ARTICLE
Auteur(s) : Martha Rodríguez-Morán, Fernando
Guerrero-Romero
Medical Research Unit in Clinical Epidemiology, General
Hospital of the Mexican Social Security Institute, and Research
Group on Diabetes and Chronic Illnesses Durango, Mexico
Introduction
Tumor necrosis factor alpha (TNF-alpha) is a cytokine released
in response to physiological stressors and damaged tissue [1]. In
addition to malignancy, cachexia, and infection, TNF-alpha also is
released by adipose tissue [2-4] contributing to the pathogenesis
of the obesity-related disorders [4-10], which support the
hypothesis that TNF-alpha could mediate insulin resistance in obese
subjects with diabetes [11] who exhibited threefold TNF-alpha
levels compared to non-diabetic subjects [12]. In this regard, it
has been suggested that TNF-alpha may act as an auto/paracrine
regulator of fat cell function[13].
Focusing on elucidation of potential pathways involved in the
TNF-alpha release, it has recently been shown in rats that
TNF-alpha production is an early event during magnesium-deficiency
[14].
Nevertheless the recent evidence showing that
magnesium-deficient animals have elevated circulating levels of
TNF-alpha [14, 15], and the potential relationship between
cytokines and magnesium, has received little attention, and at
present there are no studies based on humans that show the link
between decreased serum magnesium and elevation of TNF-alpha. With
this concern, the objective of this study was to examine the
relationship between serum magnesium and TNF-alpha levels in obese
subjects.
Material and methods
With the approval of the Mexican Social Security Institute
Scientific Research Committee, non-diabetic, non-hypertensive
subjects, inhabitants of Durango, a city in the North of Mexico,
were enrolled to participate in a cross-sectional study according
to two-stage cluster sampling, as has been previously described
[16]. In brief, in the first stage of sampling a middle-income
neighborhood of Durango was randomly selected; in the second stage
of sampling, households of such neighborhoods were randomly chosen
and visited by field workers to invite apparently healthy men and
non-pregnant women to participate in the study. Eligible subjects
were recruited between July 2001 and July 2003. All
participants gave their informed consent, and the study was
conducted according the principle expressed in the declaration of
Helsinki.
Conditions likely to provoke inflammation such as pregnancy,
alcohol consumption, smoking, diabetes, high blood pressure,
cardiovascular and coronary heart disease, renal disease, chronic
disorders of the joints and connective tissues, infectious
diseases, and malignancy were exclusion criteria.
Subjects were allocated into two groups according to their serum
TNF-alpha concentration; a group with TNF-alpha ≥ 3.5 pg/mL
and a control group with TNF-alpha
level < 3.5 pg/mL.
Criteria Diagnosis. Low serum magnesium levels were
defined as a fasting serum magnesium value ≤ 0.74 mmol/L,
equivalent to the low quartile of distribution in the studied
population [17, 18]. Elevated serum TNF-alpha levels, was defined
by serum TNF-alpha ≥ 3.5 pg/mL [19, 20].
Results of glycemia 2-h post oral glucose load (2h PG) were
categorized according to the American Diabetes Association criteria
[21]. Diagnosis of diabetes was based on serum glucose
concentration 2-h PG ≥ 11.1 mol/L. Blood pressure measurements
and diagnosis of high blood pressure were based in the VI Joint
National Committee recommendation [22].
The homeostasis model analysis insulin resistance (HOMA-IR)
index was used for estimating insulin action [23]. HOMA-IR index
value ≥ 2.8, equivalent to the upper quartile of distribution, were
considered as diagnostic for insulin resistance.
To evaluate the contribution of Body Mass Index on serum
TNF-alpha concentration, three categories of BMI were
compared: < 25, ≥ 25 to < 30, and ≥
30 kg/m2. These categories correspond to
international recommendations to define healthy weight (BMI ≥
19 to < 25 kg/m2), overweight
(BMI ≥ 25 to < 30 kg/m2), and
obesity (BMI ≥ 30 kg/m2) [24].
Measurements. Height and weight were taken using standard
protocols with the subjects in light clothing and without shoes;
waist circumference was taken as the minimum circumference at
umbilicus level and hip ratio as the maximum circumference on
antero-superior iliac crest. BMI was calculated as weight (in
kilograms) divided by height (in meters) squared, and Waist-to-hip
ratio (WHR) was calculated as waist circumference divided by hip
circumference.
Venous whole blood samples were drawn after 10 hours
overnight fasting. Plasma was separated from blood cells by
centrifugation and stored in fraction of 0.5 ml
at – 70 °C until analysis. Serum glucose was
measured by the glucose-oxidase method; its intra- and inter-assay
coefficients of variations (CVS) were 2.5% and 4.0%. The lipid
profile was measured by enzymatic methods; the intra- and
inter-assay CVs were 2% and 3.0%. TNF-alpha was measured by
chemiluminescent immunometric assay (immulite TNF, EURO/DPC, USA),
with intra- and interassay CVs of 1.8% and 3.5%. Serum magnesium
concentrations were measured by colorimetric method, the intra- and
inter-assay CVs were 1.0% and 2.5%. Insulin levels were measured by
radioimmunoassay (Diagnostic Products, Corporation, Los Angeles,
CA. USA) with intra- and inter-assay CVs of 4.5 and 6.9,
respectively.
Statistical analysis. Differences between the groups were
established by unpaired student t test (Mann-Whitney U
test), or one-way ANOVA test. Pearson’s analysis was performed to
examine the correlation between variables in study. All the skewed
numerical data were transformed to its Log n, which gave
symmetrical distribution.
Multivariate regression model analyses that quantify odds ratios
(OR) between serum magnesium and TNF-alpha concentrations were
performed. The model was adjusted by gender, HOMA-IR index, and
glucose tolerance status.
A confidence interval of 95% (Cl95%) was considered,
and a P value < 0.05 defined the level of
statistical significance. Data were analyzed using the statistical
package SPSS 10.0 (SPSS Inc., Il USA 1998).
Results
A total of 162 subjects were enrolled, of them 91 (56.2%)
showed elevation of serum TNF-alpha concentration. The clinical and
metabolic characteristics of the target population are given in
table I. Subjects with elevated
TNF-alpha were more obese and exhibited higher 2-h post-load
insulin, HDL-cholesterol levels, and C-reactive protein, and lower
serum magnesium levels than subjects in the control group.
Table I. Characteristics of
target population according to the serum TNF- a
concentrations
|
|
TNF-α ≥ 3.5 pg/mL
n = 91 |
TNF-α < 3.5 pg/mL
n = 71 |
P value* |
|
Age, yr |
43.1 ± 14.9 |
40.4 ± 12.6 |
0.22 |
|
Male/Female, n (%) |
65/26 |
41/30 |
0.09 |
|
Body mass index, kg/m2 |
28.8 ± 5.1 |
27.1 ± 5.0 |
0.04 |
|
Waist-to-hip ratio |
0.92 ± 0.07 |
0.88 ± 0.07 |
0.03 |
|
Systolic blood pressure, mmHg |
119 ± 19 |
116 ± 18 |
0.34 |
|
Diastolic blood pressure, mmHg |
73.5 ± 13 |
70 ± 10 |
0.12 |
|
Fasting glucose, mmol/L |
5.8 ± 1.2 |
5.7 ± 1.5 |
0.69 |
| 2-h
post-load glucose, mmol/L |
7.4 ± 1.9 |
6.8 ± 2.8 |
0.18 |
|
Fasting insulin, pmol/L |
68.0 ± 40.8 |
66.6 ± 58.2 |
0.86 |
| 2-h
post-load insulin, pmol/L |
424.8 ± 301.8 |
299.4 ± 331.2 |
0.04 |
|
Total-cholesterol, mmol/L |
5.7 ± 1.6 |
5.9 ± 1.5 |
0.62 |
|
HDL-cholesterol, mmol/L |
1.1 ± 0.3 |
1.2 ± 0.4 |
0.03 |
|
LDL-cholesterol, mmol/L |
3.5 ± 1.7 |
3.8 ± 1.3 |
0.18 |
|
Triglycerides, mmol/L |
2.2 ± 1.4 |
2.0 ± 1.6 |
0.45 |
|
HOMA-IR index |
2.7 ± 1.9 |
2.5 ± 1.9 |
0.56 |
|
C-reactive protein, mg/L |
52.1 ± 43.7 |
5.1 ± 10.9 |
< 0.0001 |
|
TNF-alpha, pg/mL |
8.3 ± 6.1 |
1.7 ± 0.8 |
< 0.0001 |
|
Serum magnesium, mmol/L |
0.74 ± 0.16 |
0.82 ± 0.15 |
0.02 |
Data are mean ± standard deviation
* P value estimated by student t test
(Mann-Whitney U test).
There were no differences by gender, 65 (40.1%) and 26 (16%)
versus 41 (25.3%) and 30 (18.5%), P = 0.09,
women and men, respectively, in the groups with and without
elevated TNF-alpha. Among the subjects with elevation of TNF-alpha,
men exhibited higher WHR, P = 0.01 and
TNF-alpha concentrations, P = 0.0002 than
women, whereas other variables did not show significant statistical
differences by gender. The sociodemographic and clinical
characteristics by gender of the target population are shown in
table II. There were significant
differences between the groups in WHR, HOMA-IR index, and serum
concentrations of C-reactive protein, TNF-alpha, and magnesium.
Table II. Characteristics of
the target population stratified by serum TNF-alpha concentrations
and gender
|
|
TNF-α ≥ 3.5 pg/mL
|
TNF-α < 3.5 pg/mL
|
P value* |
|
|
Women, n = 65 |
Men, n = 26 |
Women, n = 41 |
Men, n = 30 |
|
|
Age, yr |
42.8 ± 13.7 |
44.0 ± 17.6 |
41.5 ± 12.5 |
40.7 ± 12.9 |
0.74 |
|
Body mass index, kg/m2 |
28.5 ± 4.0 |
29.5 ± 5.9 |
27.7 ± 5.4 |
26.9 ± 4.4 |
0.04 |
|
Waist-to-Hip ratio |
0.90 ± 0.06 |
0.96 ± 0.07 |
0.89 ± 0.07 |
0.90 ± 0.05 |
0.03 |
|
Systolic blood pressure, mmHg |
112 ± 19 |
125 ± 16 |
117 ± 19 |
122 ± 18 |
0.21 |
|
Diastolic blood pressure, mmHg |
72 ± 10 |
75 ± 9 |
73 ± 14 |
74 ± 12 |
0.91 |
|
Fasting glucose, mmol/L |
5.8 ± 1.3. |
6.0 ± 1.2 |
5.8 ± 1.4 |
5.7 ± 1.7 |
0.85 |
| 2-h
post-load glucose, mmol/L |
7.4 ± 1.8 |
7.5 ± 2.0 |
6.9 ± 2.0 |
6.7 ± 2.2 |
0.08 |
|
Fasting insulin, pmol/L |
61.8 ± 29.4 |
79.8 ± 55.8 |
70.8 ± 68.4 |
58.8 ± 33.6 |
0.07 |
| 2-h
post-load insulin, pmol/L |
396.6 ± 301.8 |
478.8 ± 334.8 |
357.6 ± 386.4 |
205.8 ± 190.2 |
0.11 |
|
Total-cholesterol, mmol/L |
5.7 ± 1.6 |
5.9 ± 1.5 |
6.0 ± 1.4 |
5.6 ± 1.6 |
0.74 |
|
HDL-cholesterol, mmol/L |
1.1 ± 0.3 |
1.0 ± 0.3 |
1.3 ± 0.5 |
1.0 ± 0.3 |
0.06 |
|
LDL-cholesterol, mmol/L |
3.4 ± 1.7 |
3.8 ± 1.6 |
3.8 ± 1.3 |
4.0 ± 1.5 |
0.66 |
|
Triglycerides, mmol/L |
2.1 ± 1.9 |
1.7 ± 1.0 |
2.1 ± 1.4 |
2.2 ± 1.3 |
0.58 |
|
HOMA-IR index |
3.4 ± 1.6 |
3.2 ± 2.0 |
2.6 ± 2.0 |
2.4 ± 1.8 |
0.001 |
|
C-reactive protein, mg/L |
39.5 ± 49.9 |
53.3 ± 56.4 |
5.7 ± 11.4 |
4.2 ± 10.2 |
< 0.0001 |
|
TNF-alpha, pg/mL |
7.5 ± 5.1 |
10.3 ± 5.3 |
3.0 ± 0.7 |
2.4 ± 0.8 |
0.0001 |
|
Serum magnesium, mmol/L |
0.76 ± 0.46 |
0.73 ± 0.52 |
0.82 ± 0.49 |
0.81 ± 0.49 |
< 0.0001 |
Data are mean ± standard deviation.
*P value estimated by one-way ANOVA test.
A significant positive correlation was identified between
TNF-alpha and WHR (r = 0.395,
P < 0.05), but not between TNF-alpha and BMI
(r = 0.115, P = 0.097). Among the
subjects with elevated levels of TNF-alpha, 7 (7.7%), 31 (34.1%),
and 53 (58.2%) were lean, overweight, and obese, respectively.
Table III shows the distribution of
the target population according to the BMI categories. Obese
subjects showed dyslipidemia and exhibited significantly higher
fasting glucose, post-load insulin, HOMA-IR index, C-reactive
protein (C-RP), and TNF-alpha levels, and lower serum magnesium
than lean and overweight individuals.
Table III. Characteristics
of target population
|
BMI < 25 kg/m2
n = 54 |
BMI
≥ 25 < 30 kg/m2
n = 54 |
BMI
≥ 30 kg/m2
n = 54 |
P value* |
| Age, yr |
39.6 ± 14.6 |
41.9 ± 14.7 |
43.1 ± 12.4 |
0.33 |
| Body mass index, kg/m2 |
22.9 ± 1.5 |
27.0 ± 1.8 |
33.9 ± 3.6 |
< 0.0001 |
| Waist-to-Hip ratio |
0.88 ± 0.07 |
0.91 ± 0.06 |
0.95 ± 0.06 |
< 0.0001 |
| Systolic blood pressure, mmHg |
110 ± 19 |
116 ± 18 |
122 ± 19 |
0.03 |
| Diastolic blood pressure, mmHg |
65 ± 9 |
71 ± 12 |
77 ± 11 |
0.01 |
| Fasting glucose, mmol/L |
5.3 ± 1.0 |
5.8 ± 1.3 |
6.3 ± 1.3 |
0.001 |
| 2-h post-load glucose, mmol/L |
6.8 ± 2.8 |
6.8 ± 2.0 |
7.7 ± 1.6 |
0.15 |
| Fasting insulin, pmol/L |
51.5 ± 63.9 |
69.6 ± 29.3 |
72.4 ± 45.4 |
0.17 |
| 2-h post-load insulin, pmol/L |
215.0 ± 153.2 |
403.2 ± 374.7 |
448.7 ± 311.0 |
0.006 |
| Total-cholesterol, mmol/L |
5.1 ± 1.6 |
5.8 ± 1.4 |
6.4 ± 1.5 |
< 0.0001 |
| HDL-cholesterol, mmol/L |
1.2 ± 0.3 |
1.2 ± 0.4 |
1.0 ± 0.3 |
0.26 |
| LDL-cholesterol, mmol/L |
3.3 ± 1.5 |
3.5 ± 1.5 |
4.3 ± 1.4 |
0.01 |
| Triglycerides, mmol/L |
1.6 ± 1.1 |
2.1 ± 1.5 |
2.4 ± 1.6 |
0.03 |
| HOMA-IR index |
1.4 ± 1.1 |
2.5 ± 2.1 |
3.2 ± 1.9 |
0.004 |
| C-reactive protein, mg/L |
8.7 ± 20.6 |
27.8 ± 48.0 |
50.1 ± 52 |
< 0.0001 |
| TNF-alpha, pg/mL |
4.1 ± 2.9 |
6.2 ± 4.1 |
8.4 ± 5.8 |
0.002 |
| Serum magnesium, mmol/L |
0.83 ± 012 |
0.81 ± 0.18 |
0.67 ± 0.16 |
< 0.0001 |
Data are mean ± standard deviation
*P value estimated by one-way ANOVA test
In the target population, TNF-alpha and serum magnesium
exhibited an inverse correlation
(r = – 0.663,
P < 0.0001). Sixty-four (39.5%) subjects showed
low serum magnesium levels, of them 57 (89.1%) also showed elevated
TNF-alpha concentration (OR 22.5, Cl95% 8.7-60.1,
P < 0.0001).
Insulin resistance was identified in 60 (31.2%) subjects, 41
(68.3%) of them with elevation of TNF-alpha, 50 (83.3%) with low
serum magnesium levels, and 39 (65%) with both low serum magnesium
and elevated TNF-alpha concentrations (OR 6.8, Cl95%
1.3-37.9, P = 0.01).
The multivariate regression model adjusted by age, gender,
HOMA-IR index, and glucose tolerance status showed an independent
relationship between low serum magnesium and TNF-alpha levels in
the obese subjects (OR 1.5, Cl95% 1.2-10.2,
P = 0.01), but not in the overweight (OR 1.2,
Cl95% 0.9-9.4, p = 0.07) or subjects intra
healthy weight (OR 1.0, Cl95% 0.7-11.1;
P = 0.23).
Discussion
Although TNF-alpha is preponderantly released by cell-types
traditionally implicated in the host defense [25], TNF-alpha is
also released by adipose tissue [26-31]. In this respect, the data
of this study show a significant positive correlation between
TNF-alpha and WHR, but not between TNF-alpha and BMI, suggesting
that in the absence of inflammatory disease TNF-alpha is
preponderantly released by the abdominal fat tissue. This TNF-alpha
overexpression by fat tissue may be a physiological pathway to
limit obesity by increasing insulin resistance [32] and promoting
lipolysis in mature adipocytes [13]. Although these findings
support the hypothesis that TNF-alpha might contribute to the
obesity-associated disorders [26-31], little is known about the
regulatory mechanisms of TNF-alpha released from human adipose
tissue.
Recent studies show a significant increase of TNF-alpha in
magnesium-deficient animals, which is successfully reduced by
inhibition of substance P receptor, chloroquine, and magnesium
replacement therapy [15, 33-37] supporting the hypothesis that the
inflammatory response could be an early consequence of magnesium
deficiency [38]. In this regard, we recently reported an
independent association between low serum magnesium levels and
elevation of CRP levels in obese subjects [39]. The release of
substance P, which has been documented in magnesium-deficient
animals, might be one of the earliest pathophysiological events in
the obesity-related inflammatory response linked to decreased
magnesium status [15, 34, 40] suggesting a central role for
neurogenic peptides, especially substance P, during magnesium
deficiency [40]. Furthermore, i t has been described that decreased
magnesium levels are involved in the activation of immune cells
implicated in the inflammatory response [36] and thus, in the
elevation of TNF-alpha.
In accordance with previous reports, this study also showed an
independent relationship between elevated TNF-alpha and insulin
resistance. Although the precise pathways involved are still
unclear, it seems that TNF-alpha induces insulin resistance, at
least in part, through inhibition of tyrosine kinase activity
[41-45]. In a similar way, decreased magnesium levels also produce
a malfunction of tyrosine-kinase activity [46, 47] and impairment
of insulin action [48-50]. Although the role of cytokines [51-53]
and magnesium deficiency [14, 15, 49, 50] in the pathophysiology of
insulin resistance has been described, and both decreased magnesium
[15, 48, 50] and elevated TNF-alpha are regulators of the early
insulin-stimulated tyrosine phosphorylation events [54-62], our
data are the first showing the link between low serum magnesium and
elevation of TNF-alpha in humans.
Several potential limitations of this study should be mentioned.
First, our conclusions are based on cross-sectional analysis, which
cannot demonstrate a cause-effect associations. Thus, it will be
necessary to conduct prospective studies to convincingly
demonstrate whether magnesium supplementation decreases TNF-alpha
levels in obese subjects. Second, our study was limited to measures
of TNF-alpha, and we did not ascertain whether other cytokines were
also elevated in relation with the low serum magnesium levels;
evaluation of specific cytokines will be necessary to add data on
this issue.
Conclusion. The results of this study indicate that low serum
magnesium levels and elevated TNF-alpha are related in obese
subjects, a relationship that has not previously been reported in
human based studies.
Acknowledgement
This work was supported by grants from the National Science and
Technology Council of Mexico (SIVILLA 20000402008) and the Research
Promotion Fund of the Mexican Social Security Institute (FP
2001/354).
We sincerely appreciate the assistance of the Chemists Victor
Manuel Avila Valdez and Felipe Torres Navarrete.
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