ARTICLE
Auteur(s) : Y
Rayssiguier1, E Gueux1, W
Nowacki2, E Rock1, A Mazur1
1INRA, Unité de Nutrition Humaine, Clermont
Ferrand/Theix, 63122 Saint-Genès-Champanelle, France
2Veterinary Faculty, Norwida Str. 31, 50375 Wroclaw,
Poland
The metabolic syndrome is a cluster of common pathologies,
including abdominal obesity linked to an excess of visceral fat,
insulin resistance, dyslipidemia and hypertension. This syndrome
and type 2 diabetes are occurring at epidemic rates with frightful
consequences for human health worldwide [1].The increased
prevalence of insulin resistance is linked to the western diet and
reduced physical activity. In the past, diets high in saturated
fats have been shown to induce insulin resistance and
hyperlipidemia. However, recent studies suggest that a high intake
of refined carbohydrates may also contribute to the risk of
developing insulin resistance. In animal models, diets high in
fructose have specifically been shown to contribute to a metabolic
disturbance leading to insulin resistance. A significant change in
the western diet is the substantial increase in dietary fructose
consumption, which is due to a high intake of sucrose and high
fructose corn syrup, a common sweetener used in the food industry
[1]. Moreover, an increase in the consumption of empty calorie
foods contributes to a decrease in the total mineral and vitamin
density per unit of energy consumed and consequently, the marginal
magnesium intake induces a high prevalence of marginal magnesium
deficiency. A healthy magnesium intake supports efficient insulin
function, whereas magnesium deficiency contributes to insulin
resistance [2-6]. In industrialized countries, magnesium intake has
been reduced, while fructose consumption has been rapidly
increasing, and the aim of this review is to emphasize the
consequences of this eating pattern, particularly in the
development of the metabolic syndrome and to discuss the pathogenic
role of inflammation.
Role of inflammation in the metabolic syndrome
In recent years, several studies have demonstrated that subclinical
chronic inflammation is an important pathogenic factor in the
development of insulin resistance and cardiovascular diseases [7,
8]. Markers for this inflammatory response include acute phase
proteins, cytokines and mediators associated with endothelial
activation. In obese individuals, the white adipose tissue contains
an increased number of macrophages, when compared with lean
individuals, and the macrophages appear to be activated. The
adipocytes and macrophages produce leptin and other factors, which
upregulate the number of adhesion molecules on endothelial cells.
This leads to transmigration of monocytes, an increase in white
adipose tissue-resident macrophages and consequently, cytokines are
released in large amounts from the adipose tissue [9]. According to
this hypothesis, an excess energy intake leads to obesity and
hyperglycemia, which can cause oxidative stress and inflammatory
changes (nuclear factor-kappaB [NFkB] activation, increased levels
of tumour necrosis factor [TNF] alpha and interleukin [IL] [6]).
These inflammatory changes inhibit insulin signalling and can lead
to insulin resistance. Moreover, the inflammatory state induces
beta cells dysfunction, which in combination with insulin
resistance leads to type 2 diabetes [10, 11].
High-fructose diet and metabolic syndrome
The fructose fed rat represents a model for the metabolic syndrome,
including insulin resistance, hypertension and dyslipidemia, and
growing evidence suggests a role for inflammation and oxidative
stress in this model [12]. High fructose feeding of rats is
associated with a rapid increase in reactive oxygen species (ROS)
production by polymorphonuclear leukocytes (PMN) and tissues. This
overproduction of ROS is dependent on NADPH oxidase activation and
leads to an oxidative stress response as evidenced by elevated
concentrations of plasma and urinary thiobarbituric acid reactive
substances (TBARS). In rats, the fructose diet, when compared with
a starch diet, lowers the plasma vitamin E/triglycerides (TG)
ratio, which results in an increase in TG-rich lipoprotein
susceptibility to lipid peroxidation, and hearts are less protected
against in vitro peroxidation [13, 14]. Recent findings suggest
that the pro-oxidant effect induced by a high fructose diet can be
decreased by consumption of fermentable carbohydrates such as
oligofructose [15]. The link between inflammation, oxidative stress
and metabolic syndrome is supported by the fact that females, which
are protected against the pro-oxidant effects of a high-fructose
diet when compared with males, do not develop insulin resistance
[16]. Diets rich in fructose can alter cellular metabolism via
several pathways, thereby accelerating oxidative stress. Fructose
feeding results in the activation of the renin-angiotensin system
and it is well-established that angiotensin 2 production is
associated with oxidative stress. This oxidative stress is
characterized by overproduction of ROS and is dependent on the
activation of NADPH oxidase [17]. Moreover, increased IL1 and IL6
plasma levels have been documented in rats fed a high-fructose diet
[18]. Finally, in addition to the possible roles of uric acid and
kidney damage [19], the inflammatory response and oxidative stress
may be key events in the development of insulin resistance in rats
fed a high fructose diet. These events are likely to contribute to
other aspects of the metabolic syndrome. The hypertriglyceridemic
effect of fructose can be reduced by lipooxygenase inhibitors,
which decrease the inflammatory response [20], and inflammation and
oxidative stress are important factors in cardiovascular effects.
Inflammatory effects of magnesium deficiency
A characteristic allergy-like crisis occurs spontaneously in
magnesium deficient rats. They present hyperemia and oedema of the
ears and legs, and a greater spleen size due to phagocytic cell
infiltration [5, 6, 21]. An inflammatory response has also been
observed in other magnesium-deficient rodents. However, it was
shown that in mice the response depends on the experimental
conditions [22-24]. The inflammatory syndrome is accompanied by
hyperalgesia, which can be prevented by an N-methyl-D-aspartate
(NMDA) receptor antagonist [25]. In blood, the most prominent
change is leukocytosis, which results from the increased number of
PMN leukocytes, mainly neutrophils and eosinophils. An increase in
the number of eosinophils is considered a typical allergic
response. An important phenomenon during inflammation is the
production of cytokines. Early studies reported that, in rats,
experimental magnesium deficiency led to increased plasma levels of
orosomucoid [26]. In the same experimental model, several positive
acute phase protein plasma concentrations, and/or their liver mRNA
levels, have been shown to be induced, including
alpha2-macroglobulin, alpha1-acid glycoprotein, complement,
fetoprotein, haptoglobulin and fibrinogen. These changes are
related to increased IL6 concentrations, which stimulate the
synthesis of many acute phase proteins by the liver. The decrease
of several negative acute phase proteins, such as albumin,
apolipoprotein (apo) E, retinol-binding protein (RBP), is a
classical finding of an acute phase response. This inflammatory
response and its consequences are only observed in male rats.
Female animals are partially protected, suggesting that estrogens
may be protective against the proinflammatory effects of magnesium
deficiency [27]. It is of particular interest that females, when
compared with males, do not develop the metabolic syndrome on the
fructose diet. Several studies have been performed to assess the
activation of inflammatory cells in magnesium deficiency [28-30].
Free radical generation from PMN was measured in vitro using
chemiluminescence, and via NADPH oxidase activation, both
macrophages and neutrophils generated superoxide anions in response
to various stimuli. There was a low basal neutrophil activity in
control rats, but the basal neutrophil activity of magnesium
deficient rats was significantly higher. Neutrophils from control
and magnesium-deficient rats were responsive to activation by
phorbol 12-myristate 13-acetate (PMA) and zymosan, and the response
was higher for PMN magnesium-deficient rats. Differential gene
expression analysis of stress proteins has confirmed the neutrophil
activation [30] and in fact, the majority of stress proteins were
upregulated in neutrophils from magnesium-deficient animals.
Resident macrophages of magnesium-deficient rats present the
morphological aspects of an activated cell and their
chemiluminescence activity is elevated. In vitro, these cells are
more sensitive to PMA stimulation. Magnesium-deficient rats are
more sensitive to immune stress as measured by TNF response
following an endotoxin challenge [31]. The specific mechanisms of
the inflammatory response in magnesium deficiency have not been
elucidated. However, magnesium acts as a natural calcium antagonist
and the molecular basis for the inflammatory response is probably
linked to the modulation of the intracellular calcium concentration
[32]. Potential mechanisms include the priming of phagocytic cells,
the opening calcium channels and activation of NMDA receptors [33],
the release of neurotransmitters such as substance P [34, 35], the
activation of NFkB [36] and the activation of the renin angiotensin
systems [37].
High-fructose diet combined with magnesium deficiency
Inflammation is a key event in the initiation and development of
metabolic syndrome. A high-fructose diet induces both inflammation
and the metabolic syndrome in rats. If magnesium deficiency has a
proinflammatory effect, one likely consequence of combining
magnesium deficiency with a high-fructose diet is an amplified
effect, which has been shown by recent data from rats. The fructose
diet, as compared to a starch diet, induces hyperglycemia and
hyperinsulinemia. Magnesium deficiency induces hyperglycemia and
hyperinsulinemia when compared to a control diet. The combined
effects are higher, using the high fructose low magnesium diet, and
the binding of insulin to the red blood cell (RBC) insulin
receptors is reduced [38]. Thus, this study clearly documents the
effects of magnesium deficiency in the development of insulin
resistance in the rat model. We have shown that fructose feeding in
magnesium deficient rats is associated with an increase in
oxidative stress when compared with magnesium deficient rats fed a
starch diet [39]. This observation is consistent with the
hypothesis that inflammation and increased oxidative stress,
induced by magnesium deficiency, contribute to the development of
insulin resistance. In the same model, the proinflammatory effect
of magnesium deficiency contributes to other aspects of the
metabolic syndrome: hyperlipemia, elevated blood pressure,
endothelial dysfunction and increased thrombosis tendency [5, 6].
Fructose has been shown to increase the hyperlipemic effect of
magnesium deficiency, when compared to starch [40]. As previously
discussed, magnesium deficiency is accompanied by alterations in
lipid metabolism including accumulation of TG-rich lipoproteins
(TGRLP), a decrease in high density lipoprotein (HDL) levels, an
increase in apoB, a decrease in apoA1 and apoE, modifications in
the composition of lipoproteins, and a defect in the clearance of
TGRLP [41, 42]. Several factors contribute to these alterations
including decreases in the activities of lipoprotein lipase,
hepatic lipase [43, 44] and lecithin-cholesterol acyl transferase
(LCAT) [45]. Together, these changes could contribute to decreased
reverse cholesterol transport. TGRLP and tissues from
magnesium-deficient rats are more susceptible to ex vivo oxidation
than those from controls [46-48]. Thus, oxidative modification of
lipoproteins could play a significant role in the pathogenesis of
vascular lesions following magnesium deficiency and furthermore,
magnesium affects the inflammatory-dependent events leading to
atherosclerosis. The lipid metabolism changes observed in
experimental magnesium deficiency have been observed in other
models in inflammation [49]. On the basis of these studies, it is
possible to conclude that the proatherogenic lipoprotein changes in
magnesium deficient rats are the consequence of the inflammatory
response. Epidemiological and experimental studies have
demonstrated an inverse association between magnesium status and
blood pressure [50, 51]. Chronic dietary magnesium deficiency
causes elevated blood pressure; initially, a hypotension phase is
observed, which is due to the release of inflammatory agents, the
subsequent hypertension is a result of oxidative stress and
structural modifications in the vascular system [52, 53]. In fact,
free radicals may partly inactivate NO and an increased degradation
of NO by superoxide anions could contribute to hypertension during
chronic magnesium deficiency. In vitro studies have shown that low
magnesium levels results in endothelial dysfunction [54, 55]. Serum
from magnesium deficient rats stimulates the proliferation of
endothelial cells, increases the adhesion of monocytes to these
cells, and the endothelial cells upregulate the plasminogen
activator inhibitor (PAI) factor. The presence of endothelial
dysfunction and dyslipidemia triggers platelet aggregability [56].
Platelet aggregation is increased in magnesium deficiency, while
magnesium supplementation inhibits platelet dependent thrombosis
[44, 57]. We have investigated the thrombotic tendency in rats fed
a magnesium-deficient, high fructose diet. Following epinephrine,
the magnesium-deficient rats exhibited lesions in left atrium which
was dilated and haemorrhagic [44]. Thus, magnesium deficiency
induces predisposition to epinephrine-initiated thrombosis and
inflammatory pathway promotes thrombosis which is responsible for
myocardial infarction and stroke [28, 44].
Conclusion
Magnesium deficiency combined with a high-fructose diet induces
insulin resistance, hypertension, dyslipidemia, endothelial
activation and prothrombotic changes. In addition to well-known
factors such as overnutrition and physical inactivity, a diet rich
in fructose and deficient in magnesium results in an inflammatory
response, which may represent a triggering factor in the
development of the metabolic syndrome. Our data are in good
agreement with clinical data [58-66] showing that low serum and
dietary magnesium levels are strongly correlated with low grade
systemic inflammation and metabolic syndrome [58-66]. Large
epidemiological studies indicate that lower serum magnesium levels
are associated with insulin resistance. Magnesium intake and
systemic inflammation and the prevalence of metabolic syndrome were
inversely correlated in subjects participating in the Women Health
Study [62]. Furthermore, low magnesium serum levels are associated
with elevated serum concentrations of both TNF-alpha [64] and
C-reactive protein (CRP) [62, 63], suggesting that magnesium
deficiency may also be involved in the development of the low-grade
chronic inflammatory syndrome which can induce metabolic disorders.
Other studies have shown the correlation between low-serum
magnesium levels and TNF-alpha in obese and non-alcoholic
steatohepatitis (NASH) subjects [65]. Moreover, a longitudinal
association of magnesium intake with the incidence of metabolic
syndrome has recently been examined and the data suggests that
young adults with higher magnesium intake have a lower risk of
developing the metabolic syndrome [66]. A typical western diet is
high in fructose and often magnesium deficient. Considering the
well-documented detrimental effect of this eating pattern, there is
urgent need to explore the details of the link between diet and the
inflammatory signalling pathways.
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* Presented in part at 11th International
Magnesium Symposium, Kashikojima, Japan, October 23-26,
2006.
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