ARTICLE
Auteur(s) : Junji
Takaya, Fumiko Yamato, Kazunari Kaneko
Department of Pediatrics, Kansai Medical University, Moriguchi,
Osaka, Japan
Several studies have shown the association of size at birth or
indications of poor fetal growth with later development of
metabolic syndromes and insulin resistance [1]. Hales et al. [2]
proposed that impaired glucose tolerance and type 2 diabetes
may arise as a result of programming, a term used to describe
persistent changes in organ structure and function caused by
exposure to adverse environmental influences during critical
periods of development [3]. Because size at birth is determined
largely by non-genetic factors, these findings have led to the
“fetal origin” hypothesis, which proposes that fetal adaptation to
an adverse intrauterine environment affecting fetal growth may
program lifelong physiological changes [4].Magnesium (Mg) is an
important cofactor for the enzymes involved in carbohydrate
metabolism: an important role of Mg in insulin action has been
reported [5]; in adults and in children, low serum and
intracellular Mg ([Mg2+]i) concentrations are
associated with insulin resistance, impaired glucose tolerance, and
decreased insulin secretion [6, 7]. Furthermore, lower dietary Mg
intake could cause insulin resistance both in children and adults
[8, 9]. Based on these findings, we studied whether low
[Mg2+]i in the fetus may be one of the
critical abnormalities associated with low birth weight infants.In
this review, we hypothesize that intrauterine magnesium deficiency
may induce metabolic syndromes in later life. We discuss the
potential contribution of aberrant Mg regulation to low birth
weight and to the pathogenesis of metabolic syndromes.
Magnesium deficiency
It is reported that the amount of maternal Mg intake is not only
associated with pregnancy outcome but also with infant health [10].
From a cohort study consisting of 912 people, aged 50 years, born
as term singletons around the time of the 1944-1945 Dutch famine,
coronary heart disease, raised lipids, altered clotting and obesity
were more frequently observed after exposure to famine in early
gestation compared to those not exposed to famine, and decreased
glucose tolerance was more frequently found in people exposed to
famine in later gestation [12]. These findings show that maternal
undernutrition during gestation has serious effects on health in
later life. Another study demonstrated that the risk of having very
low birth weight infants (less than 1,500 g birth weight) is
reduced if the mother’s drinking water contains higher amounts of
Mg [11]. By the end of normal pregnancy, the fetus is believed to
acquire approximately 28 g of calcium, 16 g of
phosphorous and 0.7 g of Mg, mostly during the third
trimester: 80% of fetal accretion of Mg occurs during the third
trimester [13]. Barker speculated that fetal undernutrition in
middle to late gestation, which leads to disproportionate fetal
growth, programmed later metabolic disease [4].
From these findings, maternal undernutrition, including Mg
deficiency during gestation, obviously affects the health of the
fetus in adult life, while the timing of the nutritional insult on
the mother is an important determinate.
Placental transport
The levels of total calcium, ionized calcium, and Mg are higher in
fetal circulation compared to those in the maternal blood [14].
Copper and selenium share the same transport pathway in the
placental membrane along a concentration gradient in maternal-fetal
direction, while an active transport plays a predominant role for
Mg and iron [15]. In fact, the existence of an active transport
mechanism for Mg in the placenta was recently suggested by using
cultured trophoblast cells, i.e. a functional
Na+/Mg2+ exchanger that functions to maintain
low [Mg2+]i in the cells [16]. The activity
of this exchanger might be influenced by maternal plasma sodium
concentration because acute maternal hyponatremia in experimental
rats reduced the maternal-fetal transfer of Mg via placenta [17],
while there may be other pathways of Mg transport in the placenta.
Whereas mean levels of ionized calcium do not change during labor,
the mean maternal serum levels of ionized Mg and total Mg fall at
delivery, which suggests the presence of homeostatic mechanisms in
the fetus and placenta, indicating that free Mg in umbilical venous
blood may enhance Mg transport to the fetus [18].
In mammals, the nutrient exchange process takes place across the
placenta, a highly developed organ with numerous functions
throughout the most of gestational period, and maternal-fetal
homeostasis depends on a properly functioning placenta. Maternal Mg
deficiency obviously affects health of the fetus.
Placental vascular flow and magnesium
Calcium and Mg are co-factors in the synthetic activity of a
variety of enzymes. A variety of hormones, cytokines and growth
factors produced by fetal membranes and placenta can act locally on
the myometrium [19]. The ability of the uterine artery to dilate
during pregnancy may be specifically related to upregulation of
multiple pathways for production of nitric oxide (NO) [20]. The
activity of constitutive NO synthase is dependent on calcium and is
inhibited by a reduction in the concentration of Mg [21]. Markedly
reduced permeability to calcium and Mg of fetal membranes in
preterm labor suggests that this abnormality could be an important
factor for the activation of the myometrium in preterm labor [22].
Placental insufficiency as well as maternal malnutrition is also an
important cause for IUGR (( figure 1 )). Model
experiments of IUGR have been conducted by the reduced uterine
blood flow. One of these IUGR models was prepared by uterine artery
ligation in pregnant dams and their offspring were studied: Jansson
& Lambert reported that this IUGR model was associated with
impaired glucose tolerance in adult life, only in female rats [23].
Mg has an immediate effect on placental vascular flow as well as
Ca and NO. Reduced placental vascular flow is at least, in part,
responsible for placental insufficiency and IUGR.
Mg sulfate and pre-eclampsia
Mg is widely used in obstetric practice to treat pre-eclampsia.
Therapeutic levels of Mg have also been found to produce specific
placental effects such as vasodilation [24]. From the study of
human umbilical artery resistance in vitro [25], Mg sulfate exerts
a relaxant effect on umbilical arterial tone, attenuating the
vasoconstrictor effect of angiotensin II and endothelin-1 in the
fetal-placental vasculature. It did not affect, however, the
activity of thromboxane mimetic. In addition, angiotensin II and
thromboxane mimetic were shown to induce interleukin (IL)-1β
secretion by placental tissue, and this effect was completely
reduced by perfusion of Mg sulfate. These results suggest the
inhibition of local production of IL-1β could be one of the
mechanisms; i.e. Mg sulfate reduces the vasoconstrictory effect of
angiotensin II in human placenta.
Mg sulfate used for the treatment of pre-eclampsia or
hypertensive disease in pregnancy may have beneficial effects on
the feto-placental circulation.
Mg supplement and pregnancy outcome
It is well known that plasma Mg falls in pregnancy because of the
accumulation of iron in the placenta and fetus. Many women,
especially those from disadvantaged backgrounds, have lower Mg
intakes than recommended doses [26]. Mg is therefore widely given
as a supplement during pregnancy, particularly in cases of preterm
labor. There are several reports that oral Mg supplementation in
pregnancy is safe and that it has a positive effect on the fetal
morbidity [27]. Patients in preterm labor have significantly
depressed serum Mg levels, while in patients with pre-eclampsia Mg
levels were not significantly different from controls [28]. Several
papers reported that Mg supplementation during pregnancy could
reduce fetal growth retardation and pre-eclampsia and increase
birth weight. Mg therapy decreased the rate of IUGR, premature
rupture of membranes and premature delivery in risk pregnancies
treated with betamimetics [29]. Oral Mg treatment from before the
25th week of gestation was associated with a lower
frequency of preterm birth, a lower frequency of low birth weight
and fewer small for gestational age infants compared with a placebo
[30]. Mg intake of 513 women towards the end of the first trimester
of pregnancy was calculated from a record of food consumption. Mg
intake was correlated with weight, length, and head circumference
at birth as well as length of gestation up to a threshold of around
3,200 g birth weight [31]. In addition, the supplement of Mg
(100 mg/d) during the second and third trimesters had no
effect on the outcome of pregnancy.
Mg supplementation is beneficial in the management of
pregnancy-induced hypertension. The effect of Mg was compared with
that of placebo in a randomized double-blind controlled study of
patients with pregnancy-induced hypertension [32]. Mg
supplementation reduced maternal mean arterial blood pressure. The
gestational age at delivery was the same in both groups, whereas
the relative fetal birth weight among nulliparas was reduced in the
placebo group [32]. On the other hand, some papers reported that Mg
supplementation during pregnancy did not improve pregnancy outcome.
Between 13 and 24 weeks’ gestation, 400 young normotensive
primigravid women randomly received oral Mg (365 mg/d) or a
placebo. The Mg-supplemented group had significantly higher Mg
levels at delivery. However, between the groups there were no
differences in either systolic or diastolic blood pressure,
incidence of pre-eclampsia, fetal growth retardation, preterm
labor, birth weight, gestational age at delivery, or number of
infants admitted to the special care unit [10].
Any influence of Mg is confined to the first trimester or
before. However, the timing and dose of Mg supplementation may
alter the pregnancy outcome.
Neural protective effect of magnesium
Mg deficiency increases the susceptibility of cells and tissues to
peroxidation, worsens the inflammatory reaction, reduces the immune
response, exaggerates catecholamine release in stress, and
diminishes energy metabolism [33, 34]. Mg has multiple catalytic
roles in cellular enzyme systems and neuronal functioning [35] and
can block the N-methyl-D-aspartate receptor and thus prevent
excitatory amino acids, commonly released during episodes of
hypoxia and ischemia, from producing neuronal damage [36].
Apoptosis has been shown to occur within normal placental
tissues during early pregnancy (5 and 7 weeks) and during the third
trimester [37], and fetal growth restriction has been shown to be
associated with increased levels of placental apoptosis [38]. Both
hypoxia and extracellular Mg are postulated to stimulate this
placental apoptosis in vitro [39], and hypoxia-stimulated placental
apoptosis may be further advanced by increasing the extracellular
Mg concentration.
Although Mg is also used in obstetric practice to attempt to
arrest the progress of premature labor, there is controversy
regarding the advantageous effect of Mg sulfate for reducing the
risk of neonatal brain damage or cerebral palsy in low birth
infants: in one study this concept is not currently supported [40],
but in another case-control study in infants weighing less than
1,500 g at birth a substantial reduction in cerebral palsy was
demonstrated in children whose mothers received Mg sulfate in labor
[41].
Fetal/early childhood antecedents and adult chronic
diseases
Epidemiological studies in humans have shown that impaired
intrauterine growth is associated with an increased incidence of
cardiovascular, metabolic, and other diseases in later life [42].
The first indication that fetal and early development could be
involved in adult susceptibility to type 2 diabetes came from
studies of men in the United Kingdom [2]. The odds ratio of the
lightest compared with the heaviest at birth exhibiting the
features of the metabolic syndrome was 18 [1]. Subsequently
thinness at birth was found to increase the risk of insulin
resistance in later life [43]. These types of relationship have
been described in a wide variety of populations worldwide, in
females as well as males [44]. Low birth weight is often followed
by accelerated postnatal growth, and this may be important for risk
of metabolic syndromes in adult life. People who had low birth
weight or who subsequently showed catch-up growth have higher
susceptibility for central obesity, type 2 diabetes, and
cardiovascular disease in later life [45]. The nature of this link
between catch-up growth and risks for such chronic diseases remains
obscure, although several lines of evidence point to the phase of
catch-up growth as a state of hyperinsulinemia [46].
Fetal programming
Fetal programming is the phenomenon whereby alteration in fetal
growth and development in response to the prenatal environment has
long-term or permanent effects. The mechanisms are supposed to be
as a direct effect on cell number, altered stem cell function and
resetting of regulatory hormonal axes (( figure 1 )).
There are several candidates for explaining gestational
programming as follows: 1) a potential role for the
hypothalamic-pituitary-adrenal (HPA) axis has been suggested, as
the mediators of the fetal response to nutrient stress, i.e.
maternal low protein diet, were profoundly suppressed [47, 48]; 2)
fetal programming of the growth hormone insulin-like growth factor
(GH-IGF) axis also has been proposed to serve as a link between
fetal growth and adult-onset disease [49]. Glutamate decarboxylase
2 promoter variant is associated with childhood obesity in the
French population and influenced fetal growth, feeding behavior,
and possibly insulin secretion [50]. The potential effects of the
maternal low protein diet on fetal growth and programming of
hypertension and dysregulation of glucose metabolism are thought to
be mediated by inhibition of placental 11β-hydroxysteroid
dehydrogenase 2 activity [51, 52].
Furthermore, there is strong evidence regarding the association
between low birth weight and insulin resistance in later life. The
“thrifty phenotype hypothesis”, which postulates that fetal
programming for adaptation to an adverse intrauterine environment
results in lower insulin sensitivity in utero, is one of the
hypotheses to explain this association.
Recently, we reported that [Mg2+]i of cord
blood platelets correlated well with birth weight and that infants
born small for gestational age (SGA) showed lower
[Mg2+]i compared to those born with
appropriate weight for gestational age [53]. We also previously
reported that [Mg2+]i is lower in children
with diabetes mellitus and obesity [54].
Taking these findings together, we believe that decreased
[Mg2+]i in infants with SGA can be the
initial pathophysiologic event leading to one of these events. In
fact, a recent animal study supported our data demonstrating that
the maternal Mg restriction irreversibly increases body fat and
induces insulin resistance in pups by 6 months of age [55].
Although low birth weight and poor prenatal nutrition are
strongly associated with metabolic syndromes in later life [56],
postnatal catch-up growth was recently considered also to be a
pivotal element associated with developing various pathological
conditions [57]: Desai et al. reported that if catch-up growth is
controlled by continuing maternal food restriction during the
period of suckling, individuals born with low birth weights are not
different from controls in adulthood, with respect to body weight,
fat, or leptin in experimental rats [58]. Thus the degree of
newborn nutrient enhancement and timing of catch-up growth of IUGR
newborns may determine the programming of orexigenic hormones and
offspring obesity.
It is intriguing in clinical practice that the concept of a
sensitive or crucial period may operate to cause long-term changes
in development and adverse outcomes in later life.
Conclusion
The fetal origin hypothesis by Barker et al. states that fetal
undernutrition in middle to late gestation leading to
disproportionate fetal growth programs later metabolic diseases. As
low [Mg2+]i is an intrinsic abnormality seen
in infants with low birth weight, it is considered that the fetal
Mg deficiency is an important determinant of insulin resistance in
later life. Further exploration is, however, obviously needed to
investigate the pathophysiological mechanisms underlying the
development of metabolic syndromes in the light of the unknown
developmental abnormalities during the fetal period.
Acknowledgements
Authors would like to express their sincere gratitude to Dr.
Yohnosuke Kobayashi, Professor emeritus, for fruitful discussion. A
part of this study was supported by the Mami Mizutani foundation
and by Grant-in-Aid for Scientific research (C) from the Japan
Society for the Promotion of Science (No. 17591123).
References
1 Barker DJ, Hales CN, Fall CH, Osmond C,
Phipps K, Clark PM. Type 2 (non-insulin-dependent)
diabetes mellitus, hypertension and hyperlipidaemia (syndrome X;
relation to reduced fetal growth. Diabetologia 1993; 36: 62-7.
2 Hales CN, Barker DJ, Clark PM, et al.
Fetal and infant growth and impaired glucose tolerance at age 64.
BMJ 1991; 303: 1019-22.
3 Lucas A. Programming in determing adult morbidity. Arch
Dis Child 1994; 71: 288-90.
4 Barker DJP. Fetal origin of coronary heart disease. BMJ
1995; 311: 171-4.
5 Paolisso G, Scheen A, D’Onofrio F,
Lefebvre P. Magnesium and glucose homeostasis. Diabetologia
1990; 33: 511-4.
6 Rosolova H, Mayer Jr. O, Reaven GM.
Insulin-mediated glucose disposal is decreased in normal subjects
with relatively low plasma magnesium concentrations. Metabolism
2000; 49: 418-20.
7 Resnick LM, Gupta RK, Gruenspan H,
Alderman MH, Laragh JH. Hypertension and peripheral
insulin resistance: possible mediating role of intracellular free
magnesium. Am J Hypertens 1990; 3: 373-9.
8 Nadler JL, Buchanan T, Natarajan R, et al.
Magnesium deficiency produces insulin resistance and increased
thromboxane synthesis. Hypertension 1993; 21: 1024-9.
9 Huerta MG, Roemmich JN, Kington ML, et al.
Magnesium deficiency is associated with insulin resistance in obese
children. Diabetes Care 2005; 28: 1175-81.
10 Sibal BM, Villar MA, Bray EA. Magnesium
supplementation during pregnancy: a double blind randomized
controlled clinical trial. J Obstet Gynecol 1989; 161: 115-9.
11 Yang CY, Chiu HF, Tsai SS, Chang CC,
Sung FC. Magnesium in drinking water and the risk of
delivering a child of very low birth weight. Magnes Res 2002; 15:
207-13.
12 Painter RC, Roseboom TJ, Bleker OP. Prenatal
exposure to the Dutch famine and disease in later life: an
overview. Reprod Toxicol 2005; 20: 345-52.
13 Widdowson EM. Changes in body composition during growth.
In: Davis JA, Dobbing J, eds. Scientific foundations of
paediatrics. London: William Heinemann Medical Books Ltd, 1981:
330-42.
14 Husain ME, Mughal MZ. Mineral transport across the
placenta. Arch Dis Child 1992; 67: 874-8.
15 Nandakumaran M, Dashti HM, Al-Zaid NS.
Maternal-fetal transport kinetics of copper, selenium, magnesium
and iron in perfused human placental lobule: in vitro study. Mol
Cell Biochem 2002; 231: 9-14.
16 Standley PR, Standley CA. Identification of a
functional Na+/Mg2+ exchanger in human
trophoblast cells. Am J Hypertens 2002; 15: 565-70.
17 Husain SM, Mughal MZ, Sibley CP. Effects of
acute maternal hyperglycaemia and hyperosmolarity on maternofetal
transfer of calcium and magnesium across the in situ perfused rat
placenta. Magnes Res 2000; 13: 239-47.
18 Handwerker SM, Altura BT, Jones KY,
Altura BM. Maternal-fetal transfer of ionized serum magnesium
during the stress of labor and delivery: a human study. J Am Coll
Nutr 1995; 14: 376-81.
19 Bischof P, Meisser A, Campana A. Paracrine and
autocrine regulators of trophoblast invasion – a review. Placenta
2000; 14(Suppl A): S55-S60.
20 Yi FX, Magness RR, Bird IM. Simultaneous
imaging of [Ca2+]I and intracellular NO
prodiuction in freshly isolated uterine artery endothelial cells:
effect of ovarian cycle and pregnancy. Am J Physiol Regul Integr
Comp Physiol 2005; 288: R140-R148.
21 Pearson PJ, Evora PRB, Seccombe JF,
et al. Hypomagnesemia inhibits nitric oxide release from
coronary endothelium: protective role of magnesium infusion after
cardiac operations. Ann Thorac Surg 1998; 65: 967-72.
22 Lemancewicz A, Laudanska H, Laudanski T,
Karpiuk A, Barta S. Permeability of fetal membranes to
calcium and magnesium: possible role in preterm labour. Hum Reprod
2000; 15: 2018-22.
23 Jasson T, Lambert GW. Effect of intrauterine growth
restriction on blood pressure, glucose tolerance and sympathetic
nervous system activity in the rat at 3-4 months of age. J
Hypertens 1999; 17: 1239-48.
24 David R, Leitch IM, Read MA, Boura ALA,
Walter WAW. Actions of magnesium, nifedipine and clonidine on
the fetal vasculature of the human placenta. Aust New Zealand J
Obstet Gynecol 1996; 36: 267-71.
25 Holcber G, Sapir O, Hallak M, et al.
Selective vasodilator effect of magnesium sulfate in human
placenta. Am J Reprod Immunol 2004; 51: 192-7.
26 USDA. Continuing survey of food intake by individuals 1989
and 1990, USDA Public Use Data Tape. Washington, DC: USDA,
1990.
27 Spatling L, Spatling G. Magnesium supplementation
in pregnancy. A double-blind study. Br J Obstet Gynaecol 1988; 95:
120-5.
28 Kurzel RB. Serum magnesium levels in pregnancy and
preterm labor. Am J Perinatol 1991; 8: 119-27.
29 Conradt A, Weidinger H, Algayer H. Magnesium
therapy with betamimetics decreased the rate of intrauterine fetal
retardation, premature rupture of membranes and premature delivery
in risk pregnancies treated with betamimetics. Magnesium 1985; 4:
20-8.
30 Makrides M, Crowther CA. Magnesium supplementation in
pregnancy. Cochrane Database Syst RevIn: The Cochrane Library,
Issue 4: CD 000937. Update Software, Oxford 2002.
31 Doyle W, Crawford MA, Wynn AH, Wynn SW.
Maternal magnesium intake and pregnancy outcome. Magnes Res 1989;
2: 205-10.
32 Rudnicki M, Frolich A, Rasmussen WF,
McNair P. The effect of magnesium on maternal blood pressure
in pregnancy-induced hypertension. A randomized double-blind
placebo-controlled trial. Acta Obstet Gynecol Scand 1991; 70:
445-50.
33 Malpuech-Brugere C, Nowacki W, Gueux E,
et al. Accelerated thymus involution in magnesium-deficient
rats is related to enhanced apoptosis and sensitivity to oxidative
stress. Br J Nutr 1999; 81: 405-11.
34 Lukaski HC, Nielsen FH. Dietary magnesium depletion
affects metabolic responses during submaximal exercise in
postmenopausal women. J Nutr 2002; 132: 930-5.
35 Thordstein M, Bagenholm R, Thiringer K,
et al. Scavengers of free oxygen radicals in combination with
magnesium ameliorate perinatal hypoxic-ischemic brain damage in the
rat. Pediatr Res 1993; 34: 23-6.
36 Marret S, Gressens P, Gadisseux JP,
Evrard P. Prevention by magnesium of excitotoxic neuronal
death in the developing brain: an animal model for clinical
intervention studies. Dev Med Child Neurol 1995; 6: 273-84.
37 Sakuragi N, Ishikura H, Hareyama H,
et al. Apoptosis in human trophoblastic cells identified by in
situ nick end labeling of fragmented DNA. Acta Obstet Gynaecol Jpn
1994; 46: 533-4.
38 Smith SC, Baker PN, Symonds EM. Placental
apoptosis in normal human pregnancy. Am J Obstet Gynecol 1997; 177:
57-65.
39 Gude NM, Stevenson JL, Moses EK, King RG.
Magnesium regulates hypoxia-stimulated apoptosis in the human
placenta. Clin Sci 2000; 98: 375-80.
40 Paneth N, Jetton J, Pinth-Martin J,
Susser M. Magnesium sulfate in labor and risk of neonatal
brain lesions and cerebral palsy in low birth weight infants.
Pediatrics 1997; 99: e1.
41 Nelson KB, Grether JK. Can magnesium sulfate reduce
the risk of cerebral palsy in very low birth weight infants?
Pediatrics 1995; 95: 263-9.
42 Barker DJP. Mothers, babies and disease in later life.
London: BMJ Publishing group, 1994.
43 Phillip DI, Barker DJ, Hales CN, Hirst S,
Osmond C. Thinness at birth and insulin resistance in adult
life. Diabetologia 1994; 37: 150-4.
44 Hales CN, Barker DJ. The thrifty phenotype
hypothesis. Br Med Bull 2001; 60: 5-20.
45 Eriksson JG, Forsen T, Tuomilehto J,
et al. Effects of size at birth and childhood growth on the
insulin resistance syndrome in elderly individuals. Diabetologia
2002; 45: 342-8.
46 Cettour-Rose P, Samec S, Russell AP,
et al. Redistribution of glucose from skeletal muscle to
adipose tissue during catch-up fat: a link between catch-up growth
and later metabolic syndrome. Diabetes 2005; 54: 751-6.
47 Phillips ID, Simonetta G, Owens JA,
Robinson JS, Clarke IJ, McMillen IC. Placental
restriction alters has functional development of the
pituitary-adrenal axis in the sheep fetus during late gestation.
Pediatr Res 1996; 40: 861-6.
48 Ozanne SE, Smith GD, Tikerpae J,
Hales CN. Altered regulation of hepatic glucose output in the
male offspring of protein-malnourished rat dams. Am J Physiol 1996;
270: E559-E564.
49 Holt RI. Fetal programming of the growth hormone
insulin-like growth factor axis. Trends Endocrionol Metab 2002; 13:
392-7.
50 Meyre D, Boutin P, Tounian A, et al. Is
glutamate decarboxylase 2 (GAD2) a genetic link between low birth
weight and subsequent development of obesity in children? J Clin
Endocrinol Metab 2005; 90: 2384-90.
51 Langley-Evans SC, Phillips CJ, Benediktsson R,
et al. Protein intake in pregnancy, placental glucocorticoid
metabolism and the programming of hypertension. Placenta 1996; 17:
169-72.
52 Edwards CRW, Benediktsson R, Lindsay RS,
Seckl JR. Dysfunction of the placental glucocortocoid barrier
a link between the fetal environment and adult hypertension? Lancet
1993; 341: 355-7.
53 Takaya J, Yamato F, Higashino H,
Kobayashi Y. Relationship of intracellular magnesium of cord
blood platelets to birth weight. Metabolism 2004; 53: 1544-7.
54 Takaya J, Higashino H, Kotera F,
Kobayashi Y. Intracellular magnesium of platelets in children
with diabetes and obesity. Metabolism 2003; 52: 468-71.
55 Venu L, Kishore YD, Raghunath M. Maternal and
perinatal magnesium restriction predisposes rat pups to insulin
resistance and glucose intolerance. J Nutr 2005; 135: 1353-8.
56 Sayer AA, Cooper C. Fetal programming of body
composition and musculoskeletal development. Early Hum Dev 2005;
81: 735-44.
57 Ros MG, Desai M. Gestational programming:
population survival effects of drought and famine during pregnancy.
Am J Physiol Regul Integr Comp Physiol 2005; 288: R25-R33.
58 Desai M, Gayle D, Babu J, Ross MG.
Programmed obesity in intrauterine growth-restricted newborns:
modulation by newborn nutrition. Am J Physiol Regul Integr Comp
Physiol 2005; 288: R91-R96.
|
Version imprimable
Version PDF
