ARTICLE
Auteur(s) : Luis E Simental-Mendía, Martha
Rodríguez-Morán, Fernando
Guerrero-Romero
Biomedical Research Unit, Mexican Social Security Institute,
Durango, Mexico, and The Research Group on Diabetes,
Durango, Mexico
Magnesium, the second most abundant intracellular cation [1], is
an essential cofactor of enzymatic pathways involved in energetic
metabolism and the modulation of glucose transport across cell
membranes [2].
A large body of evidence shows that hypomagnesemia reduces
tyrosine-kinase activity at the insulin receptor level resulting in
the impairment of insulin action [2-8] and that oral magnesium
supplementation improves insulin sensitivity [9-13]. These data
support the important role that magnesium plays in the regulation
of insulin action; however, data regarding the link between
magnesium and insulin secretion are controversial.
The physiological relationship between beta cell function and
insulin sensitivity is distributed as a hyperbolic line [14] that
shows that the increase in insulin secretion compensates the
decrease in insulin sensitivity [15, 16]. The product of insulin
secretion and insulin sensitivity, the disposition index, is a
useful tool for identifying at-risk individuals [17, 18]; however,
because determination of the disposition index is based on data
derived from the hyperinsulinemic-euglycemic and hyperglycemic
clamp [14], it is not available in a clinical setting. In this
regard, based on a 5-y follow-up study, we recently reported that
the relationship between insulin secretion and insulin action
estimated by the HOMA-β and Belfiore indexes is distributed as a
hyperbolic line that represents the progressive adaptation of
β-cells to compensate the decrease in insulin sensitivity [19].
In this study, we tested the hypothesis that the decreased
insulin sensitivity is not appropriately compensated by β-cell
function in individuals with hypomagnesemia.
Material and methods
With the approval of the protocol by the Mexican Social Security
Institute Research Committee and after obtaining written informed
consent, a cross-sectional study was performed.
One-hundred and sixty-five individuals 20 to 65 years of
age, inhabitants of Durango, a city in northern Mexico, were
randomly enrolled in a cross-sectional study. Subjects were
allocated into groups with and without hypomagnesemia, matched by
age, gender, waist circumference (WC), and Body Mass Index
(BMI).
Pregnancy, smoking, alcohol consumption, high blood pressure,
type 2 diabetes, chronic diarrhea, renal disease, malignancy, and
heavy physical activity were exclusion criteria. The clinical
condition was corroborated by medical history, physical
examination, and laboratory tests.
Definitions
Hypomagnesemia was defined by serum magnesium concentration <
1.8 mg/dL and normomagnesemia by serum magnesium ≥ 1.8 mg/dL.
As a surrogate of the hyperbolic model of β-cell function [20],
we used the relationship between Belfiore’s and HOMA-β indices, as
measurements of insulin sensitivity and β-cell function [19]. The
fasting Belfiore’s index [21] was estimated by the formula 2/[1 +
(Fasting insulin pmol/L x Fasting glucose mmol/L)] and the β-cell
function index [22] as the 20 x Fasting insulin μU/mL/(Fasting
glucose mmol/L – 3.5). The cut off point of normal Belfiore and
HOMA-β indexes are ≤ 0.034 and ≥ 107.
Measurements
In the standing position, weight and height were measured using a
fixed scale with stadimeter with the subjects in light clothing and
without shoes. Body Mass Index (BMI) was calculated as weight
(kilograms) divided by height (meters) squared. The WC was measured
to the nearest centimeter with a flexible 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.
The technique for measurement of blood pressure was that
recommended in the Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure [23].
Assays
Whole blood samples were collected from antecubital venous after
8-10 h overnight fasting. The blood samples were centrifuged
at 3 000 x G for 30 min. The serum was separated and kept
frozen at – 80oC until further analysis. Serum magnesium
concentrations were measured by colorimetric methods that comprise
putting the serum sample in contact with the reagent, a
metallochromic dye substance together with a selective complexing
agent for removing interfering cations; the intra- and interassay
variations were 1.0 and 2.5%, respectively. Serum glucose was
measured using the glucose-oxidase method, the intra- and
inter-assay coefficients of variation were 1.1% and 1.5%. Insulin
levels were measured by microparticle enzyme immunoassay (Abbot
Axsym System, Chicago IL, USA), with intra- and inter-assay
coefficients of variation 4.5% and 6.9%. Measurements were
performed in a Data Pro Plus Clinical Analyzer (Arlington, TX,
USA).
Statistical analysis
Differences were assessed using the unpaired Student t test
(Mann-Whitney U test for skewed data) for numeric variables, and
the Chi-squared test for testing differences between proportions.
The mean Area Under Curve (AUC), which evaluates the adaptation
of beta-cell function to variation in insulin sensitivity, was
calculated for each group using the trapezoidal rule [24], which
facilitates the calculation of the AUC in standard units of area
(cm2).
The correlation between serum magnesium levels and the HOMA-β
index was estimated using Pearson’s correlation analysis.
Data were analyzed using the statistical package SPSS 15.0 (SPSS
Inc., Chicago Il).
Results
A total of 50 subjects with hypomagnesemia were compared with 115
normomagnesemic subjects. Subjects with hypomagnesemia had
significantly higher FPG and 2-h post load glucose than subjects in
the control group; nonetheless, the groups in study were comparable
in terms of the distribution of Impaired Fasting Glucose (IFG) and
Impaired Glucose Tolerance (IGT) (table
1).
The proportion of subjects with insulin resistance (Belfiore
index ≤ 0.034) was similar in the groups with hypomagnesemia (46%)
and normomagnesemia (31.3%), p = 0.10. Although the mean Belfiore
index was significantly lower in the subjects with hypomagnesemia,
the mean HOMA-β index and insulin levels were similar between the
groups in study. Other variables showed not significant differences
between the groups (table 1).
Serum magnesium levels and the HOMA-β index showed a significant
inverse correlationship (r = - 0.187, p = 0.02).
The relationship that evaluates the adaptation of β-cell
function to variation in insulin sensitivity in the hypomagnesemic
and normomagnesemic individuals is given in figure 1. Subjects with
hypomagnesemia showed a curve displaced to the left and below, that
suggests the failure of insulin secretion to compensate the
decrease in insulin sensitivity. The AUC in the hypomagnesemic and
normomagnesemic groups was 7.955 cm2 and
19.906 cm2 (proportion 1:2.5), respectively.
Subsequent analysis adjusted by BMI, showed that the AUC which
evaluates the adaptation of beta-cell function to variation in
insulin sensitivity was 6.891.and 19.121 (proportion 1:2.8).
Table 1 Characteristics of the targeted population
according to serum magnesium levels.
|
Hypomagnesemia
|
Normomagnesemia
|
p value
|
|
n = 50
|
n = 115
|
|
|
Age, years
|
43.6 ± 13.6
|
43.4 ± 11.4
|
0.77
|
|
Male/Female, n (%)
|
24.3/75.7
|
34.0/66.0
|
0.27
|
|
Obesity (BMI ≥ 30 kg/m2)
|
21 (42.0)
|
45 (39.1)
|
0.86
|
|
Impaired Fasting Glucose, n (%)
|
20 (40.0)
|
29 (25.2)
|
0.08
|
|
Impaired Glucose Tolerance, n (%)
|
15 (30.0)
|
50 (43.3)
|
0.14
|
|
Waist circumference, cm
|
101.6 ± 12.9
|
101.9 ± 13.4
|
0.92
|
|
Body Mass Index, kg/m2
|
28.4 ± 5.7
|
29.5 ± 6.3
|
0.34
|
|
Systolic blood pressure, mmHg
|
114.2 ± 24.2
|
119.1 ± 21.9
|
0.27
|
|
Diastolic blood pressure, mmHg
|
71.4 ± 11.1
|
75.2 ± 11.8
|
0.08
|
|
Fasting glucose, mg/dL
|
113.6 ± 23.0
|
106.8 ± 18.4
|
0.04
|
|
Postload glucose, mg/dL
|
134.6 ± 32.9
|
121.4 ± 29.7
|
0.01
|
|
Fasting insulin, μU/mL
|
8.6 ± 5.4
|
9.6 ± 4.8
|
0.17
|
|
Magnesium, mg/dL
|
1.4 ± 0.2
|
2.3 ± 0.4
|
<0.0001
|
|
Triglycerides, mg/dL
|
141.3 ± 65.5
|
145.0 ± 66.1
|
0.72
|
|
HDL-cholesterol, mg/dL
|
42.4 ± 14.4
|
44.5 ± 22.0
|
0.42
|
|
Fasting Belfiore index
|
0.041 ± 0.021
|
0.053 ± 0.030
|
0.005
|
|
HOMA-β index
|
82.5 ± 48.5
|
91.2 ± 79.9
|
0.32
|
Discussion
Results of this study indicate that variations of insulin
sensitivity are not appropriately compensated by β-cell function in
the individuals with hypomagnesemia.
The body of evidence shows that magnesium has an important role
in insulin-mediated glucose uptake [25-29]; however, reports
regards the role of magnesium on insulin secretion in subjects with
hypomagnesemia are controversial, with some studies showing a high
insulin response [26, 30] but others an impairment of insulin
secretion [12, 13]. Among non-diabetic subjects, a low magnesium
concentration has been associated with relative insulin resistance
and hyperinsulinemia [30] and among diabetic subjects, the direct
relation of plasma magnesium concentration with glucose disposal is
related to insulin sensitivity but is unexplained in its influence
on insulin secretion [26]. These findings suggest that
hypomagnesemia may be an important determinant of insulin
sensitivity but they are not conclusive regarding the link between
hypomagnesemia and insulin secretion.
In this study, individuals with hypomagnesemia exhibited
significantly higher glucose levels and insulin resistance but
similar β-cell function and insulin levels than those found in
normomagnesemic subjects, suggesting that the β-cell function to
compensate the decrease in insulin sensitivity was inappropriate.
Normal glucose tolerance is maintained by a precise balance between
insulin secretion and insulin action on sensitive tissues, in a way
that a reduction of insulin sensitivity is compensated by an
increase in insulin secretion, and the improvement of insulin
action by a decrease of β-cell insulin secretion, a relationship
consistent with a classic feedback loop [31, 32]. On the basis of
this hyperbolic relationship, the product of these two variables,
referred to as the disposition index, can be calculated and it has
highlighted the inability of the β-cell to compensate for insulin
resistance in subjects at risk for diabetes [33]. Thus, our results
support the statement that subjects with hypomagnesemia are at high
risk of developing type 2 diabetes [8], and that, in addition to a
decrease in insulin sensitivity, an inappropriate compensatory
β-cell function contributes to the increased risk. Furthermore, our
results suggest that hypomagnesemia could be linked to inadequate
β-cell compensation.
To the best of our knowledge, this study is the first that
evaluates the response of β-cells to compensate for insulin
resistance using a hyperbolic model that represents the
physiological relationship between insulin secretion and insulin
sensitivity.
Some limitations of this study deserve to be mentioned. First,
assessment of the β-cell response is a complex issue that requires
use of mathematical models applying data derived from the
hyperglycemic clamp [34] so, approximations from a fasting state
for evaluating β-cell function do not accurately reflect the β-cell
function. However, the fasting model for estimating the
relationship between insulin secretion and action that we used
proved to be a good predictor for progression from IFG to IGT, and
diabetes, which supports its reliability for use in epidemiological
studies. Second, subjects were classified according to their serum
magnesium concentrations; because magnesium is predominantly an
intracellular ion, its serum measurements could be not
representative of the magnesium status or intracellular pool. In
this regard, is necessary to keep in mind that, although
significant intracellular magnesium depletion can be seen with
normal serum concentrations, once serum magnesium declines, normal
intracellular levels of magnesium are unlikely to be found [35];
therefore, because we included only patients with decreased serum
magnesium levels, the possibility of normal intracellular magnesium
in the study population, which might be a source of bias, is
minimal.
On the other hand, the main strength of our study is that the
population included subjects with different glucose tolerance and
insulin sensitivity status and that the evaluation of insulin
secretion was performed in the context of insulin action.
As a conclusion, our results show that the decrease in insulin
sensitivity is not appropriately compensated by β-cell function in
individuals with hypomagnesemia, suggesting that hypomagnesemia
could be linked to inadequate β-cell compensation.
Acknowledgments
This work was supported by grants from the Fundación IMSS, A.C.
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