Theoretical ReviewSleep apnea is a manifestation of the metabolic syndrome
Introduction
Obstructive sleep apnea (OSA) is a prevalent disorder particularly among middle-aged, obese men, although its existence in women, as well as in lean individuals, is increasingly recognized.1, 2, 3, 4, 5 Four percent of adult men and 2% of adult women in general population random samples meet the current clinical and polysomnographic criteria for the diagnosis of sleep apnea warranting immediate therapeutic intervention.2, 3, 4 A much larger group, 17–24% of men and 5–9% of women, demonstrate an apnea/hypopnea index of more than five events per hour of sleep,2, 3, 4 which was the originally proposed criterion for sleep apnea,6 however, it is now clear that the majority of subjects do not experience excessive daytime sleepiness and/or cardiovascular problems.
As currently defined, OSA is associated with considerable morbidity and mortality, whereas the currently available treatments are associated either with limited efficacy and/or poor compliance.1 An improvement in the understanding of the nature and pathophysiology of the disorder may lead to novel treatments.
In this review, we summarize the accumulating evidence that sleep apnea, to a large extent, is a manifestation of the (dys) metabolic syndrome or syndrome X.7, 8
Section snippets
Sleep apnea: a manifestation of a metabolic syndrome
Despite the extensive literature on the role of anatomic abnormalities in the pathogenesis of sleep apnea,9 the large majority of adult sleep apneics do not demonstrate structural abnormalities in their upper airways,10, 11 whereas inversely many patients with narrow upper airways due to clear-cut anatomic abnormalities do not have sleep apnea.12 On physical examination, very few features have been helpful in defining the risk for OSA and the response to therapy. Several reports have emphasized
Sleep apnea, cytokines, and EDS
Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients referred for sleep apnea to Sleep Disorder Centers. There is published evidence that the inflammatory cytokines tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are involved in physiological sleep regulation,21, 22 and that their increased secretion or exogenous administration to humans is associated with sleepiness
Sleep apnea is associated with insulin resistance independently of obesity
The data, showing that sleep apnea is associated with hypercytokinemia, in connection with (a) the emerging literature linking cytokines to obesity and insulin resistance,29, 30, 31, 32, 33, 34, 35, 36, 37 (b) the well-known relations between insulin resistance and cardiovascular disease risk,7, 38, 39, 40, 41, 42 and (c) the increased prevalence of cardiovascular disease in obstructive sleep apnea,14, 17 have prompted us to explore whether sleep apnea is associated with insulin resistance
Sleep apnea and hyperleptinemia
Leptin is an adipocyte-derived hormone that regulates body weight through control of appetite and energy expenditure.51 Leptin levels correlate with BMI and insulin levels, and its secretion is further modulated by the stress system and cytokines.51 Administration of leptin in animals is associated with increased blood pressure while it could prevent respiratory depression in obesity.52
Several studies have shown that sleep apnea is associated with hyperleptinemia that correlates to insulin
Visceral fat is the predominant fat problem in sleep apnea
Based on our finding that SDB is associated with insulin resistance independently of obesity, we proceeded to examine whether visceral fat, which is closely associated with insulin resistance, correlates more strongly to sleep apnea than subcutaneous (SC) or total fat. We assessed body fat distribution using computed tomographic (CT) scanning. There were no significant differences between the two groups in terms of total body fat or SC fat. However, sleep apneics compared to obese controls had
Effects of continuous positive airway pressure on metabolic measures
Most studies on the effects of continuous positive airway pressure (CPAP) on insulin resistance have failed to demonstrate an improvement of insulin resistance indices.60 In contrast, most studies have reported that CPAP decreases leptin levels after a short-term (2–4 days) or a long-term (3–6 months) use53 with the exception of a recent study and our own unpublished data that showed no effect of CPAP on leptin levels in obese apneics.56 The lack of effect of CPAP on insulin resistance may be
Sleep apnea is very frequent in disorders in which insulin resistance is a primary pathophysiologic abnormality
Our finding that sleep apnea is associated with insulin resistance independently of obesity prompted us to explore the other side of this bi-directional association. In other words, if insulin resistance is underlying sleep apnea's pathogenetic mechanisms, then the latter should be more prevalent in disorders in which insulin resistance is a primary abnormality, such as the polycystic ovary syndrome (PCOS).64, 65
Sleep loss and sleep apnea are associated with impaired glucose metabolism and diabetes
Sleep deprivation of 60 h is associated with decreased peripheral insulin sensitivity.69 More recently, Van Cauter and colleagues demonstrated that restricting sleep to four hours per night for six nights in young, healthy individuals lowers glucose tolerance.70
Several studies have shown an increased prevalence of sleep apnea and sleep disordered breathing in patients with diabetes mellitus type II.45, 71 Two large prospective studies, the one from Sweden and the other from the US (Nurses'
Effects of menopause and hormone replacement therapy on sleep apnea
In a recent large epidemiologic study, Bixler and colleagues demonstrated that the prevalence of sleep apnea is quite low in pre-menopausal women (0.6%) as well as post-menopausal women on hormone therapy (HT).4 Further, in these women, the presence of sleep apnea appeared to be associated exclusively with obesity (BMI>32.3%). Post-menopausal women without HT had a prevalence of sleep apnea that was close, although still lower, to the prevalence in men. Loss of estrogen after menopause is
The age distribution of symptomatic sleep apnea and metabolic syndrome are similar
Efforts to characterize apnea based on the number of apneic events during sleep have provided inconsistent results. The apnea/hypopnea index as a summary measure cannot predict the clinical impact of the disorder, i.e. degree of sleepiness or presence of cardiovascular problems.1, 3, 4, 10, 11, 14, 17 Both clinical experience and findings from large epidemiologic studies point to at least two types of adult OSA; one type associated with significant morbidity, e.g. daytime sleepiness and/or
Metabolic abnormalities are associated with excessive daytime sleepiness
Daytime sleepiness is a critical symptom of sleep apnea but is not pathognomonic. A number of sleep, medical, and mental diseases and disorders include this symptom. We here review evidence that obesity and diabetes may be key mediators of this symptom.
The effects of cytokine antagonists and exercise on excessive daytime sleepiness and sleep apnea
In order to test our hypothesis that the pro-inflammatory cytokines TNFα and IL-6 are mediators of excessive daytime sleepiness in humans, we proceeded with a pilot study during which we administered etanercept, a medication that neutralizes TNFα, or placebo, in eight male, obese apneics.89 There was a significant and marked decrease of sleepiness by etanercept, which increased sleep latency during the multiple sleep latency test (MSLT) by about 3.1 min compared to placebo (Fig. 8). Also, the
Metabolic abnormalities and collapse of the upper airway during sleep
Sleep apnea is broadly thought of as a disorder that is characterized by recurrent collapse of the upper airway during sleep, leading to periods of intermittent hypoxia and sleep fragmentation. It is not known how the metabolic abnormalities associated with sleep apnea and reviewed in this paper lead to a collapse of the upper airway during sleep. However, some emerging data provide hints for the link between systemic metabolic aberrations and upper airway collapse. First, it has been reported
Conclusions
The studies reviewed in this article provide support to our model of the bi-directional, feed forward, pernicious association between sleep apnea and insulin resistance primarily in obese patients. Indeed, visceral obesity/insulin resistance, determined by both genetic/constitutional and environmental factors, may be the principal culprit leading to sleep apnea, which, in turn, may accelerate these metabolic abnormalities, possibly through progressive elevation of stress hormones and cytokines
Acknowledgements
Supported by the National Institutes of Health Grants: HL40916, HL51931, and HL64415*.
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