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* From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
Correspondence to: Mary S. M. Ip, MD, FCCP, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; e-mail: msmip{at}hkucc.hku.hk
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Abstract |
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Design: Case control study.
Setting: Sleep Laboratory, Queen Mary Hospital, University of Hong Kong, China.
Methods: Thirty OSA subjects were matched with 30 non-OSA subjects for body mass index (BMI), age, sex, and menopausal status. Neck, waist, and hip girth, skinfold thickness, and fasting serum levels of lipids, glucose, insulin, and leptin were compared between these two groups.
Results: Compared with control subjects with a similar BMI but without OSA, the OSA group had a significantly more adverse vascular risk factor profile, including dyslipidemia, higher diastolic BP, insulin resistance, and greater adiposity reflected by skinfold thickness. OSA subjects also had higher circulating leptin levels (9.18 ± 4.24 ng/mL vs 6.54 ± 3.81 ng/mL, mean ± SD, p = 0.001). Serum leptin levels correlated positively with BMI, skinfold thickness, serum cholesterol, low-density lipoprotein cholesterol, insulin, insulin/glucose ratio, apnea-hypopnea index, and oxygen desaturation time; multiple stepwise regression analysis identified skinfold thickness, waist/hip ratio, serum low-density lipoprotein cholesterol, and diastolic BP as independent correlates, while only serum insulin and diastolic BP were independent correlates in OSA subjects. After treatment with nasal continuous positive airway pressure for 6 months, there was a significant decrease in circulating leptin (p = 0.01) and triglyceride levels (p = 0.02) without change in other parameters.
Conclusion: Despite controlling for BMI, OSA subjects showed distinct profiles with clustering of vascular risk factors. Hyperleptinemia was present in the OSA subjects, but it can be normalized by treatment with nasal continuous positive airway pressure, suggesting that increased leptin resistance was not the cause of OSA or its associated vascular risks.
Key Words: leptin • metabolic variates • sleep apnea • vascular risks
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on clinical observation, OSA has been described as an
additional vascular risk factor (syndrome Z)12
that
interacts with the well-known cluster of central obesity, insulin
resistance, dyslipidemia, and hypertension in syndrome
X/abdominal obesity syndrome.13
14
It has been
reported that men with OSA have excess fat, evidenced by skinfold
thickness, in reference to their weight,7
suggesting
preferential fat accumulation. The pathogenesis of obesity remains
largely unknown, but studies have shown that, in obese humans, there is
resistance to leptin, an adipocyte-derived hormone that regulates body
weight through the control of appetite and energy
expenditure.15
16
17
There is also increasing evidence that
leptin affects several neuroendocrine mechanisms and regulates multiple
hypothalamic-pituitary axes.17
Conversely, leptin
expression and secretion may be regulated by many hormones, cytokines,
and physiologic mechanisms.17
It has been demonstrated in
animal studies that leptin could prevent respiratory depression in
obesity, suggesting that a deficiency in CNS leptin levels or activity
may induce hypoventilation in some obese subjects,18
while
work with subjects with COPD has shown that circulating leptin levels
correlated with body mass and fat mass, independent of the
-tumor-necrosis factor system.19
The present study was
conducted to investigate the possible roles of leptin in OSA. We
examined the profiles of circulating leptin and metabolic variates in a
cohort of OSA subjects compared with the profiles in control subjects
without OSA, matched for sex and body mass index (BMI), to assess
whether OSA was associated with an increase in cardiovascular risk and,
if so, to determine the role of leptin therein. We also measured leptin
levels in OSA subjects before and after treatment with nasal continuous
positive airway pressure (nCPAP) to understand the relationship between
leptin and sleep apneic activity.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5 and by symptoms of excessive daytime sleepiness, were
compared with asymptomatic subjects with AHI < 5 who were matched for
age, gender, and BMI (and menopausal status in females). Only OSA
subjects for whom a matched control subject could be identified were
included in the analysis. The OSA subjects were advised on nCPAP therapy according to clinical protocol, and those who agreed to try nCPAP were further recruited for post-nCPAP assessment. To study the effect of overnight application of nCPAP, only those who underwent the 1-night nCPAP treatment within 2 weeks of the baseline study were evaluated, to avoid any change of body weight and sleep apneic activity over time. Those subjects who received regular treatment with nCPAP were recruited to the reassessment study at 6 months, and only those whose body weights were stable (< 5% change from baseline) were included in the evaluation.
Sleep Study
All subjects underwent an overnight sleep study, using a
computerized polysomnogram system (Alice 3; Healthdyne; Respironics;
Pittsburgh, PA) at the Sleep Laboratory, Queen Mary Hospital. Sixteen
channels were used to document the following parameters: sleep stages
(4-channel EEG, electro-oculogram, chin electromyogram), ECG, airflow
at nose and mouth (thermistors), chest and abdominal respiratory
movement (respiratory impedance), oxygen saturation (pulse oximetry),
snoring (microphone), body position. Recordings were manually scored
according to standard criteria.20
Apnea was defined as
cessation of airflow for > 10 s, and hypopnea was defined as a
discernible decrease in airflow from baseline associated with a fall in
oxygen saturation of 4% from baseline. AHI was determined by
taking the average of the number of apneic and hypopneic events per
sleep hour.
Anthropometric Measurements
BMI was calculated from body weight and height measured by a
scale (Detecto Scale; Webb City, MO). Neck
circumference and waist and hip girth were measured using a tape
measure. Neck circumference was taken at the level of the cricothyroid
membrane, 21
waist circumference at the level of
umbilicus, 22
and hip circumference at the maximal girth
level. Caliper readings for skinfold thickness were measured at the
biceps, triceps, subscapular sites, and abdominal sites23
by one technician throughout the study.
Determination of Circulating Metabolic Parameters
All subjects had fasting blood samples taken between 8:00
AM and 9:00 AM. Blood samples were immediately
sent to the hospital laboratory for estimation of glucose and lipids,
while a specimen of clotted blood was centrifuged at 3000g
for 10 min for serum, which was stored at -70°C in aliquots until
analysis. Serum leptin concentrations were measured in duplicates with
a highly sensitive radioimmuoassay24
(Linco Res; St.
Louis, MO). Serum insulin concentrations were measured by immunoassay
using commercially available kits (IM System; Abbott Laboratories;
Tokyo, Japan), according to the manufacturer’s description.
Statistical Analysis
Results were expressed as mean ± SD. Comparison of data
between two groups was made by application of Mann-Whitney U
test for nonparametric variables. Correlation between serum leptin
concentration and other parameters was evaluated with the Spearman rank
correlation test. Significance was determined at the 5% level.
Multiple regression analysis was applied to define factors that
correlated with serum leptin levels. Statistical analysis was performed
with the SPSS statistical software package (SPSS Inc; Chicago,
IL).25
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5 was
significantly higher than in the control group.
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After one overnight application of nCPAP, there were no significant differences in morning fasting leptin levels (n = 7; level before = 10.32 ± 6.15 ng/mL; level after = 10.5 ± 6.51 ng/mL; p = 0.31). After 6 months of nCPAP treatment, there were significant decreases in the levels of serum leptin despite similar BMIs (n = 9; level before = 10.45 ± 4.55 ng/mL; level after = 6.97 ± 1.82 ng/mL; p = 0.012; BMI before = 27.1 ± 2.43 ng/mL; BMI after = 26.8 ± 2.24 ng/mL) (Fig 2 , right, B). Serum triglycerides also decreased significantly (before = 1.9 ± 0.9 mmol/L; after = 1.2 ± 0.5 mmol/L; p = 0.017), while fasting insulin, glucose, and cholesterol levels did not change significantly.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Obesity is known to be an important pathogenetic factor in OSA, and BMI and other indexes of obesity have been predictive factors for OSA in several population studies.26 27 28 29 It is believed that increased deposition of fat or soft tissue in the neck and upper- airway region predisposes the subject to upper airway collapse and apnea during sleep; a larger neck circumference, probably reflecting greater fat or soft tissue deposition, is more significantly associated with sleep apnea.21 Greater adiposity in the region near the upper airway has also been shown with MRI in relatively nonobese subjects with OSA compared with their BMI-matched counterparts without OSA.30 Furthermore, other studies have reported that central obesity, reflected by waist-to-hip ratio (WHR), was a similar or better predictor of OSA than was BMI,5 26 and the correlation between waist circumference and neck circumference was very strong,5 supporting the idea that OSA is closely linked to central obesity. Central obesity is associated with diabetes mellitus,13 as well as being an indicator of coronary heart disease.14 The presence of central obesity in OSA may confer pathogenetic risks as a result of the mechanical effect on the upper airway, in addition to the vascular implications of central obesity. Since obesity may be an overwhelming confounding factor in the vascular risk profile, the control group was matched to the OSA group for BMI, the most widely applied surrogate marker of obesity. The subjects in this study, similar to most subjects with OSA encountered in clinical practice in our community,31 had BMIs in the overweight range for the reference population values in the local Chinese community,32 with a mean BMI significantly above that of the average age- and sex-matched population (men, mean BMI 24.4 for age 40 to 44 years; women, mean BMI 25.1 for age 50 to 54 years).32 These study subjects also had features of central obesity with mean WHR of 0.91 (men, 0.92; women, 0.86) and 0.89 (men, 0.90; women, 0.86) in OSA and control groups, respectively, when the local population mean WHR was 0.88 for men and 0.81 for women.32 Interestingly, despite similar BMIs in OSA and control groups, the OSA subjects had comparatively greater subcutaneous adiposity, reflected by the higher skinfold thickness indexes, consistent with previous hypotheses that OSA subjects may have preferential fat accumulation.5 7
Insulin resistance or clinically apparent diabetes mellitus has been reported to be common in OSA subjects. Some studies have found that the relationship between insulin resistance and sleep-disordered breathing could be completely explained by the differences in body mass after adjusting for confounding variables.33 However, studies on the effect of nCPAP treatment have yielded conflicting results, with some, but not all, investigators finding an improved insulin sensitivity without a concomitant change in body weight, which suggested that OSA has an independent effect on insulin resistance.8 34 In this study, having controlled for body mass, the OSA group still had significantly higher fasting insulin levels with a trend toward higher fasting glucose, suggesting the presence of insulin resistance. This could be explained by a subtle confounding effect of greater adiposity in the OSA subjects, or by an independent effect due to OSA. In our study, the latter has not been confirmed as there was no significant decrease in serum insulin after nasal CPAP treatment.
Hyperlipidemia is an established independent risk factor for coronary
heart disease and cerebrovascular disease. Lipid profiles in OSA
subjects have not been widely studied, although clinical observation
suggests that dyslipidemia is common in subjects with OSA. In a
previous case series of 45 OSA subjects, the prevalence of
hypercholesterolemia and elevated LDL cholesterol was not
increased.6
In the present study, the OSA group had
significantly more subjects who had dyslipidemia with elevated
triglyceride and TC/HDL cholesterol ratio 5, an indicator of
increased cardiovascular risk.
It is now believed that leptin is essential to the normal regulation of body weight and energy expenditure in human subjects. Obesity and body fat are the major factors regulating circulating leptin,15 16 17 which is also influenced by gender and age.35 36 Levels of circulating leptin correlate with indexes of adiposity, including BMI, body fat mass, and percentage body fat.15 16 17 35 36 Consistent with being overweight, the serum leptin levels of both OSA and control subjects were higher than those of lean healthy subjects in our population: men, n = 7, BMI = 23, leptin = 4.1 ± 0.81 ng/mL; premenopausal women, n = 6, BMI = 21.5, leptin = 7.5 ± 5.7 ng/mL; postmenopausal women, n = 3, BMI = 20.3, leptin = 5.5 ng/mL (M. Ip, MD; unpublished data; October 1999). However, despite being matched for the established determinants of serum leptin levels including BMI, sex, age, and menopausal status, compared with subjects who had no evidence of sleep apnea, increased degrees of hyperleptinemia were present in OSA subjects. Since we demonstrated greater skinfold thickness in the OSA subjects, which also correlated strongly with serum leptin levels, our finding suggests that at least part of the elevation of leptin was related to increased fat mass in these OSA subjects. The higher leptin levels may reflect either an increased leptin resistance, contributing to preferential fat deposition and thus predisposing the subjects to development of OSA, or the existence of increased fat stores in subjects who also have a tendency to develop OSA. However, the increased hyperleptinemia could be abrogated after treatment with nCPAP with no significant change in the anthropometric parameters measured, suggesting that other mechanisms apart from fat mass could have contributed to the increased leptin levels in OSA subjects.
Apart from its role in regulation of fat metabolism, leptin may also regulate insulin release as part of an adipoinsular feedback.37 Conversely, insulin resistance has been shown to lead to increased secretion of leptin independent of body fat mass.38 39 Obesity with intra-abdominal fat accumulation is particularly associated with insulin resistance and with noninsulin-dependent diabetes mellitus,13 14 but a previous study has demonstrated that serum leptin levels are not associated with abdominal obesity or elevated serum insulin and serum lipoproteins independently, after adjusting for percentage body fat, gender, and age.36 In our study, serum insulin was a significant independent correlate of serum leptin in the OSA group. However, the decrease in serum leptin after nCPAP treatment was not accompanied by a similar fall in serum insulin. This finding was consistent with a recent report in which serum leptin, but not serum insulin, decreased after nCPAP treatment.34
The baseline levels of leptin correlated with two parameters of sleep-disordered breathing, the AHI and sleep time with oxygen desaturation, and there was a significant decrease of leptin levels in subjects who received nCPAP for about 6 months despite similar BMIs, suggesting either that sleep-disordered breathing contributed to elevated leptin levels or that nCPAP itself could modify leptin expression. The finding of decreases in circulating leptin levels in OSA patients after treatment is consistent with a recently published study in which circulating leptin levels were demonstrated to decrease significantly after 3 or 4 days and after several months of nCPAP treatment in OSA subjects whose body weight was maintained.34 One interpretation of the elevated leptin levels in OSA patients would be the mediation of sleep-disordered breathing by leptin via the common factor of obesity. This is unlikely to be the entire explanation, since the leptin levels decreased after treatment of OSA with no change in BMI. However, nCPAP treatment decreases visceral fat without changing BMI,34 and this possibility has not been firmly excluded in our subjects, although we have seen no change in the anthropometric index of WHR. Alternatively, the AHI and oxygen desaturation may be considered indicators of the degree of physiologic stress due to sleep-disordered breathing. Stress may lead to increased leptin levels either through an increase in leptin secretion or indirectly.40 It has been reported that increased muscle sympathetic nerve activity was associated with increased plasma leptin levels.41 In OSA patients, there is evidence of cerebral arousal as well as increased sympathetic nerve discharge induced by nocturnal events of asphyxiation,10 11 and abolition of the neuroexcitation with nCPAP treatment may result in decrease in leptin expression. An increase in HDL cholesterol has previously been found in OSA after 6 months of nCPAP treatment,34 suggesting that treatment of OSA may result in an improvement in dyslipidemia. In agreement with this observation, a reduction in serum triglyceride was observed in our OSA subjects treated with nCPAP for 6 months. It is possible, therefore, that sleep-disordered breathing and its heightened neuroexcitation and sympathetic activity may lead to alteration in leptin expression as well as to adverse cardiovascular risk profiles. Furthermore, recent work with animal (mouse) models of obesity demonstrated that leptin could prevent respiratory depression.18 Hence, the elevated serum leptin levels in OSA subjects could represent a homeostatic response to the hypoventilation induced by OSA, which decreased with the control of OSA by nCPAP therapy.
In summary, our findings confirm definitively a distinct profile of excess adiposity not adequately reflected by BMI, dyslipidemia, insulin resistance, and elevated BP in subjects with OSA, representing a clustering of multiple cardiovascular risk factors in these subjects. Hyperleptinemia is present in subjects with OSA and cannot be explained entirely by increased adiposity. The reversibility of hyperleptinemia with nCPAP treatment in our patients agrees with the observation in a recent report,34 and suggests that the increased hyperleptinemia is a marker of OSA. The exact mechanisms by which nCPAP treatment for OSA decreased leptin levels require further delineation.
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Acknowledgements |
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Footnotes |
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This study was partially supported by Earmarked Competitive Grant no. HKU 457/96M, Research Grants Council, University Grants Committee, Hong Kong, China.
Received for publication November 16, 1999. Accepted for publication April 19, 2000.
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= women; 
= men.