European Journal of Internal Medicine 24 (2013) 639643

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original article

Serum magnesium in the metabolically-obese normal-weight and healthy-obese subjects

Fernando Guerrero-Romero, Martha Rodriguez-Moran
Biomedical Research Unit, Mexican Social Security Institute, Predio Canoas # 100, Col. Los Angeles, ZC 34067, Durango, Mexico

a r t i c l e

i n f o

a b s t r a c t
Background: Given that hypomagnesemia is related with hyperglycemia, hypertension, hypertriglyceridemia, and insulin resistance, the objective of this study was to determine whether serum magnesium levels are associated with the metabolically obese normal weight (MONW) and the metabolically healthy obese (MHO) phenotypes. Methods: Population-based cross-sectional study that enrolled 427 subjects, men and non-pregnant women aged 20 to 65 years, to participate in the study. Subjects were allocated into groups with and without obesity; among non-obese individuals, the subgroup of MONW subjects was compared with a control group of healthy normal-weight individuals. Among obese individuals, the subgroup of MHO subjects was compared with a control group of obese subjects who exhibited at least one metabolic abnormality. In the absence of obesity, the presence of fasting hyperglycemia, insulin resistance, hypertriglyceridemia, and/or hypertension dened the presence of MONW phenotype. In the absence of hypertension, insulin resistance and metabolic abnormalities of fasting glucose and triglycerides levels, the phenotypically obese subjects were dened as MHO individuals. Results: The sex-adjusted prevalence of MONW and MHO phenotypes was 40.8% and 27.9%. The multivariate logistic regression model adjusted by family history of diabetes, age, body mass index, and waist-circumference, showed a positive association between hypomagnesemia and the MONW phenotype (OR 6.4; 95%CI 2.320.4) and negative relationship between serum magnesium and the MHO phenotype (OR 0.32; 95%CI 0.170.61). Conclusions: Our results show that hypomagnesemia is positively associated with the presence of MONW phenotype, and the normomagnesemia negatively with the MHO phenotype. 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Article history: Received 20 December 2012 Received in revised form 21 February 2013 Accepted 25 February 2013 Available online 20 March 2013 Keywords: Metabolically obese normal weight Metabolically healthy obese Magnesium Hypomagnesemia

1. Introduction The concept of metabolically obese but normal weight (MONW) individuals was originally developed to describe a subgroup of normalweight individuals displaying obesity-related phenotypic characteristics [1]. It has been proposed that these individuals, despite having a body mass index (BMI) b 25 kg/m2, are characterized to have insulin resistance, hyperglycemia, hypertriglyceridemia, and/or high blood pressure [2,3]. It has been speculated that the origin of increased cardiovascular risk among the normal-weight individuals may be genetic and/ or related with diet composition [35]. The concept of metabolically healthy obese (MHO) individuals was introduced to characterize the obese individuals who have no metabolic disorders [6,7]. These individuals, despite the presence of obesity, are free of components of the metabolic syndrome [8] and are characterized by the early onset of obesity. The fat distribution,

insulin resistance, and physical activity levels account only partially for differences between the obese and MHO individuals [9]. Among the components of metabolic syndrome, hypertension, dislipidemia, and hyperglycemia are strongly related to low serum magnesium levels [1012]; so, as magnesium intake is inadequate in the western diet [13], hypomagnesemia could be a contributing factor in the development of cardiovascular risk factors in the MONW phenotype. Given the scarce data about physiopathology of MONW and MHO phenotypes and because magnesium depletion could be an important contributing factor, we have hypothesized that hypomagnesemia might be related with metabolic disturbances in the normal-weight individuals and that normal magnesium levels might contribute to the metabolically normal status in the obese individuals; thus, the objective of this study was to determine whether serum magnesium levels are associated with the MONW and MHO phenotypes. 2. Materials and methods With the approval of the protocol by the Mexican Social Security Institute Research Committee and after obtaining the written informed consent, a population-based cross-sectional study was carried out. The sampling strategy was based on advertising strategies to the general population of Durango, city in northern Mexico, for inviting

Grant support: This work was supported by grants from the Mexican Social Security Institute Foundation, Civil Association. Corresponding author at: Siqueiros 225, 34000, Durango, Dgo., Mexico. Tel.: +52 618 8120997; fax: +52 618 8132014. E-mail address: rodriguez.moran.martha@gmail.com (M. Rodriguez-Moran).

0953-6205/$ see front matter 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.02.014

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F. Guerrero-Romero, M. Rodriguez-Moran / European Journal of Internal Medicine 24 (2013) 639643

men and non-pregnant women aged 20 to 65 years, to participate in the study. A total of 427 individuals were enrolled. Subjects were allocated into groups with and without obesity; among non-obese individuals, the subgroup of MONW subjects was compared with a control group of healthy normal-weight individuals. Among obese individuals, the subgroup of MHO subjects was compared with a control group of obese subjects who exhibited at least one metabolic abnormality. A standardized interview, clinical examination, and laboratory tests were performed to determine the presence of diabetes, pregnancy, smoking, alcohol consumption, chronic diarrhea, renal disease, malignancy, and the intake of magnesium supplements in the previous three months, which were the exclusion criteria. 2.1. Denitions In the absence of obesity, the presence of fasting hyperglycemia, insulin resistance, hypertriglyceridemia, and/or hypertension dened the presence of the MONW phenotype. The phenotypically normal-weight subjects, without metabolic abnormalities, dened the control group of the MONW individuals. In the absence of hypertension, insulin resistance, and metabolic abnormalities of fasting glucose and triglycerides levels, the phenotypically obese subjects were dened as MHO individuals. The phenotypically obese subjects with at least one metabolic abnormality, dened the control group of the MHO phenotype. In order to minimize the rate of false positive test and consequently, to reduce the possibility of bias in the analysis, hypomagnesemia was dened by serum magnesium concentration 0.7 mmol/dL (1.7 mg/dL) and normomagnesemia by serum magnesium levels > 0.7 (1.7 mg/dL) and b 1.15 mmol/L (2.8 mg/dL). Normal-weight was dened by BMI b 25 kg/m 2 and obesity by BMI 25 kg/m 2. Fasting hyperglycemia was dened by fasting plasma glucose 5.6 and b 7.0 mmol/L ( 100 and b 126 mg/dL) [14]. Hypertriglyceridemia was dened by the presence of serum triglyceride levels 1.7 mmol/L (150 mg/dL) [15]. Insulin resistance was dened by the presence of HOMA-IR index 3. 2.2. Measurements In the standing position, weight and height were measured using a xed scale stadimeter with the subjects in light clothing and without shoes. The BMI was calculated as weight (kilograms) divided by height (meters) squared. The WC was measured to the nearest centimeter with a exible steel tape measure with the subjects in standing position. The anatomical landmarks were: laterally, midway between the lowest portion of the rib cage and iliac crest, and the umbilicus anteriorly. Brachial artery blood pressure was measured in seated participants after they had rested for 5 min with the use of a baumanometer (Microlife AG, Heerbrugg Switzerland) and stethoscope (3M Littman Classic II, Neuss, Germany). The technique of blood pressure measurement was according the criteria by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [16]. The HOMA-IR index was calculated using the formula fasting insulin (U/mL) fasting glucose (mmol/L) / 22.5 [17]. 2.3. Assays Whole blood sample was collected from antecubital venous after 810 h overnight fasting. Serum magnesium concentrations were measured by colorimetric method, the intra- and interassay variations were 1.0 and 1.5%, respectively. Serum glucose was measured using the glucose-oxidase method; the intra- and inter-assay coefcients of

variation were 1.1% and 1.3%. Insulin levels were measured by microparticle enzyme immunoassay (Abbot Axsym System), with intra- and inter-assay coefcients of variation 3.4% and 5.9%. Triglycerides were measured enzymatically. HDL-cholesterol fraction was obtained after precipitation by phosphotungstic reagent. The intra- and inter-assay coefcients of variation were 1.9% and 3.7% for triglycerides, and 1.5% and 3.1% for HDL-cholesterol. Measurements were performed in a Data Pro Plus Clinical Analyzer (Arlington, TX, USA). 2.4. Statistical analysis Differences between the groups were assessed using unpaired Student's t test (MannWhitney U test for skewed data) for numeric variables, and the Chi-squared test for testing differences between proportions. The correlationship between serum magnesium levels with hyperglycemia, hypertriglyceridemia, and HOMA index in MONW subjects, was estimated using Pearson correlation test. Multiple logistic regression analysis adjusted by family history of diabetes (FHD), age, BMI, and WC was used to compute the Odds Ratio (OR) between serum magnesium levels (independent variable) and the MONW and MHO phenotypes (independent variables). An additional adjusted multiple logistic regression analysis was performed to establish the relationship between serum magnesium and the cardiovascular risk factors (dependent variables), in the normal-weight and obese individuals. Data were analyzed using the statistical package SPSS 15.0 (SPSS Inc., Chicago Il). 3. Results A total of 427 individuals were enrolled; 274 (64.2%) women and 153 (35.8%) men, with average age and BMI of 41.5 13.7 years and 29.9 6.2 kg/m 2. Seventy-six (17.8%) individuals exhibited normal-weight; of these, 31 (40.8%) had the MONW phenotype. Table 1 shows the characteristics of the population with normalweight according metabolically status. The percentage of FHD, HOMA-IR value, and fasting glucose levels were higher, and serum magnesium levels were lower, in the MONW individuals than in the control group. There were no signicant differences between the groups for the BMI and WC. Among the individuals with the MONW phenotype, the frequency of hyperglycemia, hypertriglyceridemia, insulin resistance, and hypertension was of 70.1%; 67.7%, 28.6%, and 3.2%, respectively; a total of 2 (6.4%), 17 (54.8%), 12 (38.7%), and 0 (0.0%) of the MONW individuals exhibited 1, 2, and 3 cardiovascular risk factors. There were a negative correlationship between serum magnesium levels and hyperglycemia, hypertriglyceridemia, and HOMA index in the MONW subjects, Fig. 1. Hypomagnesemia was identied in 22 (70.1%) of the MONW individuals and 8 (17.8%) of the normal-weight individuals without metabolic disturbances, p b 0.0005. The crude OR that computes the relationship between hypomagnesemia and the MONW phenotype was 11.3 (95%CI 3.8 to 33.6, p b 0.0005). In the adjusted multivariate logistic regression model, the hypomagnesemia remained signicantly associated with the MONW phenotype (OR 6.4; 95%CI 2.320.4). A total of 351 (82.2%) individuals exhibited obesity; of them, 98 (27.9%) subjects had the MHO phenotype. Table 1 shows the characteristics of the obese population according to metabolic status. The MHO individuals showed similar BMI and WC than the obese individuals in the control group; however, the HOMA-IR index, fasting glucose, insulin, and triglyceride levels were signicantly lower, whereas the serum magnesium levels were signicantly higher,

F. Guerrero-Romero, M. Rodriguez-Moran / European Journal of Internal Medicine 24 (2013) 639643 Table 1 Characteristics of the target population, according to the weight and metabolic status. MONW n = 31 Family history of type 2 diabetes, n (%) Age, years Body mass index Waist circumference, cm Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Fasting glucose, mmol/L Fasting insulin, pmol/L HOMA-IR HDL-c, mmol/L Triglycerides, mmol/L Serum magnesium, mmol/L MONW, metabolically obese normal-weight. MHO, metabolically-healthy obese. 11 (35.5) 39.0 19.2 22.5 1.6 84.2 9.1 112.2 16.2 87.0 8.0 5.8 1.0 63.9 27.38 2.8 1.0 1.2 0.4 3.7 2.8 0.66 0.21 Normal-weight n = 45 6 (13.3) 36.2 13.1 22.3 2.0 86.0 10.5 105.0 14.5 86.1 9.2 4.8 0.5 51.4 27.1 1.50 0.7 1.2 0.4 1.3 0.2 0.78 0.12 P value 0.04 0.48 0.64 0.43 0.50 0.67 0.0005 0.85 0.03 0.80 b 0.0005 0.04 MHO n = 98 17 (17.3) 42.1 14.0 30.1 1.5 100.8 8.3 114.3 22.7 77.6 11.6 5.0 0.5 46.5 20.1 1.5 0.7 1.1 0.1 1.2 0.4 0.78 0.12 Obese n = 253 44 (17.4) 42.4 13.1 31.7 1.6 104.6 14.0 118.3 18.3 76.2 10.9 5.6 0.9 80.6 43.1 2.9 1.5 1.0 0.4 2.4 2.1 0.66 0.21

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P value 0.88 0.94 0.57 0.19 0.59 0.38 0.002 b 0.0005 b 0.0005 0.17 b 0.0005 0.01

in the MHO individuals as compared with the control group of obese subjects. Among the obese individuals, the frequency of hyperglycemia, hypertriglyceridemia, hypertension, and insulin resistance was 48.2%; 54.1%, 38.7%, and 11.5%, respectively; a total of 100 (39.5%), 101 (39.9%), 48 (19.0%), and 4 (1.6%), of the obese individuals exhibited 1, 2, 3, and 4 cardiovascular risk factors. Hypomagnesemia was identied in 10 (10.2%) of the MHO individuals and 121 (47.8%) of the obese individuals with metabolic disturbances, p b 0.0005. The crude OR that computes the relationship between normomagnesemia and the MHO phenotype was 0.11 (95%CI 0.014 to 0.88, p = 0.03). In the adjusted multivariate logistic regression model, the normomagnesemia remained negatively associated with the MHO phenotype (OR 0.32; 95%CI 0.17 to 0.61). Table 2 shows the adjusted ORs between hypomagnesemia and the cardiovascular risk factors in the non-obese and obese groups. The hypomagnesemia was strongly related with hypertriglyceridemia, hyperglycemia, and insulin resistance in the non-obese group and, (in a lesser degree) with insulin resistance and hypertriglyceridemia in the obese group. 4. Discussion Our results show that hypomagnesemia is positively associated with the MONW phenotype, and the normomagnesemia negatively with the MHO phenotype. Furthermore, our results show that hypomagnesemia is strongly related with hyperglycemia, hypertriglyceridemia, insulin resistance in the non-obese individuals, and (in a lesser degree) with the hypertriglyceridemia and insulin resistance in the obese individuals. The underlying mechanisms and correlates of normal-weight individuals who display cardiovascular risk factor clustering and of obese individuals who are resistant to the development of the adiposityassociated cardio-metabolic abnormalities are not well known; our results support the hypothesis that serum magnesium levels might play an important role in the development of these phenotypes.

Recently, Wildman et al. [18] reported the results of a crosssectional analysis performed on a sample of the National Health and Nutrition Examination Surveys 19992004; they found a prevalence of MONW and MHO, of 23.5% and 31.7%, respectively; ndings that emphasize the magnitude of this public health problem and encourage for further research into the underlying physiologic mechanisms of these phenotypes. On this regard, Hwang et al. [8] in a nation-wide population cohort, in which the prevalence of the MHO phenotype was of 28.5%, report that the MHO individuals are at higher risk to develop hypertension, type 2 diabetes, and metabolic syndrome than their non-obese counterparts, providing evidence that opposes the notion of MHO as a harmless condition. However, in both the National Health and Nutrition Examination Surveys 19992004 [18] and the study by Hwang et al. [8] there are no reports about the relationship between MONW and MHO with magnesium status. In our study, the prevalence of the MONW phenotype (40.8%) was higher than that reported in the Asian (12.7% to 13.3%) and USA populations (23.5%) [1820], whereas the prevalence of the MHO phenotype (27.9%) was similar to previous reports in the Asian (31.7% to 47.9%) [19,20] and USA (23.5% to 31.7%) [8,18] subjects, ndings that support the possible role of ethnicity in the development of both phenotypes and emphasizes, that regardless of weight status, the health behaviors should be modied to prevent the development of cardiovascular risk factors. On this matter, the main contribution of our study suggests that serum magnesium status might play an important role in either the development of MONW or the prevention of MHO phenotypes. Taking into account that serum magnesium levels are easy to detect and magnesium deciency is easy to modify, through diet and/or oral magnesium supplementation, our nding could be of interest for researchers and clinicians in the eld. Further research, based on double blind placebo controlled clinical trials is mandatory. A growing body of evidence, derived from epidemiological studies [2126] and clinical trials [2730], consistently shows an inverse

Fig. 1. Correlationship between serum magnesium and hyperglycemia, hypertriglyceridemia, and HOMA index in metabolically obese normal-weight subjects.

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F. Guerrero-Romero, M. Rodriguez-Moran / European Journal of Internal Medicine 24 (2013) 639643 [7] Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie ME, Messier V, et al. Characterizing the prole of obese patients who are metabolically healthy. Int J Obes (Lond) 2011;35:97181. [8] Hwang LC, Bai CH, Sun CA, Chen CJ. Prevalence of metabolically healthy obesity and its impacts on incidences of hypertension, diabetes and the metabolic syndrome in Taiwan. Asia Pac J Clin Nutr 2012;21:22733. [9] Hayes L, Pearce MS, Firbank MJ, Walker M, Taylor R, Unwin NC. Do obese but metabolically normal women differ in intra-abdominal fat and physical activity levels from those with the expected metabolic abnormalities? BMC Public Health 2010;10:723. [10] Rasic-Milutinovic Z, Perunicic-Pekovic G, Jovanovic D, Gluvic Z, Cankovic-Kadijevic M. Association of blood pressure and metabolic syndrome components with magnesium levels in drinking water in some Serbian municipalities. J Water Health 2012;10:1619. 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J Diabetes Sci Technol 2011;5:43946. [20] Lee K. Metabolically obese but normal weight (MONW) and metabolically healthy but obese (MHO) phenotypes in Koreans: characteristics and health behaviors. Asia Pac J Clin Nutr 2009;18:2804. [21] Lopez-Ridaura R, Willett WC, Rimm EB, Liu S, Stampfer MJ, Manson JE, et al. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care 2004;27:13440. [22] He K, Liu K, Daviglus ML, Morris SJ, Loria CM, Van Horn L, et al. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation 2006;113: 167582. [23] Kirii K, Iso H, Date C, Fukui M, Tamakoshi A, JACC Study Group. Magnesium intake and risk of self-reported type 2 diabetes among Japanese. J Am Coll Nutr 2010;29: 99106. [24] Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA, et al. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. 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Table 2 Odds ratio (OR) that computes the relationship between low serum magnesium levels and metabolic disorders in the non-obese (n = 76) and obese (n = 351) individuals. Non-Obese OR Hypertension Hyperglycemia Hypertriglyceridemia HOMA-IR index 3 0.11 4.15 6.67 9.00 95% CI 0.11 to 12.41 1.4 to 11.8 2.1 to 20.4 0.99 to 81.4 Obese OR 0.88 1.48 1.61 2.89 95% CI 0.41 to 1.71 0.97 to 2.26 1.5 to 2.46 1.84 to 4.53

relationship between dietary magnesium intake and serum magnesium levels with the risk of developing metabolic glucose disorders and insulin resistance. In addition, also it has been emphasized the strong relationship between magnesium depletion and hypertriglyceridemia [11,20,29,3133]. Finally, it is well known that magnesium affects blood pressure acting as a calcium channel antagonist, stimulating production of prostacyclins and nitric oxide, and altering vascular responses to vasoactive agonists [34]; on this regard, epidemiological studies [3537] and clinical trials [3841] also have demonstrated an inverse correlation between blood pressure and serum magnesium levels. However, to the best of our knowledge, the relationship between serum magnesium levels with the MONW and MHO phenotypes has not been previously evaluated; our results strongly suggest that, hypomagnesemia plays an important role in the development of MONW as well as that normomagnesemia is negatively associated with MHO individuals. We did not measure the customary diet, body fat composition, physical activity, and gene expression, which is the main limitation of this study. However, taking into account the aimed objective in the study and the sampling strategy for including a representative sample of the target population, this limitation does not exert an important role on our main conclusion. Learning points The frequency of the MONW and MHO phenotypes is common. Hypomagnesemia is positively associated to the MONW phenotype. Normomagnesemia is negatively associated to the MHO phenotype. Hypomagnesemia is strongly related with hyperglycemia, hypertriglyceridemia and insulin resistance in the non-obese individuals and (in a lesser degree) with the hypertriglyceridemia and insulin resistance in the obese individuals. Hypomagnesemia is strongly related with hypertriglyceridemia and insulin resistance in the obese individuals.

Conict of interests The authors state that they have no conicts of interest. References
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