Obstructive Sleep Apnea and the Metabolic Syndrome

Jamie C.M. Lam; Mary S.M. Ip


Expert Rev Resp Med. 2009;3(2):177-186. 

In This Article

OSA and Metabolic Syndrome: A Mechanistic Review

Repeated episodes of obstructed breathing result in intermittent hypoxemia with reoxygenation and disturbed sleep architecture with sleep fragmentation and sleep loss, which may lead to a plethora of downstream cellular events altering metabolism (Figure 1). Epidemiologic, clinical and translational studies have provided the background and clues to the many intermediary mechanisms that may be involved. The oxygenation status in OSA may be simulated by intermittent hypoxic exposure in animal experiments and cell-culture systems, allowing further exploration of the mechanistic pathways involved.[89]

Figure 1.

Proposed mechanisms for the pathogenesis of cardiometabolic dysfunction in obstructive sleep apnea.

Sympathetic Activation and Other Neurohumoral Changes

Obstructive sleep apnea is postulated to be a chronic stress state with activation of neurohumoral pathways that participate in metabolic regulation. Obese subjects are shown to have increased sympathetic activity, although most of these studies did not characterize sleep apnea status, while studies of OSA subjects demonstrated further elevation of sympathetic activity beyond that attributed to obesity.[90,91,92,93] Surges of sympathetic overactivity accompany transient increases in systemic blood pressure in phase with sleep apneic episodes, and sympathoadrenal activation persists in the day, as evidenced by muscle sympathetic nerve activity and catecholamine output.[90,91,92,93] Apart from vasoconstriction, sympathetic activation may modulate many other mechanisms or mediators, including the angiotensin-renin system, insulin and adiponectin, which may all contribute to cardiometabolic dysfunction in OSA.[92,93,94,95,96,97] Sympathetic overactivity in OSA is believed to be an important factor in the pathogenesis of blood-pressure elevation, while its role in glucose and lipid metabolism is less clear. A study in mice found that intermittent hypoxia resulted in insulin resistance, despite abolition of autonomic nervous system activity.[98]

Angiotension-renin system activation, circulatory volume expansion and baroreceptor impairment have been described in OSA, and may play a role in the pathogenesis of elevated blood pressure.[92,93,94,95,99]

Changes in the duration or quality of sleep may affect neuroendocrine and metabolic function.[100,101,102] Healthy subjects subjected to sleep restriction in the laboratory setting showed upregulation of the hypothalamic-pituitary-adrenal axis and somatotrophic axis.[101,102] OSA subjects have been reported to have altered pattern of cortisol secretion, although there is significant disagreement about this among studies.[101,102,103,104]

Obstructive sleep apnea may also modulate hormones that regulate energy metabolism. In a population-based study, those reporting short sleep duration were found to have higher ghrelin and lower leptin levels, in keeping with promotion of weight gain.[43] Again, results of the changes in these hormones in OSA have been variable, as discussed later in this review in the section on the role of adiposity.

Intermittent Hypoxia and Oxidative Stress

Hypoxia in OSA is unique in that the phenomenon is one of recurrent intermittent hypoxia with reoxygenation, analogous to ischemia reperfusion. Other than direct hypoxic injury, this may result in generation of oxidative stress, which in itself is believed to be an early step in the pathogenetic cascade of cardiometabolic dysfunction.[87,105,106] Obesity and the metabolic syndrome have been associated with heightened oxidative stress.[105,106] Intermittent hypoxic exposure in animal models induced various metabolic alterations, including insulin resistance[107] and upregulation of lipid biosynthesis and lipid peroxidation.[108] It was also found that the effect of intermittent hypoxia on oxidative stress was organ specific.[109] OSA subjects have been reported to have increased levels of various oxidative stress markers, such as nitric oxide, 8-isoprostane, reactive oygen species and lipid peroxidation, although there is considerable disagreement in the literature.[87,105,110,111,112]


It is established that inflammation plays a key role in the pathogenesis of endothelial dysfunction, insulin resistance and lipid peroxidation, which are the forerunners of atherosclerosis, glucose intolerance and dyslipidemia, and inflammation is well described in association with the metabolic syndrome or cardiometabolic dysfunction.[113,114,115,116] The obesity state per se is associated with inflammation, probably through the expression of various adipocytokines.[115,116] Evidence for increased inflammation attributable to OSA, independent of obesity, includes activation of neutrophils, lymphocytes, monocytes and platelets; activation of NF-κB, increased circulating levels of proinflammatory or prothrombotic substances such as C-reactive protein, cell-adhesion molecules, TNF, IL-6, leptin, plasminogen-activator inhibitor 1, fibrinogen and adipocyte fatty-acid binding protein; and decreased levels of anti-inflammatory substances, including IL-10 and adiponectin.[87,104,105,111,117,118,119,120,121,122,123,124,125,126] However, most of the studies in this area were observational and the results not always consistent.[69]

Role of Adiposity

Abdominal obesity is part of the definition of the metabolic syndrome, and it is suggested to be a key driver of the syndrome.[18] In obesity, heightened inflammation occurs in adipose tissue and impacts further upon glucose, lipid and energy metabolism.[113,114,115,116] Although the exact reasons for this heightened inflammation are not known, it has been proposed recently that adipose tissue hypoxia may be a trigger.[106] The metabolic syndrome is associated with an inflammatory state,[16,113,114,115,116] and it is tenable that OSA-induced intermittent hypoxia may interact with adiposity to promote metabolic dysfunction.

Many adipokines have an active function in the regulation of metabolism;[115,116] therefore, there is much interest in the role of adipokines as mediators of metabolic dysfunction in OSA. This review only focuses on leptin and adiponectin as more data are available for these. Leptin, a predominantly adipocyte-derived hormone, regulates bodyweight through the control of appetite and energy consumption, and human obesity is associated with increased leptin levels, probably reflecting a leptin-resistant state.[116] Leptin is a pleiotropic hormone and, apart from metabolic effects, there is evidence that relative leptin resistance may be partly responsible for the ventilatory depression seen in obesity, thus potentially playing a role in pathogenesis of sleep-disordered breathing, as well as metabolic dysregulation in OSA.[26,116,127] Most human studies so far have only measured circulating leptin levels in OSA, and the data have been very conflicting - some studies showed an elevation beyond that of obesity while others did not, and the responses to treatment were similarly inconsistent.[80,81,82,128,129] In genetically obese mice, intermittent hypoxia exposure led to an increase in insulin resistance and the response was dependent on the disruption of leptin pathways.[107]

Lower levels of adiponectin, an adipokine with antiinflammatory, anti-atherogenic and insulin-sensitizing actions, have been described in obesity, hypertension, diabetes mellitus and the metabolic syndrome.[115,116] The data in OSA are conflicting, and we reported recently that hypoadiponectinemia was associated with severe OSA, independent of obesity and visceral obesity, and that adiponectin levels were predicted by nocturnal urinary catecholamine levels and insulin resistance.[97]

In summary, a number of intermediary mechanisms and an armamentarium of mediators may take part in generating cardiometabolic dysfunction in OSA. Despite similar overall mechanisms, the signaling processes and their complex interplay for each metabolic parameter, further subject to the influences of intrinsic and lifestyle factors in the individual,[130] are necessarily different, and we are only beginning to see a glimpse of the vast array of biologic possibilities that exist.


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