ARTICLE
Auteur(s) : Dharam P Chaudhary1,2, Ravneet K
Boparai1, Devi D
Bansal1
1Department of Biochemistry, Panjab University,
Chandigarh 160014, India
2Present address: Department of Plant Breeding Genetics
& Biotechnology, Punjab Agricultural University, Ludhiana
141004, India
Magnesium is the second most abundant intracellular cation. It
serves as a co-factor in a number of enzymatically catalyzed steps
regulating glucose metabolism [1]. All of the enzymatic reactions
that hydrolyze and transfer phosphate groups, including those
associated with the reactions involving adenosine triphosphate
(ATP), show an absolute requirement for magnesium [2]. Magnesium
deficiency is common and multifactorial and is associated with a
number of diseases as hypertension, diabetes mellitus,
atherosclerosis, cardiovascular disease and myocardial infarction,
etc. It is believed that an estimated 50%-85% population of the
United States is receiving an inadequate magnesium intake. There is
a great volume of literature that suggests an association between
reduced magnesium intake and insulin resistance, central to type 2
diabetes. Hall et al. [3] have reported that magnesium deficiency
produces insulin resistance in isolated skeletal muscles
preparations. In the recent past, many researchers have studied and
elaborated the link between magnesium deficiency and insulin
resistance [4-6].Serum magnesium concentrations have been shown to
correlate inversely with glucose disposal in diabetic patients and
magnesium administration has been found to increase the utilization
of carbohydrates [5]. The link between magnesium deficiency and the
development of diabetes is strengthened by the observation that
several treatments for type 2 diabetes appear to promote an
increase in magnesium levels. Metformin, for example, has been
shown to raise magnesium levels in the liver [7]. Pioglitazone, a
thiozolidinedione anti-diabetic agent that increases insulin
sensitivity, is reported to increase free magnesium concentration
in adipocytes [8].Sucrose is considered to be another important
factor associated with the development of insulin resistance. It
has been reported that the inclusion of refined sucrose in the diet
for 2-8 weeks could increase fasting glucose, insulin, total
triglycerides, and very low-density lipoprotein triglycerides in
non-insulin diabetes mellitus, non-diabetic hyperinsulinemic and
normal humans [9-11]. In particular, Storlein et al. [12]
demonstrated that sucrose feeding for a 4-week period produced a
major impairment in insulin action that was predominantly accounted
for by impaired suppression of hepatic glucose production and to a
lesser extent by reduced insulin mediated glucose utilization.
However, the effect of sucrose remains quite controversial. A range
of in vitro and in vivo studies have shown impairment [10, 13-16],
no change [17-21], and even improvement [22, 23] in various aspects
of glycemic control after increases in dietary intake of sucrose.
The controversies regarding the ability of sucrose to produce
insulin resistance is probably due to the various populations
studied, the dose of sucrose used and/or the duration of sucrose
exposure. However, the fructose component of sucrose is
non-controversial regarding its ability to produce insulin
resistance. Thornburn et al. [24] have reported that feeding rats
35% of their calories as fructose for 4 week severely reduced
insulin sensitivity with major impairments in both liver and
peripheral tissues. Fructose has been labelled as more deleterious
than sucrose in regard to insulin resistance [25, 26].
Nevertheless, it is becoming increasingly clear that dietary
nutrients can modify insulin action in a number of target tissues.
Therefore, it seems that sucrose consumption as well as low
magnesium intake are two dietary patterns that independently appear
to play increasingly important roles in the development of insulin
resistance.We have already reported that the feeding of a high
sucrose low magnesium diet to male Wistar rats for a period of
three months produces substantial hyperglycemia, hyperinsulinemia
and hypertriglyceridemia [27]. The present study is an extension of
our previously published work and investigates the effect of a low
magnesium diet on in vitro 14C-glucose uptake in liver,
diaphragm and thigh muscle of sucrose fed rats.
Materials and methods
Chemicals
2-[1-14C]-deoxy-D-glucose was procured from Bhabha
Atomic Research Centre (Mumbai, India). Methyl thymol blue (MTB),
poly vinyl pyrrolidine (PVP) and ethylene glycol tetra acetic acid
(EGTA) were from Sigma Chemical Company (St. Louis, MO, USA) and
were kindly provided by Prof. Ronal R. MacGregor (Department of
Anatomy and Cell Biology, University of Kansas Medical Center,
Kansas City, Kansas, USA). All other chemicals used were of
analytical grade.
Animals and diet
Male Wistar rats each weighing approximately 130 g were obtained
from the Central Animal House (Panjab University, Chandigarh,
India). The animals were kept in polypropylene cages under
controlled conditions of temperature and light. The rats were
randomly divided into four groups of six animals each. Group I was
fed a synthetic control diet (C), group II was fed a low magnesium
diet (LM), group III was fed a high sucrose diet (HS) while group
IV was fed a diet low in magnesium and high in sucrose (HSLM). The
animals were fed these experimental diets for a period of three
months. Composition of the diets is shown in table 1. The rats were given feed in small metal
dishes just before the beginning of dark cycle. Any spillage was
collected in the morning and its weight equivalent added to
following day’s feed. Diets were freshly made every 3-4 days and
stored at 4oC. The rats were allowed free access to
deionized water to avoid consumption of magnesium from normal
drinking water.
Table 1 Composition of the experimental diets.
|
Ingredients (g/kg diet)
|
Control (C)
|
High sucrose (HS)
|
Low magnesium (LM)
|
High sucrose low magnesium (HSLM)
|
|
Starch
|
650
|
-
|
650
|
-
|
|
Sucrose
|
-
|
650
|
-
|
650
|
|
Casein
|
200
|
200
|
200
|
200
|
|
Corn oil
|
50
|
50
|
50
|
50
|
|
Cellulose
|
50
|
50
|
50
|
50
|
|
Salt mixturea,b
|
35
|
35
|
35
|
35
|
|
Vitamin mixturec
|
10
|
10
|
10
|
10
|
|
DL-methionine
|
3
|
3
|
3
|
3
|
|
Choline chloride
|
2
|
2
|
2
|
2
|
aSalt mixture expressed in g/kg: CaHPO4, 60
g; KCl, 200 g; NaCl, 120 g; MgO, 21.0 g; MgSO4..
2H2O, 100 g; Fe2O3, 6 g;
FeSO4. 7H2O, 10 g; trace elements 10 g/kg
including Mn, 0.8 g; CuO, 125 g; Co, 0.0009 g; Zn, 0.450 g; I,
0.0049 g.
bA similar composition was used in all the
experimental groups, except for the addition of MgO and
MgSO4.2H2O to provide (per kg) 507.0 mg of Mg
in the control and high sucrose diets and 90.0 mg of Mg in the low
magnesium and the high sucrose low magnesium diets.
cExpressed per kg of the vitamin mixture: retinol,
539 mg; cholecalciferol, 6250 mg; thiamine, 2000 mg;
riboflavin, 1500 mg; niacin, 7000 mg; pyridoxine, 1000 mg;
cyanocobalamine, 5 mg; ascorbic acid; 80.000 mg;
D,L-α-tocophenyl acetate, 17,000 mg; menadione, 1000 mg/kg;
nicotinic acid, 10,000 mg; folic acid, 500 mg; para-amino benzoic
acid, 5000 mg; biotin, 30 mg/kg.
Sample preparation and biochemical analysis
Blood samples were drawn from the orbital sinus of light ether
anaesthetized, overnight fasted rats and immediately centrifuged at
2000 g for 15 minutes at 4oC. Serum was separated
immediately and the red cells were washed thrice with normal saline
in cold centrifuge and finally packed; an aliquot of RBCs was
digested using digestion mixture (HNO3:HClO4;
3:1) and dried to ash. After appropriate dilution magnesium was
analyzed by the method of Thuvasethakul and Wajjwalku [28].
At the end of three months of feeding synthetic diets, glucose
uptake was determined using the uptake of the radioactive glucose
analogue, 2-[1-14C]-deoxy-D-glucose (2-DG) as described
previously by Chang et al. [29]. The target tissues were quickly
excised after sacrificing the animals, dissected free of any
adjoining connective tissue, blotted and divided into long
longitudinal strips (25-30 mg each). Tissues were placed in
3 mL of Krebs-Ringer bicarbonate buffer (KRB) (37°C, pH 7.4)
containing 1 mmol/L glucose, 1% fatty acids, free bovine serum
albumin (BSA) under aeration of 5% CO2 in O2.
After preincubation for 30 min, tissues were incubated with
1.0 nM bovine insulin for 30 min and then with 50 μL Krebs’
Ringer Bicarbonate buffer containing 2-DG (1 μCi/mL) for 5 min
at 37°C in the shaking water bath under aeration. Reactions were
terminated by quickly blotting the tissues and dissolving them in
0.5 mL of 0.5 N NaOH for 45 min before neutralization
with 0.5 mL of 0.5 N HCl. After centrifugation, 800 μL of the
supernatant was added to 1 mL of aqueous counting scintillant
and the radioactivity was determined using a β-counter.
Statistical analysis
Results were expressed as means with their standard deviation
(S.D.). Further, the statistical significance of the differences
among the various dietary groups was determined by subjecting the
data to two way ANOVA with carbohydrate (starch/sucrose) and
magnesium (adequate/low) as the two factors, followed by inspection
of all differences between pairs of means by Tukey’s test.
Differences were considered statistically significant at p <
0.05.
Results
This paper shows additional results on the effect of low magnesium
diet on in vitro glucose uptake in sucrose fed rats and is an
extension to our previously published results [27] on the combined
effect of a high sucrose low magnesium diet in rats. Figure 1 represents weight
gain in rats after feeding the respective diets for 3 months in
different experimental groups. Animals of LM and HSLM groups
exhibited slower body weight gain compared to control and high
sucrose fed rats (p < 0.05). Compared to initial values, body
weights of control and sucrose fed rats increased by ≈ 117%,
whereas rats in LM and HSLM groups registered a lesser increase in
body weight of 46.15% and 76.92% respectively. Two way analyses of
variance revealed that the magnesium content of the diet had a
significant effect on changes in the body weight of experimental
animals while the carbohydrate constituent was not a significant
factor. Figures
1 and 3
represent time course changes in serum as well as RBC magnesium
levels, respectively, during the experimental period. The magnesium
status of rats fed the magnesium adequate diets (control and HS
groups) remained constant throughout the study period. However,
serum as well as RBC magnesium levels in rats fed low magnesium
diets showed a significant (p < 0.005) fall in low magnesium and
high sucrose low magnesium fed animals. When the data was subjected
to two way ANOVA, out of the two factors on which comparisons were
based, it was observed that it was the Mg content of the diet which
exerted a significant effect.
Figure 4
depicts the in vitro glucose uptake in liver, thigh muscle and
diaphragm of rats after feeding the respective experimental diets
for three months. As is clear from this figure, compared to control
animals, insulin-mediated glucose uptake was reduced significantly
(p < 0.005) in all the above mentioned tissues of rats consuming
low magnesium, high sucrose and high sucrose low magnesium diets.
Glucose uptake values in the combined high sucrose low magnesium
group rats were found to be lower than those in the low magnesium
(p < 0.01) and high sucrose groups (p < 0.01). 2 X 2 analyses
of variance of data obtained on glucose uptake in liver, thigh
muscle and diaphragm showed that both carbohydrate constituent and
magnesium content of diet had significant effects on glucose
uptake, while the interaction of these two factors also had a
significant effect, as seen in the combined HSLM group. The greater
magnitude of reduction in HSLM rats would appear to suggest that
the combined high sucrose low magnesium diet has an additive effect
in lowering the insulin-mediated glucose uptake in these target
tissues.
Discussion
Within the first week of feeding the experimental diet, classical
signs of magnesium deficiency (including hyperemia of the ears,
growth retardation, hair loss and edema of paws) were observed in
the LM and HSLM group animals. The present study clearly indicates
that the body weights of animals fed the combined high sucrose low
magnesium diet remained below those of the control animals (p <
0.05). Previous studies have shown that magnesium deficiency leads
to a decrease in body weight [30-32] whereas sucrose has been shown
to either cause an increase in body weight or to not affect body
weight [33-37]. Since the present work has been carried out to
study the combined effect of a low magnesium high sucrose diet it
appears that the net effect is a lesser increase in body weight
associated with a low magnesium diet which is somewhat compensated
by increased weight gain due to high sucrose feeding. It seems that
inadequate magnesium in the diet exerts a growth retarding effect,
as observed after statistical analysis using 2 way ANOVA.
The deficiency in dietary intake of magnesium was reflected by a
significant reduction in serum and RBC magnesium levels in the LM
and HSLM groups. Serum magnesium levels are considered to be the
first indicator of magnesium deficiency. Shills et al. [38]
reported that during experimentally induced magnesium deficiency,
the first change appears to be a fall in serum magnesium
concentration. Some previous studies have reported similar findings
and suggested that serum magnesium falls rapidly during magnesium
depletion in humans [39, 40] and animals [41, 42]. Alfrey et al.
[43] have correlated serum magnesium with bone magnesium status
during both hyper- and hypomagnesaemia and suggested that for
clinical purposes serum magnesium is a suitable indicator of total
body magnesium. Similarly, erythrocyte magnesium content is
reported to be another reliable indicator of total body stores of
magnesium. Ellin et al. [44] have found a marked reduction in
plasma and erythrocyte magnesium contents in magnesium deficient
animals. Therefore our findings of significantly (p < 0.005)
reduced serum as well as RBC magnesium content in the LM and HSLM
groups is basically an indication of reduced body magnesium
stores.
The present study demonstrates that a high sucrose low magnesium
diet significantly suppresses insulin-mediated glucose uptake in
liver, thigh muscle and diaphragm of rats. Statistical analysis
revealed that both the carbohydrate composition as well as the
magnesium content of the diet were independent factors that have
significant effects on glucose uptake in various tissues, while the
interaction of these factors also affected glucose uptake
significantly. Our results are consistent with reports published
previously. Tobey et al. [45] have reported that liver is the most
likely site responsible for the decline in insulin mediated glucose
uptake in sucrose fed rats. In a previous study, Vrana et al. [46]
observed that insulin stimulated glucose uptake was reduced in
adipose tissue from sucrose fed rats. However, adipose tissue
accounts for only a small fraction of total glucose disposal in the
intact organism [47]; a defect at this level cannot account for the
glucose intolerance and insulin resistance seen in sucrose fed
animals. In another study Maegawa et al. [48] compared a high
sucrose diet with a high fat diet and found that insulin-stimulated
glucose uptake into soleus muscle was decreased with both the
experimental diets. In vivo insulin stimulated glucose uptake was
reportedly decreased in rats fed a diet high in sucrose for a
period of ten months as compared with animals given a diet high in
complex carbohydrates [49]. It has also been shown that chronic
sucrose feeding alters the activity of specific enzymes regulating
hepatic carbohydrate metabolism, and both a decrease in the
activity of glucokinase [49, 50] and an increase in
glucose-6-phosphatase [51] have been described. Furthermore,
fructose feeding has been shown to lead to a decrease in the
ability of insulin to suppress activation of glucose-6-phosphatase
and fructose-1,6-bisphosphatase activity [51, 52]. These findings,
along with several other observations, seem to indicate that
fructose feeding would lead to a decrease in both hepatic glucose
and glycogen synthesis, stimulation of glycogenolysis and
gluconeogenesis, as well as interference with the effect of insulin
on hepatic glucose metabolism.
Similarly, reduced dietary magnesium intake and subsequently
depressed serum magnesium have been associated with insulin
resistance and reduced glucose uptake by target tissues. Low serum
magnesium levels have been implicated in the induction of insulin
resistance. It has been reported that hypomagnesemia induced in
rats by feeding a low magnesium diet produced a decrease in the
submaximal insulin-stimulated glucose uptake by the perfused
hindquarters, which could be prevented by supplementation with
magnesium [53]. Many other in vitro studies have shown a reduction
in insulin-mediated glucose uptake during magnesium deficiency
[54-56]. Rosolova et al. [57] have reported that relatively low
magnesium concentrations in non-diabetic subjects are associated
with a decrease in insulin-mediated glucose disposal. Earlier
studies suggest several possible mechanisms whereby low serum
magnesium levels may lead to the development of type 2 diabetes.
First of all, it is an essential cofactor in reactions involving
phosphorylation, thus magnesium deficiency could impair the insulin
signal transduction pathway [58, 59]. Secondly, low serum or
erythrocyte magnesium levels may affect the interaction between
insulin and insulin receptors by decreasing hormone receptor
affinity or by increasing membrane micro viscosity [60]. Finally,
magnesium can also be a limiting factor in carbohydrate metabolism,
since many of the enzymes in this process require magnesium as a
cofactor during reactions that utilize the phosphorus bond [58, 59,
61, 62].
Conclusion
Magnesium deficiency is fairly common and is a potential risk
factor for the development of insulin resistance. Sucrose feeding
has also been independently implicated in the induction of
diet-induced insulin resistance. Combined together, a diet rich in
sucrose and deficient in magnesium could possibly be used as a tool
to study and characterize the development of insulin resistance. A
high sucrose low magnesium diet has been reported to induce fasting
hyperglycemia, hyperinsulinemia and hypertriacylglycerolemia in
rats. The present study clearly demonstrates that a high sucrose
low magnesium diet reduces in vitro glucose uptake in target
tissues of rats, thereby inducing insulin resistance in rats.
Therefore, it may be concluded that a high sucrose low magnesium
diet produces insulin resistance by decreasing the entry of glucose
in the target tissues of rats.
Acknowledgements
This work was supported by Council for Scientific and Industrial
Research (CSIR) fellowships to Dharam P. Chaudhary and Ravneet K.
Boparai.
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