence Assimina Galli-Tsinopoulou, 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 564 03 Thessaloniki, Greece. Tel./Fax: +30 2310 991537 Email: [email protected] Received 25 June 2013; revised 14 December 2013; accepted 25 December 2013. doi: 10.1111/1753-0407.12118
Abstract Background: Magnesium levels may be decreased in patients with type 1 diabetes mellitus (T1DM), influencing disease control. Relevant studies concern mainly adults and there are few data from the pediatric population. The aim of the present study was to evaluate magnesium levels and examine their possible association with glycemic control in youths with T1DM. Methods: In all, 138 children and adolescents with T1DM aged between 1.9 and 20.3 years were recruited to the study. Using a cross-sectional design, we measured anthropometric parameters, HbA1c, serum magnesium, ionized and total calcium, phosphorus, potassium, sodium, and urinary albumin (UA). Estimated glomerular filtration rate (eGFR), based on serum creatinine concentrations, was also calculated. Results: Lower levels of magnesium were found in subjects with poor versus good glycemic control (0.79 ± 0.09 vs 0.82 ± 0.09 mmol/L, respectively; P = 0.002). Serum magnesium levels were negatively correlated with HbA1c (P < 0.001) and positively correlated with UA, calcium, phosphorus, and potassium levels (P < 0.05). After adjustment for confounding factors, only magnesium levels remained significantly associated with HbA1c (adjusted r2 = 0.172; P = 0.004). The odds ratio for poor glycemic control, indicated by HbA1c >7.5%, between the highest and lowest magnesium concentration quartiles was 0.190 and amounted to a decrease of 1.7% in the HbA1c level. Conclusions: The present study shows that low serum magnesium levels in children and adolescents with T1DM are associated with an increased risk of poor glycemic control, potentially contributing to the early development of cardiovascular complications. Keywords: children and adolescents, glycemic control, hypomagnesemia, magnesium, type 1 diabetes mellitus.
Significant findings of the study: The relationship between magnesium status and diabetes control begins in childhood. Hypomagnesemia in youths with type 1 diabetes mellitus (T1DM) is associated with an increased risk of poor glycemic control. What this study adds: New quantitative data on the relationship between serum magnesium levels and glycemic control in youth with T1DM. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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electrolytes in the glycemic regulation of diabetes in childhood and adolescence.
Introduction Magnesium is the second most abundant intracellular cation after potassium; it is obtained from the diet and is present in high amounts in a variety of unprocessed foods, including nuts, legumes, and vegetables; in contrast, meat, fish, and dairy products have a relatively low magnesium content.1 Although clinically evident magnesium deficiency is uncommon in otherwise healthy subjects, it may result from renal dysfunction, endocrine causes, gastrointestinal losses, or inadequate intake. Magnesium deficit may also coexist with deficiencies of other dietary elements, such as vitamins, calcium, and potassium, particularly in cases of malnutrition. It may manifest as anorexia, nausea, muscle weakness, ataxia, tetany, convulsions, mental confusion, and irritability, typically within 1–3 months after beginning a magnesium-free diet.1 What is interesting is that it has been known from relatively early on that a low dietary intake or a deficiency of magnesium is associated with cardiac arrhythmias, hypertension, coronary vasospasm, atherogenesis, ischemic heart disease, and sudden death.2 Recently, a significant inverse association was found between dietary magnesium intake or serum magnesium concentrations and risk of total cardiovascular events,3 whereas low serum magnesium levels have been shown previously to predict cardiovascular and all-cause mortality in a population-based study during follow-up as well.4 Moreover, serum magnesium levels have been inversely and independently associated with the intima– media thickness of common carotid artery in adolescents with type 1 diabetes mellitus (T1DM), which is a well-accepted early marker of atherosclerosis.5 In addition, low serum magnesium concentrations were shown to be associated with a high prevalence of premature ventricular complexes in patients with type 2 diabetes mellitus (T2DM) in a dose-dependent manner.6 All these data suggest that there may be a direct link between magnesium status, diabetes, and cardiovascular disease. Hypomagnesemia is common in patients with both T1DM and T2DM, especially in poorly controlled and chronically treated patients.7 However, to our knowledge, little research has addressed the relationship between serum magnesium levels and diabetes in youth. Although most studies have demonstrated lower magnesium concentrations in youngsters with T1DM,8–11 data concerning the association between magnesium and glycemic control remains obscure. In the present study we measured serum magnesium levels, along with levels of other electrolytes, in children and adolescents with T1DM to investigate the possible involvement of these 370
Methods Study design and subjects In all, 138 children and adolescents with T1DM aged between 1.9 and 20.3 years (61 children, 77 adolescents; 72 boys, 66 girls) who were followed-up in the Outpatient Unit of the 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, were enrolled in the present cross-sectional study. All subjects were treated with insulin given by either multiple daily injections (n = 119) or continuous subcutaneous infusion (n = 19) and were included in the study if they were 3 months. Exclusion criteria included the presence of acute disease or chronic conditions that could influence magnesium homeostasis. In addition, none of the children or adolescents had hypertension, diabetic retinopathy, or nephropathy. The study was approved by the Scientific Ethics Committee of the Faculty of Medicine, Aristotle University of Thessaloniki. Informed written consent was also obtained from the parents and/or guardians of all the study subjects who underwent clinical and laboratory investigations. Data collection Weight (SECA 711; Seca, Hamburg, Germany) and height (HARPENDEN stadiometer; Veeder-Root, Elizabethtown, NC, USA) were measured (in kg and m, respectively) and body mass index (BMI) was calculated as weight divided by height squared. All subjects underwent complete physical examination and were classified as prepubertal or pubertal using Marshall and Tanner staging.12,13 After overnight fasting, blood samples were collected from all subjects for measurement of serum levels of magnesium, ionized calcium, total calcium, phosphorus, potassium, sodium, and creatinine using standard methods and an Olympus AU-400 clinical chemistry analyzer (Olympus, Hamburg, Germany). Estimated glomerular filtration rate (eGFR), based on serum creatinine concentrations, was also calculated using the updated Schwartz formula after an agedependent adaptation for k.14 In addition, we collected data on total daily magnesium intake by all subjects, in line with the method used previously for the determination of nutritional status in a group of diabetic and healthy children and adolescents;15 specifically, we recorded dietary habits over 3 continuous days and analyzed these data using the US Department of Agriculture
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(USDA) 19 HealtheTec SR computer program (Nutrient Data Laboratory, Human Nutrition Research Center, USDA, Beltsville, MD, USA) and compared them against the dietary reference intakes (DRI) for the appropriate age and gender.16 Glycemic control was estimated for each patient through HbA1c, measured with a DCA 2000 analyzer (Bayer, Elkhart, IN, USA). In addition, each subject gave a random morning urine specimen for the determination of urinary albumin (UA), which was also measured using the DCA 2000 analyzer (Bayer).
Kruskal–Wallis tests where appropriate. Analysis of covariance (ANCOVA) was used to analyze data after controlling for potential covariates. Categorical variables were compared using the Chi-squared test and correlations were calculated with Spearman’s correlation coefficients. Logistic regression analysis was performed to investigate the association between magnesium concentration quartiles and poor glycemic control (HbA1c >7.5%) before and after adjustment for potential confounding factors. All tests were two-sided and the level for statistical significance was set at P < 0.05.
Groups and definition of cut-off points To define “glycemic control”, we used standard international criteria.17 Based on HbA1c levels, subjects were divided into two groups: (i) those with good glycemic control (normoglycemic group), defined as HbA1c levels ≤7.5%; and (ii) those with poor glycemic control, defined as HbA1c levels >7.5%. Moreover, to examine the association between demographics, clinical or laboratory measurements, and magnesium, subjects were divided into four groups (quartiles) based on magnesium serum concentrations as follows: quartile (Q) 1, serum magnesium 0.85 mmol/L. Statistical analysis Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). Data are presented as frequencies and percentages for categorical variables and as the mean ± SD for continuous variables. All continuous variables were tested for normal distribution by the Kolmogorov–Smirnov or Shapiro–Wilk test, and the significance of differences between groups was tested with an unpaired t-test and/or Mann–Whitney U-test or one-way analysis of variance (ANOVA) and/or
Table 1
Results Baseline data The mean age of the study population was 11.5 years, whereas the mean duration of diabetes was 4.1 years (Table 1). Serum magnesium levels of subjects varied from 0.51 to 2.11 mmol/L, with a mean value of 0.80 mmol/L. Overall, the mean daily dietary intake of magnesium was 181.1 mg/day, without differences between children and adolescents, in accordance with the recommended dietary allowance.15,16 Pubertal subjects had significantly higher HbA1c (8.3 ± 2.0 vs 7.7 ± 1.5%; P = 0.02), UA (30.9 ± 50.6 vs 13.5 ± 16.2 mg/L; P = 0.003) and eGFR (138.8 ± 28.3 vs 123.3 ±17.0 mL/ min per 1.73 m2; P < 0.001) levels than prepubertal subjects, but there were no significant differences in pubertal versus prepubertal subjects in terms of serum magnesium (0.80 ± 0.08 vs 0.80 ± 0.11 mmol/L, respectively; P = 0.571) or total and ionized calcium, phosphorus, potassium, and sodium levels (data not shown). Finally, no gender differences were detected in any of the parameters studied, including magnesium concentrations, except for eGFR, which was higher in boys than in girls (140.5 ± 27.3 vs 122.6 ±18.7 mL/min per 1.73 m2, respectively; P < 0.001).
Baseline data and comparisons between those with poor and good glycemic control Glycemic control
Age (years) Duration of diabetes (years) HbA1c (%) BMI (kg/m2) Magnesium (mmol/L) UA (mg/L) eGFR (mL/min per 1.73 m2)
Total sample (n = 138)
Poor (n = 73)
Good (n = 65)
P-value
11.5 ± 3.9 4.1 ± 3.4 8.0 ± 1.8 19.5 ± 3.8 0.80 ± 0.09 23.2 ± 40.1 132.0 ± 25.1
12.1 ± 4.0 4.5 ± 3.6 9.2 ± 1.7 19.9 ± 4.0 0.79 ± 0.09 30.5 ± 51.3 131.5 ± 23.8
10.8 ± 3.6 3.7 ± 3.1 6.7 ± 0.6 18.9 ± 3.5 0.82 ± 0.09 15.1 ± 18.9 132.4 ± 26.7
0.025 0.294 7.5% (%)
OR (95% CI)
P-value
OR (95% CI)
P-value
137 34 32 37 34
72 24 19 17 12
0.607 – 0.609 0.354 0.227
0.002 – 0.341 0.038 0.004
0.594 – 0.468 0.360 0.190
0.002 – 0.162 0.046 0.002
(52.6%) (70.6%) (59.4%) (45.9%) (35.3%)
(0.441, 0.836) (0.219, 1.690) (0.133, 0.945) (0.082, 0.630)
(0.426, 0.829) (0.161, 1.355) (0.131, 0.984) (0.065, 0.558)
Quartile (Q) 1, serum magnesium 0.85 mmol/L. UA, urinary albumin; OR, odds ratios; CI, confidence interval.
probability of poor glycemic control. The regression model was performed on the basis of the univariate correlations between HbA1c and other clinical or biochemical parameters (data not shown). When age, gender, serum magnesium, and UA levels were included in the model, only the association between serum magnesium and HbA1c remained significant (adjusted r2 = 0.172; P = 0.004). The odds ratio (OR) of detecting an HbA1c value >7.5% was 0.227 (unadjusted model) or 0.190 (adjusted model) for Q4 compared with Q1; this amounts to a significant decrease of approximately 1.7% in the HbA1c level (unstandardized β-value) between the highest and lowest serum magnesium quartiles. Discussion In the present study we measured serum magnesium levels, as well as other clinical and biochemical parameters, in children and adolescents with T1DM. There were 34 subjects (25% of the whole sample) who had serum magnesium concentrations 7.5%, between the highest and lowest serum magnesium quartiles was 0.190,
amounting to a decrease of 1.7% in the level of HbA1c. All these findings confirm that hypomagnesemia may be present and aggravate diabetes, even in the younger age groups, thus suggesting an additional mechanism that may contribute, at least in part, to the early development of complications. It is well established that circulating magnesium levels tend to decrease in adults with either T1DM or T2DM, especially in poorly controlled patients with a long duration of diabetes,20–30 independent of residual insulin secretory status.31 Moreover, previous studies have reported significantly lower total serum or plasma magnesium levels in children with known or newly diagnosed insulindependent diabetes mellitus (IDDM) compared with their healthy peers,8–11 although conflicting results have been published as well.32–35 Furthermore, children with IDDM retained a significantly greater percentage of magnesium than controls during a magnesium tolerance test, thus confirming lower magnesium levels.8 Nevertheless, it is of note that Husmann et al. indicated that only the ionized (i.e. active) form of magnesium and not total plasma levels of magnesium differed significantly in pediatric patients with newly diagnosed IDDM,36 although this was not confirmed in a later study.37 Serum levels of ionized magnesium were also found to be significantly reduced in T2DM patients compared with control subjects.38 In addition, when erythrocyte or platelet magnesium concentrations were determined for subjects with T1DM or T2DM and compared with those in healthy controls, significantly reduced levels were reported by a few,8,25,39,40 but not all,10,26,28,41 studies. In addition, magnesium levels have been found to differ in muscle, but not in mononuclear or polymorphonuclear cells.10,26,28,29 Although there is a lack of agreement regarding the cause of lower magnesium levels in diabetes, it has been suggested that inadequate magnesium intake, hypermagnesuria, or gastrointestinal disorders could be reason-
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Summary of mechanisms associating low magnesium status with diabetes
Mechanisms through which hypomagnesemia influences carbohydrate metabolism • Impaired insulin-mediated glucose uptake in target-cells because • Impaired glucose-induced insulin secretion by β-cells due to several intracellular phosphorylation reactions of the insulin competitive inhibition of calcium influx by magnesium signaling cascade are magnesium dependent concentration Mechanisms for the development of diabetic microvascular changes • Changes in vascular smooth muscle tone • Impaired platelet aggregation • Imbalance between prostacyclin–thromboxane synthesis • Increased blood arginase activity • Excessive production of reactive oxygen and nitrogen species
able explanations. In addition, it has been reported that young subjects with T2DM consume significantly less magnesium than those with T1DM.42 What strengthens this view is that hypomagnesemia in diabetes often coexists with other electrolyte disorders, such as hypokalemia and hypocalcemia.43 Indeed, another finding of the present study was that significant reductions in serum calcium, phosphorus, and potassium levels were observed in parallel with reductions in magnesium levels. However, the subjects in the present study were found to have a normal magnesium intake. Conversely, insulin deficiency may explain the increased urinary magnesium excretion, because insulin has been recognized to stimulate magnesium conservation in the loop of Henle and distal tubule.44 Moreover, uncontrolled hyperglycemia and hyperglycuria may increase magnesium excretion through osmotic diuresis, leading to a vicious circle.44 Actually, McNair et al. reported the occurrence of a definite hypermagnesuria in 55% of 215 outpatients with IDDM.18 Increased magnesium urinary excretion with a male predominance has also been reported in children and adolescents with T1DM compared with their healthy peers,8,34,45,46 as well as in adult patients with diabetes;26,27,29,35 however, inconsistent findings have also been published.28 As far as the relationship between magnesium status and glycemic control is concerned, incompatible results exist on this topic in youth with T1DM. Fort and Lifshitz described a negative correlation between magnesium levels and HbA1c,11 whereas others have reported that there is no relationship between hypomagnesemia and disease control,10,37 possibly because of good glycemic regulation or the small number of participants in these studies. Our findings are in agreement with previous studies that have reported a relationship between hypomagnesemia and poor glycemic control in adults with diabetes.21–24,26,28,30,38,40,41,47 Furthermore, a significant negative correlation between HbA1c and magnesium concentrations was detected when serum ionized magnesium were determined38 or when measurements were made separately in muscle, mononuclear cells, and platelets, whereas no association was found between 374
HbA1c levels and magnesium levels in erythrocytes.28,40 However, the role of magnesium administration in glycemic control remains controversial;48 it has been shown that oral or intravenous supplementation of magnesium in T1DM patients results in increased levels of magnesium in erythrocytes or skeletal muscle and decreased insulin requirements, but has no effect on metabolic control.49,50 Similar findings have been reported by studies in T2DM patients.51,52 The molecular mechanisms by which hypomagnesemia influences carbohydrate metabolism have been described in part (Table 4).53 In this context, magnesium deficit could also be associated with the development of chronic complications of diabetes, especially retinopathy, nephropathy, or neuropathy. Indeed, the relationship between metabolic control and impaired magnesium balance was corroborated when studies showed that insulin-treated T2DM or T1DM patients with severe background or proliferative retinopathy demonstrated lower plasma, serum or erythrocyte magnesium levels than those with no or mild background retinopathy;24,54–57 however, other studies failed to reveal a significant association between the severity of retinopathy and plasma magnesium concentrations in patients with T1DM or T2DM.27,58 Lower magnesium levels have also been detected previously in most,38,40 but not all,33,47 adult patients with T1DM or T2DM and micro- or macroalbuminuria compared with those without albuminuria. Analogous results have been reported for analyses of erythrocyte and intraplatelet magnesium concentrations.40,59 In addition, target serum magnesium levels for patients with diabetes of between 0.82 and 1.03 mmol/L have been suggested, because, in a previous study,19 T2DM patients who had serum magnesium levels within this range had the lowest deterioration of renal function and the best glycemic control. Erythrocyte magnesium content has also been shown to be lower in T1DM patients with polyneuropathy,60 and magnesium supplementation has been reported to improve nerve conduction and reduce the incidence of polyneuropathy, at least in young patients with a short duration of diabetes and early neurological signs.60,61 Together, these data suggest that hypomagnesemia may be an
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important risk factor for the development of diabetic micro- and macrovascular disease. However, the precise mechanism involved in the development of diabetic microvascular changes is not fully elucidated (Table 4).62–67 The cross-sectional design and the relatively small sample size of the present study may be considered limitations. In addition, because magnesium is an intracellular cation, its serum concentration may not accurately reflect total body magnesium status. However, in a recently published systematic review, it was concluded that serum and/or plasma magnesium concentrations appear to be useful biomarkers of magnesium status.68 In conclusion, the present study has shown that low serum magnesium levels in children and adolescents with T1DM are associated with an increased risk of poor glycemic control, potentially contributing to the early development of cardiovascular complications. These data indicate that the relationship between magnesium status and diabetes control begins in childhood. Intervention studies are needed to further elucidate whether restoration of magnesium balance, through the consumption of foods with a high magnesium content, or even via medication, could improve disease control and prevent potential longitudinal complications.
Acknowledgements The authors thank all the children and adolescents who participated in the study, as well as their parents and/or guardians.
Disclosure The authors declare no conflict of interests.
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