SLEEP-DISORDERED BREATHING IN CHILDREN
Adipokines in Children With Sleep Disordered Breathing
Riva Tauman, MD, Laura D. Serpero, PhD, Oscar Sans Capdevila, MD, Louise M. O’Brien, PhD, Aviv D. Goldbart, MD, Leila Kheirandish-Gozal, MD, David Gozal,
MD.
Kosair Children’s Hospital Research Institute, and Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville,
KY, USA
Study Objective: Associations between SDB, the metabolic syndrome,
and circulating levels of adipokines have emerged in adults but have not
been examined in snoring children, who, in contradistinction to adults, display insulin resistance and lipid abnormalities as a function of adiposity
rather than SDB. Therefore, we aimed to examine associations between
circulating adipokines levels, insulin resistance, and measures of SDB in
children.
Design: Prospective study.
Setting: Polysomnographic evaluation and assessment of plasma levels
of leptin, adiponectin, resistin, glucose, insulin, and CRP.
Participants: 130 children (mean age 8.2±2.8 years; 39% obese) were
studied.
Measurements and Results: Log adiponectin levels were lower in
obese than nonobese children (3.8±0.31 vs 4.0±0.30 corresponding to
8,381.4±5,841.0 vs 12,853.2±7,780.2 ng/ml, P<0.0001) and were inversely correlated with BMI Z scores (r = -0.47, P<0.0001) but not with log AHI.
Log leptin concentrations were higher in the obese group than the nonobese group (4.2±0.32 vs 3.4±0.57 corresponding to 19,542.6±13,643.6
vs 5,875.5±8,425.7 pg/ml, P<0.0001), correlated with BMI Z scores (r =
0.64, P<0.0001), and were significantly lower in children with AHI ≤1/hr
than children with AHI> 1/hr (P = 0.006) and in children with SpO2 nadir
≥90% than children with SpO2 nadir <90%, even after controlling for BMI
Z score (P<0.03). No significant differences were found in log resistin levels as a function of obesity or AHI. Significant correlations between log
adiponectin levels and log Insulin/Glucose (I/G) ratios (-0.28, P = 0.006)
and between log leptin levels and log I/G ratios (r = 0.66, P<0.0001)
emerged.
Conclusions: In close agreement with the absence of a measurable effect of SDB on insulin resistance in children, circulating adipokines levels
are primarily attributable to the ponderal index. However, SDB and associated hypoxemia may contribute to the elevation of leptin levels.
Keywords: Obstructive sleep apnea, leptin, adiponectin, resistin, insulin
resistance, metabolic syndrome
Citation: Tauman R, Serpero L, Capdevila O et al. Adipokines in children
with sleep disordered breathing. SLEEP 2007;30(4):443-449
INTRODUCTION
Recent discoveries of fat-secreted substances, such as leptin,
adiponectin, and resistin, which, in addition to local tissue effects
also serve endocrine roles, have launched renewed interest and
insights into our understanding of the complex relations/interactions between SDB, obesity, and the metabolic syndrome. Leptin,
an adipocyte-derived hormone regulating energy expenditure and
food intake is readily found in the circulation, and its levels appear to be determined by the degree of obesity9 as well as by
the severity of SDB, particularly hypoxemia.10,11 Indeed, plasma
leptin levels will decrease significantly following treatment with
weight loss13 or CPAP,6 the latter independently from changes in
BMI.13 These findings suggest that SDB is an independent contributing factor to serum leptin levels. Interestingly, leptin may
directly affect respiratory control mechanisms,14 and intermittent
hypoxia, such as found in SDB, has been shown to induce insulin
resistance via disruption of leptin pathways.15
Adiponectin is another novel adipocyte-derived hormone with
anti-inflammatory, anti-atherogenic, and insulin-sensitizing properties.16 Reduced plasma adiponectin levels increase the risk for
cardiovascular morbidity, insulin resistance, and “paradoxically”
also increase the risk for obesity.16-18 Previous studies concerning plasma adiponectin levels in adults with SDB have revealed
conflicting results.19,20
In contrast to leptin and adiponectin, the role of resistin in
humans is still unclear. Although initially described as a fat tissue-derived hormone that increased insulin resistance (thereby
its name), more recent studies have failed to demonstrate any
association between resistin levels and insulin resistance.21 Of
note, Harsch and colleagues recently reported a significant, albeit
weak correlation between plasma resistin levels and insulin resistance in obese patients with SDB.22 However, while insulin resis-
IN RECENT YEARS, IT HAS BECOME INCREASINGLY EVIDENT THAT SIMILAR TO ADULTS, SLEEP DISORDERED
BREATHING (SDB) IN CHILDREN IS ASSOCIATED WITH
cardiovascular morbidity.1,2 One of the known risk factors for
cardiovascular disease is the “metabolic syndrome” which designates the presence of insulin resistance, dyslipidemia, hypertension, and obesity. Although the association between SDB and the
metabolic syndrome in adult patients appears to be independent of
obesity,3,4 there are conflicting results regarding the reversibility
of the metabolic disturbances following treatment with CPAP.5,6 In
a cohort of snoring children, insulin resistance and lipid dysregulation were found to be primarily determined by obesity, and SDB
played a minimal, if any, role in the occurrence of such metabolic
abnormalities.7 These findings have been confirmed in a study of
Greek children.8
Disclosure Statement
This is not an industry supported study. Dr. Gozal serves on the national
speakers’ bureau for Merck Inc. Drs. Tauman, Serpero, Capdevila, O’Brian,
Goldbart, and Kheirandish-Gozal have indicated no conflicts of interest.
Submitted for publication June 2006
Accepted for publication November 2006
Address correspondence to: David Gozal, MD, Kosair Children’s Hospital
Research Institute, University of Louisville School of Medicine, 570 S. Preston Street, Suite 204, Louisville, KY 40202, USA. Tel: (502) 852 2323, Fax:
(502) 852 2215, Email: [email protected]
SLEEP, Vol. 30, No. 4, 2007
443
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
tance improved with CPAP treatment, there were no concomitant
changes in plasma resistin levels.22
Based on the cumulative evidence pointing towards a potential
association between SDB, the metabolic syndrome, and plasma
concentrations of several adipokines in adults, we examined the
relative contributions of SDB and obesity on plasma adipokines
levels in snoring children. We further assessed potential relationships between these adipokines, C- Reactive Protein (CRP) as a
marker of inflammation, and glucose homeostasis.
cose levels were measured using a commercial kit based on the
hexokinase-glucose-6-phosphate dehydrogenase method (Flex
Reagent Cartridges, Dade Behring, Newark, DE). Insulin resistance was assessed using the fasting insulin/fasting glucose ratio
(I/G ratio).
Plasma CRP was measured within 2-3 hours after collection
using the Flex reagent Cartridge (Date Behring, Newark, DE),
which is based on a particle enhanced turbidimetric immunoassay
technique. This method has a detection level of 0.05 mg/dl, and
exhibits linear behavior up to 255 mg/dl, with intra-assay and inter-assay coefficients of variability of 9% and 18%, respectively.
Plasma samples were also obtained from the blood sample, and
stored at -80°C until assayed. Plasma levels for adiponectin were
determined using a commercially available ELISA kit following the manufacturer recommendations (B-Briedge International
Sunnyvale, CA). This method has a detection level of 23.4 pg/
ml, and exhibits linear behavior up to 12 ng/ml, with intra-assay
and inter-assay coefficients of variability of 5.2% and 5.3%. For
leptin ELISA (Assay Design Inc., Ann Arbor, MI) detection level
was 25.5 pg/ml, the linearity range was between 100 and 50,000
pg/ml with intra-assay and inter-assay coefficients of variability
of 7.5% and 4.0%, respectively. Finally, plasma resistin levels
using a commercially available ELISA (Biovendor [Alexis], San
Diego, CA), with linearity range of 1.9 ng/ml to 16.3 ng/ml, and
intra-assay and inter-assay coefficients of variability of 3.6 % and
6.8%, respectively. All samples were assayed in duplicate along
with duplicate calibration curves. The average of both values was
retained unless they differed by >20%, in which case the assay
was repeated.
All assays were preformed by investigators who were unaware
of the polysomnographic findings. Plasma adiponectin, leptin,
and resistin levels were not normally distributed, and therefore
logarithmic transformation was applied for subsequent analyses.
METHODS
One hundred and thirty children consecutively evaluated for
snoring and suspected SDB at the Kosair Children’s Hospital
Sleep Medicine Center were studied. The study was approved by
the University of Louisville Human Research Committee. Parental informed consent and child assent, in the presence of a parent,
were obtained. Children were excluded if they had any chronic
medical conditions, were receiving medications known to affect
glucose homeostasis, or if they had any genetic or craniofacial
syndromes.
A standard overnight multichannel polysomnographic evaluation was performed in the sleep laboratory as described previously.7 Sleep architecture was assessed by standard techniques,
as reported. Briefly, obstructive apnea was defined as the absence
of airflow with continued chest wall and abdominal movement
of at least 2 breaths duration. Hypopneas were defined as a decrease in nasal flow of >50% with a corresponding decrease in
SpO2 of >4% and/or termination by a 3-second EEG arousal. The
obstructive apnea/hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time (TST).
Children with an AHI>1 but <5/ hr TST were considered to have
mild SDB, while children with AHI>5/ hr were considered to
have SDB. To further examine the role of hypoxemia, children
were divided according to their SpO2 nadir into 3 groups: children
with SpO2 nadir ≥90% (mimimal hypoxemia), children with SpO2
nadir of 80-89% (moderate hypoxemia), and children with SpO2
nadir <80% (severe hypoxemia). Arousals were defined as recommended by the American Sleep Disorders Association Task Force
report using the 3-second rule and/or the presence of movement
arousal.
Data Analysis
Data are presented as means ± SD unless otherwise indicated.
All analyses were conducted using SPSS software (version 11.5;
SPPS Inc., Chicago, IL). Comparisons of demographics according to group assignment were made with independent t-tests or
analysis of variance (ANOVA) followed by post hoc comparisons. Post hoc comparisons were performed using the least significant difference (LSD) when equal variances were assumed, and
Dunnett’s test when equal variances were not assumed; P values
were adjusted for unequal variances when appropriate (Levene’s
test for equality of variances), or chi square (χ2) analyses with
Fisher’s Exact Test (dichotomous outcomes). Correlations were
performed using linear regression, followed by calculation of
Pearson correlation coefficients. All P values reported are 2-tailed
with statistical significance set at <0.05. Odds ratio (OR) and 95%
confidence intervals (CI) are presented.
Body Mass Index
Height and weight were obtained using standard techniques
from each child. BMI was then calculated (body mass/height2).
BMI Z scores for age and sex were determined based on Centers
of Disease Control and Prevention growth charts.23 Children with
BMI Z scores exceeding 1.65 were classified as fulfilling the criteria for obesity.
Blood Samples
RESULTS
Blood for insulin and glucose levels was drawn the morning
after the sleep study after an overnight fast. Plasma insulin levels
were measured using a commercially available radioimmunoassay kit (Coat-A-Count Insulin, Diagnostic Products Inc.). This
method has a detection level of 1.2 μIU/ml, and exhibits linear
behavior up to 350 μIU/ml, with intra-assay and inter-assay coefficients of variability of 3.1% and 4.9%, respectively. Plasma gluSLEEP, Vol. 30, No. 4, 2007
One hundred and thirty children (54% males), aged 1-17 years
(mean 8.2±2.8 years) participated in the study. Of these, 43 children were found to have SDB, 42 children had mild SDB, and 45
children were in the control (CO) group. Subject characteristics
including glucose and insulin levels are shown in Table 1. There
were no significant differences in age and sex among the 3 groups.
444
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
Figure 1—A. Log adiponectin levels in 51 obese children and 79 nonobese children. Log plasma adiponectin levels were significantly lower in the
obese group than the nonobese group (P <0.0001). B. Scatterplot of log adiponectin levels plotted against log BMI Z score in 130 children. Linear
regression line is shown (r = -0.47, P <0.0001). C. Scatterplot of log individual fasting I/G ratios plotted against corresponding log adiponectin
levels in 130 children. Linear regression lines are shown (see text for details).
However, a significantly higher proportion of obese children were
found in the SDB group than CO. As anticipated, significant differences were found among the 3 groups in AHI, arousal index,
and SpO2 nadir, and a significant negative correlation between
SpO2 nadir and AHI (r = -0.70, P<0.0001) was found for the entire
cohort. Subject characteristics, including glucose and insulin levels after dividing the cohort based on the presence or absence of
obesity, are shown in Table 2. Significantly higher insulin levels
were found in obese children than nonobese children (P = 0.01).
SDB compared to children with mild SDB or with controls. Similarly, no significant differences were found in log plasma adiponectin levels after subdividing our cohort according to SpO2 nadir
values. No significant correlations were found between log plasma
adiponectin levels and log AHI, SpO2 nadir, and/or arousal index.
Of note, a significant negative correlation was found between
log plasma adiponectin levels and corresponding log I/G ratios
(r = -0.28, P = 0.006, Figure 1C). The OR for high I/G ratio (I/G
ratio>0.1) in subjects with low plasma levels of adiponectin compared to subjects with high plasma levels of adiponectin was 3.6
(95% CI: 1.5-8.7, P = 0.004). A significant negative correlation was
found between log plasma adiponectin levels and log plasma CRP
concentrations (r = -0.41, P = 0.001). This correlation persisted after controlling for BMI Z score (r = -0.35, P = 0.01).
Adiponectin
Log plasma adiponectin levels were significantly lower in the
obese group than the nonobese group (3.8±0.31 vs 4.0±0.30, corresponding to 8381.4±5841.0 vs 12853.2±7780.2 ng/ml respectively;
P<0.0001, Figure 1A). A significant negative correlation was found
between log plasma adiponectin levels and corresponding BMI Z
score (r = -0.47, P<0.0001, Figure 1B). No significant differences
in log plasma adiponectin levels were found between children with
SLEEP, Vol. 30, No. 4, 2007
Leptin
Log plasma leptin levels were significantly higher in the obese
children group than the nonobese group (4.2±0.32 vs 3.4±0.57
445
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
Figure 2—A. Log leptin levels in 51 obese children and 79 nonobese children. Log plasma leptin levels were significantly elevated in the obese
group compared to the nonobese group (P <0.0001). B. Log leptin levels in 85 children with AHI>1 compared to 45 children with AHI≤1. Log
plasma leptin levels were significantly elevated in children with AHI greater than 1 (P = 0.006). C. Scatterplot of log leptin levels plotted against
log AHI in 130 children. Linear regression line is shown (r = 0.27, P = 0.002). D. Log leptin levels in children with SpO2 nadir ≥90% (“minimal
hypoxemia”), SpO2 nadir of 80%-89% (“moderate hypoxemia”), and SpO2 nadir <80% (“severe hypoxemia”). Log leptin levels were significantly
lower in children in “minimal hypoxemia” group when compared to the 2 other groups (P <0.03). E. Scatterplot of log individual fasting I/G ratios
plotted against corresponding log leptin levels in 130 children. Linear regression lines are shown (see text for details).
corresponding to 19,542.6±13,643.6 vs 5,875.5±8,425.7 pg/ml,
respectively; P <0.0001, Figure 2A), and a significant association
was found between log plasma leptin levels and BMI Z scores (r
= 0.64, P<0.0001). Furthermore, log plasma leptin levels were
significantly lower in control children (3.4±0.6 corresponding to
7005.9±8842.5 pg/ml) compared with either of the 2 severity-defined SDB groups (3.9±0.58 corresponding to 14737.0±14870.6
pg/ml, P = 0.009; CO vs SDB, and 3.8±0.58 corresponding to
12040.2±12904.4 pg/ml, P = 0.05; CO vs mild SDB, Figure 2B).
A significant positive correlation was found between log plasma
leptin levels and log AHI (r = 0.27, P = 0.002, Figure 2C).
Sub-analysis of the nonobese children also revealed significant
positive correlation between log plasma leptin level and log AHI (r
= 0.25, P = 0.02). A significant albeit weak correlation was found
between log plasma leptin levels and age (r = 0.27, P = 0.003).
To examine the potential contribution of hypoxemia to leptin levels, children were subdivided according to their SpO2 nadir into 3
severity groups. Significantly lower log plasma leptin levels occurred in “minimal hypoxemia” group (3.5±0.56 corresponding to
7149.9±9717.9 pg/ml) compared to either “moderate hypoxemia”
group (3.9±0.6 13452.4±12682.4 pg/ml; P = 0.005) or “severe hypoxemia” (3.9±0.61 corresponding to 15244.2±14840.0 pg/ml; P
= 0.02, Figure 2D). These findings persisted after controlling for
BMI Z score using univariate analysis of variance.
Furthermore, when stepwise linear regression analysis was performed for prediction of plasma leptin levels using BMI Z score,
AHI, SpO2 nadir, and age as covariates, only BMI Z score, AHI,
and age were retained in the model and accounted for 49% of the
SLEEP, Vol. 30, No. 4, 2007
variance (P<0.0001). As with adiponectin, a significant positive
correlation was found between log plasma leptin levels and log I/
G ratios (r = 0.66, P <0.0001, Figure 2E). The OR for high I/G ratio (I/G ratio >0.1) in subjects with high plasma leptin levels compared to subjects with low plasma leptin levels was 13.9 (95% CI:
5.4-35.6, P <0.0001). A significant correlation was found between
log plasma leptin levels and log plasma CRP concentrations (r =
0.41, P <0.0001). This correlation persisted after controlling for
BMI Z score (r = 0.33, P = 0.002).
Resistin
No significant differences were found in log plasma resistin
levels among obese and nonobese children. Similarly, no differences emerged in resistin concentrations in children with SDB and
controls. No correlations were found between log plasma resistin
levels and BMI Z score, AHI, or SpO2 nadir, and no significant
correlation emerged between log resistin levels and I/G ratios.
DISCUSSION
This is the first study conducted in snoring children that examines plasma concentrations of 3 major adipokines that have been
suggested as important contributors to the regulation of energy
homeostasis and insulin resistance. The differential responses of
these 3 adipokines to the presence of SDB and obesity are intriguing, and they are vastly different from similar studies conducted
in adult patients.10,11,19,20,22 In children, plasma adiponectin levels
446
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
were found to associate only with obesity, while plasma leptin
levels correlated with both obesity and the severity of the disease;
no relationships emerged between plasma resistin levels and obesity or SDB severity. Furthermore, insulin resistance correlated
positively with plasma leptin levels and negatively with plasma
adiponectin levels. Plasma adiponectin and leptin levels were also
found to correlate with plasma CRP concentrations.
almost immediate reduction in leptin levels and concomitant improvements in sympathetic tone following 24 hours of treatment
with CPAP.11 On the other hand, leptin can induce increased sympathetic activity, as well as elevated heart rate and blood pressure.31 In the present study we did not measure blood pressure,
nor did we assess for other measurements of sympathetic tone,
and such studies will be clearly needed in the near future. Supporting previous reports, we also found a positive correlation
between log plasma leptin levels and insulin resistance.32,33 It is
possible that insulin plays and important role in regulating plasma
leptin concentrations; however, it is also possible that leptin plays
a role in modulating the action of insulin. 34
In a study by Yannakoulia and colleagues 35 a significant association between energy/macronutrient intake and plasma leptin
concentrations emerged. This confounder will have to be incorporated in future studies, since, although fasting leptin measurements were performed in the present study, we did not control
for diet during the days preceding blood sample draws. Previous
reports have shown diurnal changes in circulating leptin.36 However, blood was obtained from our children only in the morning;
therefore we cannot comment on circadian changes in plasma
adipokine concentrations.
To summarize our findings on leptin, higher leptin levels were
present among children with SDB and support our previous report on increased CRP levels in children with SDB.36 Thus, SDB
in childhood appears to impose an independent risk for development of subclinical inflammation ultimately promoting cardiovascular morbidity.
Leptin
Both obesity and SDB severity contributed to the elevations
of plasma leptin levels in snoring children. Plasma leptin levels
were significantly elevated in children with SDB independently
of obesity. Moreover, plasma leptin levels were significantly
lower in children with minimal hypoxemia than in children with
more pronounced/significant hypoxemia (Figure 2D). These findings support previous studies in adults showing that patients with
SDB have significantly higher leptin levels compared to weightmatched subjects without SDB, and that treatment with CPAP
may lead to significant reductions in leptin concentrations.10,11
There was no significant difference in leptin level between moderate and severe hypoxemia. This may be accounted by the fact
that we divided our severity groups using the SpO2 nadir, rather
than use a more cumulative index of desaturation. Such approach
could have dampened potentially existing differences in oxygenation between the 2 SDB groups.
Animal studies have clearly demonstrated that hypoxia induces
increases in both leptin gene expression (via nuclear binding and
transcriptional activation of HIF-1α transcription factor) and in
plasma leptin levels.15,24 Moreover in leptin-deficient mice, both
up-regulation of leptin and leptin replacement protected against
the development of glucose intolerance and insulin resistance
during intermittent hypoxia.15 Thus, the elevation of leptin levels
in children with SDB may represent an important compensatory
mechanism aiming to minimize metabolic dysfunction and preserve glucose homeostasis. In addition, leptin prevents respiratory
depression in obesity and may affect respiratory control mechanisms.14,25 Therefore, it is possible that the elevation of plasma
leptin levels in SDB may reflect a respiratory compensatory
mechanism to the alveolar hypoventilation induced by increased
upper airway resistance.
In addition to its now well-defined role in energy balance, leptin
has also pro-inflammatory properties, with the role of leptin in
the modulation of immune response and inflammation becoming
increasingly evident.26,27 Leptin circulating levels increase during
infection and inflammation, stimulate cytokine activation and immune cell proliferation,27 and appear to be involved in inflammatory bowel and joint disorders.26,27 Recent evidence further suggests that leptin is involved in several aspects of cardiovascular
morbidity, including ventricular hypertrophy, systemic hypertension, and angiogenesis, with increased leptin levels being associated with decreased arterial distensibility and with increased CRP
levels,28 independently of measures of adiposity. The association
between plasma leptin levels and CRP concentrations in the present study supports such previous reports.
Increased sympathetic activity and hypertension are present
in both adults and children with SDB.1,29,30 It has been suggested
that SDB-induced sympathetic activity may lead to alteration in
leptin expression, and that these relationships between autonomic
nervous system recruitment and leptin pathways may explain the
SLEEP, Vol. 30, No. 4, 2007
Adiponectin
The present study confirmed previous findings linking obesity
and insulin resistance to low plasma adiponectin concentrations
in children, as well as in adults. Adiponectin is the most abundant adipose tissue-specific protein, and is exclusively expressed
and secreted from the adipocytes. Similar to insulin resistance
and dyslipidemia,7,8 low adiponectin levels do not seem to correlate with SDB severity in snoring children. Adiponectin plays
a protective role against atherosclerosis, and reduced plasma adiponectin levels have been linked to the presence of endothelial
inflammatory responses, the presence of coronary artery disease,
dyslipidemia, and insulin resistance.17,18 In agreement with previous studies,18 we found an association between plasma adiponectin levels and insulin resistance measures, supporting the notion
that adiponectin may have an insulin-sensitizing effect.37 Moreover, the negative correlation found in our study between plasma
adiponectin levels and plasma CRP concentrations independently
from obesity confirms the previous observations. Despite growing evidence suggesting that increased CRP levels are determined
at least in part by SDB severity in children,38,39 we did not find any
evidence supporting a role for SDB in reducing plasma adiponectin concentrations. One possible explanation may reside in the
independent actions of CRP and adiponectin on the vascular wall.
Alternatively, it is possible that much larger sample sizes will be
needed to reveal the putative, albeit small size effects of SDB on
plasma adiponectin levels. Finally, and in agreement with previous studies, we could not identify any association between plasma
resistin concentrations and SDB severity and/or obesity.21
Of note, our study cohort consisted of an otherwise typical referral-based pediatric population requiring clinical evaluation for
447
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
suspected SDB. A large proportion of children (39%) were obese,
compared to the 17% obesity prevalence in the metropolitan Louisville. In the current study we were unable to assess body fat
distribution, particularly estimates of visceral and subcutaneous
fat; patterns of fat distribution are an important factor contributing
to the metabolic syndrome. In addition, we did not specifically assess pubertal stages, known to be another important determinant
of insulin resistance.40 However, since the groups were closely
matched for age and for male:female ratios, we believe that such
similarities reflect close matching for pubertal stage distribution
among the groups.
In summary, SDB appears to contribute to the magnitude of circulating leptin concentrations in children. However, as a whole,
circulating adipokine levels are primarily linked to obesity in
snoring children.
12. Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich
RL, Stern JS. Relationship of plasma leptin to plasma insulin and
adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J Clin Endocrinol Meatb
1996; 81:4406-13.
13. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal
fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure
therapy. Circulation 1999;100:706-12.
14. O’Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith
PL. Leptin obesity and respiratory function. Respir Physiol
2000;119:163-70.
15. Polotsky VY, Li J, Punjabi NM, et al. Intermittent hypoxia increases
insulin resistance in genetically obese mice. J Physiol 2003;552:25364.
16. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial
adhesion molecules: adipocyte-derived plasma protein adiponectin.
Circulation 1999; 100:2473-6.
17. Pilz S, Horejsi R, Moller R, et al. Early atherosclerosis in obese
juveniles is associated with low serum levels of adiponectin. J Clin
Endocrinol Metab 2005;90:4792-6.
18. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in
obesity and type 2 diabetes: close association with insulin resistance
and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930-5.
19. Harsch IA, Wallaschofski H, Koebnick C, et al. Adiponectin in
patients with obstructive sleep apnea syndrome: course andphysiological relevance. Respiration 2004;71:580-6.
20. Wolk R, Svatikova A, Nelson CA, et al. Plasma levels of adiponectin, a novel adipocyte-derived hormone, in sleep apnea. Obes Res
2005; 13:186-90.
21. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels
are not associated with obesity or insulin resistance in humans and
are not regulated by fasting or leptin administration: cross-sectional
and interventional studies in normal, insulin-resistant, and diabetic
subjects. J Clin Endocrinol Metab 2003;88:4848-56.
22. Harsch IA, Koebnick C, Wallaschofski H, et al. Resistin levels in
patients with obstructive sleep apnea syndrome – the link to subclinical inflammation? Med Sci Monit 2004;10:CR510-15.
23. National Center for Health & Statistics. CDC Growth Charts. US
Department of Health &Human Services, 2000.
24. Grosfeld A, Andre J, Hauguel-De Mouzon S, Berra E, Pouyssegur
J, Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the
human leptin gene promoter. J Biol Chem 2002; 277:42953-57.
25. O’Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;
159:1477-84.
26. Peelman F, Waelput W, Iserentant H, et al. Leptin: linking adipocyte
metabolism with cardiovascular and autoimmune diseases. Prog
Lipid Res 2004; 43:283-301.
27. Otero M, Lago R, Lago F, et al. Leptin, from fat to inflammation:
old questions and new insights. FEBS Lett 2005; 579:295-301.
28. Shamsuzzaman ASM, Winnicki M, Wolk R, et al. Independent association between plasma leptin and C-reactive protein in healthy
humans. Circulation 2004;109:2181-5.
29. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural
mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:18971904.
30. Aljadeff G, Gozal D, Schechtman VL, Burrell B, Harper RM, Ward
SL. Heart rate variability in children with obstructive sleep apnea.
Sleep 1997; 20:151-7.
ACKNOWLEDGEMENTS
We thank Evelyne Gozal, PhD, for technical advice in the initial phase of the adipokine assays.
REFERENCES
1.
Marcus CL, Greene MG, Carroll JL. Blood pressure in children with
obstructive sleep apnea. Am J Respir Crit Care Med 1998;157:10981103.
2. Amin RS, Kimball TR, Bean JA, et al. Left ventricular hypertrophy
and abnormal ventricular geometry in children and adolescents with
obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:13959.
3. Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR,
Smith PL. Sleep-disordered breathing and insulin resistance in
middle aged and overweight men. Am J Respir Crit Care Med
2002;165:677-82.
4. Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive
sleep apnea is independently associated with insulin resistance. Am
J Respir Crit Care Med 2002; 165:670-6.
5. Smurra M, Philip P, Taillard J, Guilleminault C, Bioulac B, Gin H.
CPAP treatment does not affect glucose-insulin metabolism in sleep
apneic patients. Sleep Med 2001;2:207-13.
6. Harsch IA, Schahin SP, Radespiel-Troger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity
in patients with obstructive sleep apnea syndrome. Am J Respir Crit
Care Med 2004;169:156-62.
7. Tauman R, O’Brien LM, Ivanenko A, Gozal D. Obesity rather than
severity of sleep-disordered breathing as the major determinant of
insulin resistance and altered lipidemia in snoring children. Pediatrics 2005;116:e66-73.
8. Kaditis AG, Alexopoulos EI, Damani E, et al. Obstructive sleepdisordered breathing and fasting insulin levels in nonobese children.
Pediatr Pulmonol 2005;40:515-23.
9. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive -leptin concentrations in normal-weight and obese humans. N
Eng J Med 1996;334:292-5.
10. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and
daytime sleepiness and fatigue: relation to visceral obesity, insulin
resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000;
85:1151-8.
11. Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118:580-6.
SLEEP, Vol. 30, No. 4, 2007
448
Adipokines In Children With Sleep Disordered Breathing—Tauman et al
31. Haynes WG. Interaction between leptin and sympathetic nervous
system in hypertension. Curr Hypertens Rep 2000;2:311-18.
32. Kamoda T, Saitoh H, Nakahara S, Izumi I, Hirano T, Matsui A.
Serum leptin and insulin concentrations in prepubertal lean, obese
and insulin-dependent diabetes mellitus children. Clin Endocrinol
1998;49:385-9.
33. de Courten M, Zimmet P, Hodge A, et al.. Hyperleptinaemia: the
missing link in the, metabolic syndrome? Diabet Med 1997;14:200208.
34. Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M.
Expression of the functional leptin receptor mRNA in pancreatic
islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997; 46:313-16.
35. Yannakoulia M, Yiannakouris N, Bluher S, Matalas AL, KlimisZacas D, Mantzoros CS. Body fat mass and macronutrient intake
in relation to circulating soluble leptin receptor, free leptin index,
adiponectin, and resistin concentrations in healthy humans. J Clin
Endocrinol Metab 2003;88:1730-6.
36. Patel SR, Palmer LJ, Larkin EK, Jenny NS, White DP, Redline S.
Relationship between obstructive sleep apnea and diurnal leptin
rhythms. Sleep 2004;27:235-9.
37. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat
Med 2001;7:947-53.
38. Tauman R, Ivanenko A, O’Brien LM, Gozal D. Plasma C-reactive
protein among children with sleep-disordered breathing. Pediatrics
2004;113:e564-9.
39. Larkin EK, Rosen CL, Kirchner HL, et al. Variation of C-reactive protein levels in adolescents association with sleep-disordered
breathing and sleep duration. Circulation 2005;111:1978-84.
40. Guzzaloni G, Grugni G, Mazzilli G, Moro D, Morabito F. Comparison between beta-cell function and insulin resistance indexes in prepubertal and pubertal obese children. Metabolism 2002;51:1011-16.
SLEEP, Vol. 30, No. 4, 2007
449
Adipokines In Children With Sleep Disordered Breathing—Tauman et al