Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs
Aim. In the elderly subjects metabolic syndrome (MetS) seems to be associated with low levels of circulating protective soluble receptor for advanced glycation end products (sRAGE). This secondary study aimed to answer whether this phenomenon is manifested from early childhood. Methods. 73 mothers...
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irk-123456789-1537162019-06-15T01:30:34Z Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs Klenovicsova, K. Boor, P. Hrachova, J. Furkova, K. Sebekova, K. Biomedicine Aim. In the elderly subjects metabolic syndrome (MetS) seems to be associated with low levels of circulating protective soluble receptor for advanced glycation end products (sRAGE). This secondary study aimed to answer whether this phenomenon is manifested from early childhood. Methods. 73 mothers and their 77 infants (4-to-12-months of age) were included in the study. Mothers were classified according to the presence of MetS components as negative (n = 32), those with pre-MetS (insulin resistance + 1 sign of MetS, n = 27) and overt MetS (n = 14). sRAGE and carboxymethyllysine (CML) were determined in the mothers and the infants. Results. Mothers with pre- and overt MetS displayed lower sRAGE levels, while in their children only a trend towards decline was observed. sRAGE levels significantly and inversely correlated with insulin sensitivity and BMI/body weight. No difference in CML levels across the groups was observed. Conclusions. Metabolic syndrome is associated with decreased levels of sRAGE in the mothers and a tendency towards decline of sRAGE in their offspring. Infants of mothers with MetS maintain normoglycemia on the account of higher insulin levels. Keywords: metabolic syndrome, mother-child pairs, QUICKI, sRAGE, insulin resistance, CML. Мета. У пацієнтів похилого віку розвиток метаболічного синдрому (МетС) асоційований з низьким рівнем циркулюючого розчинного рецептора для кінцевих продуктів повного глікозилювання (sRAGE). Мета цієї роботи полягала у пошуку відповіді на питання, чи проявляється таке явище у ранньому дитинстві? Методи. Досліджено 73 матері і 77 дітей віком від чотирьох до 12 місяців. Залежно від присутності компонентів МетС матерів розділили на три групи: негативна (n = 32) – без компонентів МетС; з початковою стадією МетС (резистентність до інсуліну + одна ознака МетС, n = 27) та з явно вираженим МетС (n = 14). У матерів і дітей визначали рівень концентрації sRAGE і карбоксиметиллізину (КМЛ). Результати. У матерів з початковою та явно вираженою стадіями МетС встановлено нижчий рівень sRAGE порівняно з їхніми дітьми, у яких спостерігали лише тенденцію до його падіння. Кількість sRAGE корелює з чутливістю до інсуліну та показником BM (індекс маси тіла) I /маса тіла. Різниці в концентрації КМЛ по групах не знайдено. Висновки. Метаболічний синдром пов'язаний із зниженням рівня sRAGE у матерів. Показано тенденцию до зменшення кількості sRAGE у їхніх дітей. Нормоглікемія у дітей, у матерів яких визначено МетС, підтримується вищим рівнем інсуліну. Ключові слова: метаболічний синдром, пара мати–дитина, QUICKI, sRAGE, резистентність до інсуліну, карбоксиметиллізин. Цель. У пациентов пожилого возраста развитие метаболического синдрома (МетС) ассоциировано с низким уровнем циркулирующего растворимого рецептора для конечных продуктов полного гликозилирования (sRAGE). Цель этой работы состояла в поиске ответа на вопрос, проявляется ли данное явление в раннем детстве? Методы. Исследованы 73 матери и 77 детей в возрасте от четырех до 12 месяцев. В зависимости от присутствия компонентов МетС матерей разделили на три группы: отрицательная (n = 32) – без компонентов МетС; с начальной стадией МетС (резистентность к инсулину + один признак МетС, n = 27) и с явно выраженным МетС (n = 14). У матерей и детей определяли уровень концентрации sRAGE и карбоксиметиллизина (КМЛ). Результаты. У матерей с начальной и явно выраженной стадиями МетС выявлен более низкий уровень sRAGE, в то время как у их детей наблюдалась лишь тенденция к его снижению. Количество sRAGEкоррелирует с чувствительностью к инсулину и показателем BM (индекс массы тела) I/масса тела. Разницы в концентрации КМЛ по группам не установлено. Выводы. Метаболический синдром связан со снижением уровня sRAGE у матерей. Показана тенденция к уменьшению количества sRAGE у их детей. Нормогликемия у детей, у матерей которых обнаружен МетС, поддерживается более высоким уровнем инсулина. Ключевые слова: метаболический синдром, пара мать–ребенок, QUICKI, sRAGE, резистентность к инсулину, карбоксиметиллизин. 2011 Article Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs / Klenovicsova K., Boor P., Hrachova J., Furkova K., Sebekova K. // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 132-140. — Бібліогр.: 31 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00008C http://dspace.nbuv.gov.ua/handle/123456789/153716 612.63 + 612.349.8 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Biomedicine Biomedicine |
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Biomedicine Biomedicine Klenovicsova, K. Boor, P. Hrachova, J. Furkova, K. Sebekova, K. Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs Вiopolymers and Cell |
| description |
Aim. In the elderly subjects metabolic syndrome (MetS) seems to be associated with low levels of circulating
protective soluble receptor for advanced glycation end products (sRAGE). This secondary study aimed to
answer whether this phenomenon is manifested from early childhood. Methods. 73 mothers and their 77
infants (4-to-12-months of age) were included in the study. Mothers were classified according to the
presence of MetS components as negative (n = 32), those with pre-MetS (insulin resistance + 1 sign of MetS,
n = 27) and overt MetS (n = 14). sRAGE and carboxymethyllysine (CML) were determined in the mothers
and the infants. Results. Mothers with pre- and overt MetS displayed lower sRAGE levels, while in their
children only a trend towards decline was observed. sRAGE levels significantly and inversely correlated
with insulin sensitivity and BMI/body weight. No difference in CML levels across the groups was observed.
Conclusions. Metabolic syndrome is associated with decreased levels of sRAGE in the mothers and a
tendency towards decline of sRAGE in their offspring. Infants of mothers with MetS maintain normoglycemia on the account of higher insulin levels.
Keywords: metabolic syndrome, mother-child pairs, QUICKI, sRAGE, insulin resistance, CML. |
| format |
Article |
| author |
Klenovicsova, K. Boor, P. Hrachova, J. Furkova, K. Sebekova, K. |
| author_facet |
Klenovicsova, K. Boor, P. Hrachova, J. Furkova, K. Sebekova, K. |
| author_sort |
Klenovicsova, K. |
| title |
Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| title_short |
Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| title_full |
Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| title_fullStr |
Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| title_full_unstemmed |
Metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| title_sort |
metabolic syndrome is inversely related to soluble receptor for advanced glycation end products: a study in mother-infant pairs |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2011 |
| topic_facet |
Biomedicine |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/153716 |
| citation_txt |
Metabolic syndrome is inversely related to soluble
receptor for advanced glycation end products:
a study in mother-infant pairs / Klenovicsova K., Boor P., Hrachova J., Furkova K., Sebekova K. // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 132-140. — Бібліогр.: 31 назв. — англ. |
| series |
Вiopolymers and Cell |
| work_keys_str_mv |
AT klenovicsovak metabolicsyndromeisinverselyrelatedtosolublereceptorforadvancedglycationendproductsastudyinmotherinfantpairs AT boorp metabolicsyndromeisinverselyrelatedtosolublereceptorforadvancedglycationendproductsastudyinmotherinfantpairs AT hrachovaj metabolicsyndromeisinverselyrelatedtosolublereceptorforadvancedglycationendproductsastudyinmotherinfantpairs AT furkovak metabolicsyndromeisinverselyrelatedtosolublereceptorforadvancedglycationendproductsastudyinmotherinfantpairs AT sebekovak metabolicsyndromeisinverselyrelatedtosolublereceptorforadvancedglycationendproductsastudyinmotherinfantpairs |
| first_indexed |
2025-07-14T05:12:27Z |
| last_indexed |
2025-07-14T05:12:27Z |
| _version_ |
1837597927919321088 |
| fulltext |
BIOMEDICINE
Metabolic syndrome is inversely related to soluble
receptor for advanced glycation end products:
a study in mother-infant pairs
K. Klenovicsova1, 2, P. Boor3, J. Hrachova1, K. Furkova1, K. Sebekova4
1Slovak Medical University
12, Limbova St., Bratislava, Slovak Republic, 83303
22nd Department of Pediatrics, Faculty of Medicine, Comenius University
1, Limbova St., Bratislava, Slovak Republic, 83340
3Division of Nephrology & Institute of Pathology, RWTH University of Aachen
30, Pauwelsstrabe, Aachen, Germany, 52074
4Institute of Molecular BioMedicine, Faculty of Medicine, Comenius University
4, Sasinkova St., Bratislava, Slovak Republic, 81104
kata.sebekova@gmail.com
Aim. In the elderly subjects metabolic syndrome (MetS) seems to be associated with low levels of circulating
protective soluble receptor for advanced glycation end products (sRAGE). This secondary study aimed to
answer whether this phenomenon is manifested from early childhood. Methods. 73 mothers and their 77
infants (4-to-12-months of age) were included in the study. Mothers were classified according to the
presence of MetS components as negative (n = 32), those with pre-MetS (insulin resistance + 1 sign of MetS,
n = 27) and overt MetS (n = 14). sRAGE and carboxymethyllysine (CML) were determined in the mothers
and the infants. Results. Mothers with pre- and overt MetS displayed lower sRAGE levels, while in their
children only a trend towards decline was observed. sRAGE levels significantly and inversely correlated
with insulin sensitivity and BMI/body weight. No difference in CML levels across the groups was observed.
Conclusions. Metabolic syndrome is associated with decreased levels of sRAGE in the mothers and a
tendency towards decline of sRAGE in their offspring. Infants of mothers with MetS maintain normo-
glycemia on the account of higher insulin levels.
Keywords: metabolic syndrome, mother-child pairs, QUICKI, sRAGE, insulin resistance, CML.
Introduction. Advanced glycation end products
(AGEs) are formed by nonenzymatic glycation/glyoxi-
dation on plasma/tissue proteins during ageing and in
accelerated degree under pathologic conditions (hyper-
glycemia, increased oxidative stress) [1, 2]. AGEs alter
the structure and function of proteins, and interact with
their specific cell surface receptors. Receptor for AGEs
(RAGE) is of pathophysiological importance: AGE/
RAGE interaction results in increased expression of
cytokines, adhesion molecules, growth factors, and in-
duction of oxidative stress [3, 4]. Circulating soluble
RAGE (sRAGE) represents a truncated form of RAGE,
consisting of only extracellular ligand binding domain.
It acts as a natural competitive inhibitor of signaling
pathways, removing or neutralizing the circulating
RAGE ligands [5].
Several studies suggested a direct role of accumu-
lated AGEs in pathogenesis of diabetes and its com-
plications [3, 4]. Recently, the role of low circulating
sRAGE levels and their association with higher inci-
132
ISSN 0233–7657. Biopolymers and Cell. 2011. Vol. 27. N 2. P. 132–140
Institute of Molecular Biology and Genetics NAS of Ukraine, 2011
dence of hypertension and metabolic syndrome (MetS)
was highlighted [6–9].
Nowadays MetS is an epidemics, affecting all
generations. It is considered a pre-diabetic state with
prognosis of cardiovascular disease equivalent to type
2 diabetes [10]. Although the available definitions of
MetS differ by criteria [11], visceral obesity and insulin
resistance are unequivocally considered the major
determinants in its development. Which of these two is
the primary abnormality is still a debate.
The prevalence of MetS is highly age-dependent
[12, 13]. Studies on the association of MetS and
sRAGE levels in the adult and elderly subjects showed
that MetS is linked to low circulating sRAGE levels
[7–9]. Therefore we raised the question, whether low
sRAGE is per se associated with MetS, or merely re-
presents an age-dependent feature. We postulated that
if ageing is the main determinant of the above men-
tioned relation, this association would not be present in
small infants, and probably not expressed significantly
in young healthy adults. To this point we subjected the
data obtained in frame of ICARE (Impeding neo-
formed Contaminants Accumulation to Reduce their
health Effects) study from apparently healthy mother-
child pairs to secondary analysis. ICARE clinical study
aimed to elucidate the potential health effects of the
consumption of low- (mother milk) versus high-AGE
(infant formula) diets in healthy 3-to-18-month-olds
infants [14]. Secondary aim was to study the mother-
child relationship in AGE metabolism [15].
While published studies in adult and elderly
subjects unequivocally confirm the association of
MetS with low sRAGE levels [7–9], data on relation of
single components of MetS to sRAGE are
contradictory. Herein we analyzed sRAGE levels in the
mothers not presenting any sign of MetS, and insulin
resistant mothers with pre-metabolic- and overt meta-
bolic-syndrome. To elucidate the impact of AGE/
RAGE axis, we determined plasma Nε-(carboxyme-
thyl)lysine (CML, most abundant plasma AGE and a
circulating ligand of RAGE) concentrations. Associa-
tions between single components of MetS and sRAGE
or CML levels were determined. The same analyses
were carried out in 4-to 12-month-olds infants.
Material and methods. The study was carried out
according to the Declaration of Helsinki, after the ap-
proval of the protocol by the Ethics Board of Slovak
Medical University. Written informed consent from the
mothers/legal representatives of the children was
obtained.
Subjects. As described earlier [15], blood samples
were obtained from 112 apparently healthy mothers
and their 116 healthy infants. Exclusion criteria for
infants were: pathology during physical examination,
elevated inflammatory markers, acute/recurrent in-
flammatory or chronic diseases, and positivity for an-
tibodies against HCV/HIV. Exclusion criteria for mo-
thers were: age bellow 18 years, pregnancy, any ongo-
ing disease and/or medication apart from food supple-
ments, addiction to drugs, excessive smoking and/or
alcohol consumption. The following criteria were used
to classify the signs of MetS in the mothers: insulin
resistance (QUICKI < 0.357) [16], body mass index
(BMI) > 25.0 kg/m2; triacylglycerols (TAG) ≥
≥ 1.7 mmol/l; HDL-cholesterol < 1.3 mmol/l; systolic
blood pressure (SBP) ≥ 130 mm Hg and/or diastolic
blood pressure (DBP) ≥ 85 mm Hg. BMI instead of
waist circumference was used to classify the over-
weight/obesity, since cut off values of waist circum-
ference for breast feeding mothers few weeks/months
post partum are not published. Mother-child pairs were
included into the evaluation if: a) mother and child met
the inclusion criteria; b) data essential for classification
of all 5 signs of MetS in the mother were obtained. In
total, 73 healthy mothers and their 77 healthy infants
(age range 4–12 months) were included into the
evaluation. Thirty-two mothers did not display any
sign of MetS. Insulin resistant mothers were further
classified as those with pre-MetS (insulin resistance
plus positivity for any 1 sign of MetS, n = 27) and those
with overt MetS (insulin resistance plus positivity for
any 2 or more signs, n = 14). Infants were grouped as
offsprings of mothers not presenting any sign of MetS,
those with pre- or overt MetS.
Blood was collected after overnight fasting from
the mothers. Mothers were asked not to feed the babies
3 hours prior to blood sampling. Standard blood che-
mistry parameters (Vitros 250 analyzer, «J&J», USA)
were determined. Very low density lipoprotein
(VLDL)- and low density lipoprotein (LDL)-choles-
terol concentrations were calculated (Friedewald for-
mula). Plasma was stored for special analysis at –80 oC.
133
sRAGE AND METABOLIC SYNDROME IN MOTHER-INFANT PAIRS
Immunoreactive insulin was determined by RIA me-
thod («Immunotech», Czech Republic). Quantitative
insulin-sensitivity check index (QUICKI) was calcula-
ted [17]. Commercial ELISA kits were used to deter-
mine plasma concentrations of sRAGE («R&D Sys-
tems Inc.», USA), and CML («MicroCoat Biotechno-
logie GmbH», Germany, after pre-treatment of the
samples with proteinase K). In the mothers, blood pres-
sure was recorded after 15 min rest in sitting position.
For technical reasons blood pressure and BMI were not
recorded in the infants.
Statistical analyses. Data were tested for normality
and equality of variance (Statistical program SPSS 16).
Data were compared using One way analysis of varian-
ce (ANOVA) with post-hoc least square difference test
(LSD), or Kruskal-Wallis test with Mann-Whitney test
(2-tailed), as appropriate. Spearman or Pearson corre-
lation coefficients were calculated. Chi-square was
used to compare categorical data. Data are given as me-
dian, mean ± SD. p<0.05 was considered as significant.
Results and discussion. Cohort characteristics.
M o t h e r s: 32 mothers negative for any sign of MetS
did not differ significantly by age (29.5; 29.5 ± 3.8 ye-
ars) from those with pre-MetS (27.0; 27.7 ± 5.1 years;
n = 27) or those with overt MetS (31.5; 30.8 ± 7.3 years,
n = 14). Four mothers delivered twins: 3 from the group
negative for signs of MetS and 1 from the pre-MetS
groups.
I n f a n t s: Characteristics of the infants are given
in Table 1. Infants of the mothers negative for signs of
MetS, those with pre-MetS and with overt MetS did not
differ significantly by age and body weight at investi-
gation, birth weight and the mean time of their exclu-
sive breast-feeding. At the time of the investigation the
proportion of the breast- versus formula-fed infants did
not differ significantly between the groups. Both
genders were comparably represented in the 3 cohorts.
Characteristics according to presence of signs of
metabolic syndrome. M o t h e r s: Data on different
components of MetS in the mothers negative for signs
of MetS, those with pre- and overt MetS are given in
Fig. 1 and Table 2. Mothers with overt MetS differed
significantly in all parameters from the negative cohort.
If compared with the negative mothers, those with pre-
134
KLENOVICSOVA K. ET AL.
Parameter
Classification of the mother
p
Negative (n = 35) Pre-MetS (n = 28) MetS (n = 14)
Age (months) 6.7; 7.4±2.0 8.0; 7.9±2.1 6.3; 7.0±2.1 ns
Gender (Female/Male) 17/18 14/14 5/9 nschi
Birth weight, g 3200; 2922±845 3350; 3134±827 3410; 3382±645 ns
Body weight, g 7800; 7813±1186 7690; 7911±1513 7705; 7837±940 ns
Duration of breast-feedin,g
(months) 6.0; 6.4±2.0 6.0; 5.6±3.0 5.0; 5.3±3.3 ns
Breast-/formula-feeding at
time of investigation, n
26/9 14/14 8/6 nschi
Negative: mother without any sign of metabolic syndrome; pre-MetS: insulin resistant mother with 1 other sign of metabolic syndrome;
MetS: overt metabolic syndrome; ns: not significant; chi: chi-square.
Table 1
Characteristic of the study sample of 77 infants
*
#
*
0
0,1
0,2
0,3
0,4
0,5
0,6
Mothers Infants
1
2 3
Fig. 1. Quantitative insulin-sensitivity check index (QUICKI) in the
mothers and their infants in relation to presence of signs of metabolic
syndrome: 1 – negative: no sign of metabolic syndrome in the mother;
2 – pre-MetS: insulin resistant mothers with any 1 other sigh of meta-
bolic syndrome present; 3 – MetS: mothers with overt metabolic synd-
rome (insulin resistance plus any other 2 or more signs of metabolic
syndrome). ∗ p>0.01; # p >0.05
MetS displayed significantly higher insulin resistance.
Except for insulin sensitivity and diastolic blood pres-
sure mothers with pre-MetS did not differ significantly
from those with overt MetS.
I n f a n t s: Infants of the mothers negative for signs
of MetS were significantly more insulin sensitive in
comparison with the other 2 groups (Fig. 1 and Table
2). However, the infants’ groups did not differ signifi-
cantly by the body weight (Table 1), TAG, HDL-
cholesterol and uric acid concentrations (Table 2).
Advanced glycation end products and sRAGE.
M o t h e r s: Concentration of CML was significantly
higher in the mothers negative for signs of MetS if
compared with those with overt MetS (Fig. 2, a).
sRAGE levels were significantly lower in the mothers
with overt MetS in comparison with other 2 groups
(Fig. 2, b). CML/sRAGE ratio increased across the
groups reaching significance between the negative
mothers and those with overt MetS (Table 2).
If all mothers were evaluated together, sRAGE
levels directly correlated with the index of insulin sen-
sitivity (p <0.001) (Fig. 3), while inverse relationship
between CML or sRAGE and BMI was observed
(p <0.01 and p <0.001, respectively), (Fig. 4, a–b).
Simple correlation coefficients between sRAGE or
CML and parameters characterizing MetS are given in
Table 3. Following significant relationships were
revealed: systolic and diastolic blood pressure, insulin
and uric acid concentrations correlated inversely with
sRAGE concentrations, while QUICKI or HDL-cho-
lesterol concentration correlated with sRAGE directly.
Inverse relationship was revealed between systolic blo-
135
sRAGE AND METABOLIC SYNDROME IN MOTHER-INFANT PAIRS
Parameter
Mothers Infants
Negative
(n = 32)
Pre-MetS
(n = 27)
MetS
(n = 14) p
Classification of the mother
p
Negative (n = 35) Pre-MetS
(n = 28)
MetS
(n = 14)
BMI, kg/m2 20.5;
21.0±1.9
22.2;
22.3±2.3
29.4;
29.7±4.8** 0.01 ND ND ND NA
SBP, mm Hg 118;
113±10
120;
115±8
123;
123±12** 0.01 ND ND ND NA
DBP, mm Hg 70;
72±8
80;
75±8
80;
78±12+ 0.05 ND ND ND NA
Glucose, mmol/l 4.3;
4.4±0.6*
4.8;
4.9±0.6
4.8;
4.8±0.7 0.05 4.6;
4.5±0.4
4.3;
4.4±0.4
4.4;
4.4±0.5 ns
Insulin, IU/ml 4.6;
4.5±1.6**
12.7;
16.1±10.2
16.2;
21.2±15.5 0.01 2.1;
3.0±2.4
3.2;
3.8±2.4
4.2;
5.6±5.6+ 0.05
TAG, mmol/l 0.64;
0.72±0.27
0.80;
0.91±0.31
1.23;
1.45±0.69** 0.05 1.27;
1.45±0.68
1.27;
1.37±0.69
1.66;
1.75±0.78 ns
Cholesterol, mmol/l 4.4;
4.3±0.6
4.5;
4.6±0.8
4.6;
4.6±1.0 ns 3.7;
3.8±0.8
3.4;
3.4±0.7
3.6;
3.5±0.6 ns
HDL-cholesterol,
mmol/l
1.70;
1.75±0.31
1.60;
1.61±0.40
1.10;
1.16±0.22** 0.01 1.00;
1.04±0.27
1.10;
1.09±0.31
0.95;
1.01±0.17 ns
Uric acid, mmol/l 225;
238±52
221;
235±46
299;
322±98** 0.01 178;
181±41
188;
190±55
191;
191±62 ns
CML/sRAGE, ng/pg 0.56;
0.62±0.26
0.60;
0.72±0.38
0.81;
0.76±0.39+ 0.05 0.48;
0.56±0.37
0.51;
0.66±0.40
0.59;
0.68±0.30 ns
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; IU: international units; TAG: triacylglycwerols; HDL:
high density lipoproteins; CML: Nε(carboxymethyl)lysine; sRAGE: soluble receptor for advanced glycation end products; ND: not
determined; NA: not applicable; ns: not significant; *p <0.05 vs. both other groups; **p <0.01 vs. both other groups; +p <0.05 vs. group
negative for signs of metabolic syndrome.
Table 2
Clinical characteristics of the mothers and their infants
od pressure and plasma CML concentration. HDL-
cholesterol levels showed a direct relationship to CML
concentration. Plasma CML levels did not correlate
significantly with sRAGE levels.
Infants: CML concentrations were comparable bet-
ween the infants’ groups (Fig. 2, a). sRAGE con-
centration tended to decline and CML/sRAGE ratio to
increase across the groups of the offsprings, without
reaching significance (Fig. 2, b, Table 2). If all infants
were evaluated together, sRAGE concentration was in-
versely related to actual body weight (r = –0.23, p <
0.05). CML levels and body weight or sRAGE con-
centrations showed no significant relationship. None of
the other parameters characterizing MetS showed
significant relation to CML or sRAGE concentration.
There are at least 2 splice variants of soluble RAGE
capable to bind ligands and act as decoy receptors, sin-
ce they possess a V- (ligand binding) domain [9]. Whi-
le endogenous secretory RAGE (esRAGE) represents
secreted C-terminally truncated isoform of RAGE,
sRAGE is cleaved from cell surface by matrix me-
talloproteinases [8, 9]. Whether these isoforms differ in
pathophysiological function remains unclear. How-
ever, the ELISA sRAGE assay used in present study
measures all soluble forms of RAGE in human plasma
[9]. In general population circulating sRAGE levels
seem to be determined genetically. Carriers of minor
allele in G82S RAGE gene polymorphism present with
reduced levels of protective sRAGE, and this pheno-
type is manifested from early childhood [15, 18–20].
Herein we show that decline in sRAGE levels with
increasing insulin resistance, previously described in
the adults and elderly [7–9], is not merely an age-de-
pendent phenomenon. This association is present alrea-
dy in the young women, and a same trend is observed in
their offsprings. As in the adults [20–22], body weight
and sRAGE show inverse relationship already in early
infancy.
An inverse relationship between sRAGE levels and
insulin sensitivity might be on the account of genetic
predisposition in RAGE gene, affecting the develop-
ment of insulin resistance or be in linkage disequi-
librium with a locus involved in this process [15, 18–
20]. Minor allele carriers in G82S RAGE gene poly-
morphism display reduced levels of protective sRAGE
[15, 18–20]. Young women bearing this allele display
also insulin resistance [15]. It is sought that hyper-
glycemia could inhibit sRAGE production directly [7].
However, our mothers and infants were normoglyce-
mic, and no significant relationship was observed bet-
ween glycemia and sRAGE. Indirect inhibition of
sRAGE production via AGEs [7] seems also to be im-
136
KLENOVICSOVA K. ET AL.
0
500
1000
1500
2000
2500
3000
3500
Mothers Infants
0
400
800
1200
1600
Mothers Infants
*
* #
a b
1
2
3
Fig. 2. a – plasma Nε(carboxymethyl)lysine (CML) concentration in the mothers and their infants in relation to presence of signs of meta-
bolic syndrome; b – plasma soluble receptor for advanced glycation end products (sRAGE) concentrations in the mothers and their infants in
relation to presence of signs of metabolic syndrome: 1 – negative: no sign of metabolic syndrome in the mother; 2 – pre-MetS: insulin
resistant mothers with any 1 other sigh of metabolic syndrome present; 3 – MetS: mothers with overt metabolic syndrome (insulin resistance
plus any other 2 or more signs of metabolic syndrome). ∗ p>0.01; # p >0.05
0
1
2
3
4
5
QUICKI
0,0 0,1 0,2 0,3 0,4 0,5
·103
Fig. 3. Relationship between plasma soluble receptor for advanced
glycation end products (sRAGE) concentrations and Quantitative
insulin-sensitivity check index (QUICKI) in the mothers. r = 0.394;
p <0.001
probable: mothers with overt MetS displayed lower
CML levels than their insulin sensitive counterparts,
and the infants’ groups did not differ in CML levels. In
neither cohort CML levels showed significant relation-
ship to sRAGE or glycemia. Despite our findings that
the infants of insulin resistant mothers showed only a
tendency towards lower sRAGE levels in dependence
of rising number of signs of MetS in the mothers, we
suppose that decreased circulating levels of protective
sRAGE are involved in the successive development of
insulin resistance.
Here we also show an inverse association between
sRAGE and several other components of MetS (e. g.
blood pressure, insulin and uric acid levels) in young
apparently healthy women. An inverse relationship
between insulin sensitivity and sRAGE levels in heal-
thy older adults and type 2 diabetic patients has been
reported previously, but this study found no relation-
ship between sRAGE and components of MetS in heal-
thy subjects [7]. On the other hand, same associations
as reported by us were described in older adults and
type 2 diabetic patients for esRAGE [8].
In the mothers BMI showed the tightest (inverse)
relationship to sRAGE. This finding is in line with data
in Japanese non-diabetic adults and Korean men [20–
22]. Interestingly, the single significant relationship
(inverse) in the infants was that between actual body
weight and sRAGE level. Thus, body weight/obesity
exerts significant impact on sRAGE levels from early
childhood. Question arises whether obesity per se, or
central obesity is of key importance.
Low plasma CML levels in the mothers with MetS
corresponde with previous findings that obese children
and adults display lower plasma CML levels than their
lean counterparts [23, 24]. In contrast to other AGEs, in
obesity CML is predominantly trapped into adipose
tissue [24]. Negative relationship between CML levels
and BMI in our mothers supports this finding. This
phenomenon seems to be expressed from early child-
hood, as in our infants CML levels showed inverse re-
lationship to actual body weight.
To the best of our knowledge this is the first study
investigating whether young infants of otherwise heal-
thy insulin resistant mothers with signs of pre-MetS or
overt MetS display corresponding metabolic disturban-
ces. From among 41 mothers classified as insulin re-
sistant (QUICKI <0.357) [16] only 3 displayed fasting
glycemia >5.6 mmol/l, thus they were in early stages of
insulin resistance, still capable to maintain fasting gly-
cemia within normal (or almost normal) range on the
account of hyperinsulinemia. Mothers with overt MetS
presented only mild metabolic disturbances, e. g. they
suffered from mild hypertension, mild insulin resis-
tance, displayed mild dyslipidemic phenotype and their
higher uric acid concentrations fall within the normal
range. The more striking is the observation that their
young offsprings maintain the normoglycemia at the
expense of higher insulinemia.
It is well known that breast-fed toddlers are more
insulin sensitive than their formula-fed counterparts
[25]. This is believed to be due to lower protein and
higher polyunsaturated fatty acids content of mother
milk, higher immunogeneity of the cow insulin in
comparison with human insulin in mother milk, and the
presence of various insulin sensitizing compounds in
mother milk [26–28]. On the other hand, infant formu-
137
sRAGE AND METABOLIC SYNDROME IN MOTHER-INFANT PAIRS
0
500
1000
1500
2000
2500
0 10 20 30 40 50
BMI, kg/m2
0
1000
2000
3000
4000
5000
0 10 20 30 40 50
BMI, kg/m2
a b
Fig. 4. a – relationship between plasma Nε(carboxymethyl)lysine (CML) concentration and body mass index (BMI) in the mothers r = 0.329;
p<0.01; b – relationship between plasma soluble receptor for advanced glycation end products (sRAGE) concentrations and BMI in the mothers,
r = 0.402; p <0.001
las contain, due to their fortification, higher amounts of
vitamins in comparison to mother milk. In middle-aged
and elderly men higher total carotenoid intakes, mainly
those of beta-carotene and lycopene, were associated
with a lower prevalence of metabolic syndrome, and in
adolescents and adults high plasma levels of carote-
noids are associated with higher insulin sensitivity [29–
31]. The infants in our study did not differ significantly
by age, they were breast-fed for comparable time, and
the proportion of infants breast- or formula-fed at the
time of investigation did not differ significantly. Thus,
we suppose that other factors except for formula fee-
ding may modulate insulin sensitivity in young infants.
Limitations of this study arise from the fact of se-
condary analysis of data gathered for other purposes,
and cross-sectional approach. Relatively small number
of included subjects reflects the fact that samples were
collected from healthy mother-infant pairs for exclusi-
vely research purposes, thus mother’s will to participa-
te was decisive. The number of mothers in 3 groups
was uneven.
However, it is to be taken into account that the pre-
valence of MetS is age-dependent. In Norway, 9.2 % of
20–29-old women and 14.1 % of those aged 30–39
years present with overt MetS [12]. Recent study from
Slovakia reported the prevalence of MetS in general
population being 4.3 % in 18-to-29-year olds, and
10.4 % in the age category of 30 to 39 years [13]. Thus
19 % of young mothers presenting with overt MetS in
our study even slightly exceeds the average/ expected
prevalence. However, we suppose that this follows
from the design of the study (secondary analysis in-
cluding only mothers in whom the data on all 5 signs of
MetS were determined). Since we did not measure the
blood pressure in the infants, we are not able to com-
ment whether the blood pressure correlates with
sRAGE or CML levels in early childhood.
Taken together, lower circulating sRAGE levels
seem to be an early feature of insulin resistance and
MetS-related disturbances, manifested already in yo-
ung adult women. Infants of insulin resistant mothers
with overt MetS maintain normoglycemia on the ac-
count of higher insulin demand, while the decline of
their circulating sRAGE level does not reach signifi-
cance yet. Decrease in sRAGE levels shows strongest
relationship to rise in BMI or body weight. Our data
support the assumption of the direct link between de-
creased circulating levels of protective sRAGE and the
successive development of insulin resistance. How-
ever, the design of our study does not allow any conclu-
sion in regard whether high sRAGE is a protective
factor, or low sRAGE a causal factor in development of
insulin resistance. To confirm our data larger and pro-
spective studies are required.
138
KLENOVICSOVA K. ET AL.
Parameter
CML sRAGE
Mothers Infants Mothers Infants
r p r p r p r p
Systolic BP –0.30 0.05 ND ND –0.32 0.01 ND ND
Diastolic BP –0.03 ns ND ND –0.31 0.01 ND ND
Insulin –0.02 ns –0.15 ns –0.29 0.05 –0.15 ns
Glucose –0.14 ns –0.10 ns –0.20 ns –0.02 ns
QUICKI 0.23 ns 0.07 ns 0.40 0.001 0.12 ns
TAG –0.03 ns –0.04 ns –0.21 ns 0.20 ns
HDL-cholesterol 0.24 0.05 0.16 ns 0.32 0.01 0.03 ns
Uric acid –0.03 ns 0.19 ns –0.27 0.05 0.19 ns
BP: blood pressure; QUICKI: Quantitative insulin-sensitivity check index; TAG: triacylglycerols; HDL: high density lipoproteins; ND: not
determined; ns: not significant.
Table 3
Correlation coefficients between plasma Nе(carboxymethyl)lysine (CML) and soluble receptor for advanced glycation
end products (sRAGE) concentrations and characteristics of metabolic syndrome
Acknowledgement. Study was supported by EU
6th FP grant ICARE No. COLL-CT-2005-516415.
К. Кле новічова, П. Бор, Я. Гра хо ва, К. Фур ко ва, К. Ше бе ко ва
Ме та болічний син дром об ер не но асоційо ва ний з
розчинним ре цеп то ром для кінцевих про дуктів по вно го
гліко зилювання: вив чен ня пар мати–дитина
Ре зю ме
Мета. У пацієнтів по хи ло го віку роз ви ток ме та болічно го син -
дро му (МетС) асоційо ва ний з низ ь ким рівнем цир ку лю ю чо го
розчин но го ре цеп то ра для кінце вих про дуктів по вно го гліко зи -
лю ван ня (sRAGE). Мета цієї ро бо ти по ля га ла у по шу ку від-
повіді на пи тан ня, чи про яв ляється таке яви ще у ран ньо му ди -
тинстві? Ме то ди. Дослідже но 73 ма тері і 77 дітей віком від
чотирь ох до 12 місяців. За леж но від при сут ності ком по нентів
МетС ма терів розділили на три гру пи: не га тив на (n = 32) – без
ком по нентів МетС; з по чат ко вою стадією МетС (ре зис тент-
ність до інсуліну + одна озна ка МетС, n = 27) та з явно ви ра -
же ним МетС (n = 14). У ма терів і дітей виз на ча ли рівень кон -
цен трації sRAGE і кар бок си ме тиллізину (КМЛ). Ре зуль та ти.
У ма терів з по чат ко вою та явно ви ра же ною стадіями МетС
вста нов ле но ни жчий рівень sRAGE порівня но з їхніми дітьми, у
яких спос терігали лише тен денцію до його падіння. Кількість
sRAGE ко ре лює з чут ливістю до інсуліну та по каз ни ком BM
(індекс маси тіла) I /маса тіла. Різниці в кон цен трації КМЛ по
гру пах не знай де но. Вис нов ки. Ме та болічний син дром пов'яза -
ний із зни жен ням рівня sRAGE у ма терів. По ка зано тен ден цию
до змен шен ня кількості sRAGE у їхніх дітей. Нор моглікемія у
дітей, у ма терів яких виз на че но МетС, підтри мується ви щим
рівнем інсуліну.
Клю чові сло ва: ме та болічний син дром, пара мати–ди ти на,
QUICKI, sRAGE, ре зис тентність до інсуліну, кар бок си ме -
тиллізин.
К. Кле но ви чо ва, П. Бор, Я. Гра хо ва, К. Фур ко ва, К. Ше бе ко ва
Ме та бо ли чес кий син дром об рат но ас со ци и ро ван с
рас тво ри мым ре цеп то ром для ко неч ных про дук тов
по лно го гли ко зи ли ро ва ния: из уче ние пар мать–ре бе нок
Ре зю ме
Цель. У па ци ен тов по жи ло го воз рас та раз ви тие ме та бо ли -
чес ко го син дро ма (МетС) ас со ци и ро ва но с низ ким уров нем
цир ку ли ру ю ще го рас тво ри мо го ре цеп то ра для ко неч ных про -
дук тов по лно го гли ко зи ли ро ва ния (sRAGE). Цель этой ра бо ты
состо я ла в по ис ке от ве та на воп рос, про яв ля ет ся ли дан ное яв -
ле ние в ран нем де тстве? Ме то ды. Иссле до ва ны 73 ма те ри и
77 де тей в воз рас те от че ты рех до 12 ме ся цев. В за ви си мос ти
от при су тствия ком по нен тов МетС ма те рей раз де ли ли на
три груп пы: от ри ца тель ная (n = 32) – без ком по нен тов
МетС; с на чаль ной ста ди ей МетС (ре зис тен тность к ин су ли -
ну + один при знак МетС, n = 27) и с явно вы ра жен ным МетС
(n = 14). У ма те рей и де тей опре де ля ли уро вень кон цен тра ции
sRAGE и кар бок си ме тил ли зи на (КМЛ). Ре зуль та ты. У ма те -
рей с на чаль ной и явно вы ра жен ной ста ди я ми МетС вы яв лен
бо лее низ кий уро вень sRAGE, в то вре мя как у их де тей на блю -
да лась лишь тен ден ция к его сни же нию. Ко ли чес тво sRAGE
кор ре ли ру ет с чу встви тель нос тью к ин су ли ну и по ка за те лем
BM (ин декс мас сы тела) I/мас са тела. Раз ни цы в кон цен тра -
ции КМЛ по груп пам не установлено. Вы во ды. Ме та бо ли чес -
кий син дром свя зан со сни же ни ем уров ня sRAGE у ма те рей.
По ка за на тен ден ция к умень ше нию ко ли чес тва sRAGE у их де -
тей. Нор мог ли ке мия у де тей, у ма те рей ко то рых об на ру жен
МетС, под дер жи ва ет ся бо лее вы со ким уров нем ин су ли на.
Клю че вые сло ва: ме та бо ли чес кий син дром, пара мать–ре -
бе нок, QUICKI, sRAGE, ре зис тен тность к ин су ли ну, кар бок си -
ме тил ли зин.
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UDC 612.63 + 612.349.8
Received 2.01.2011
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