An update on obstructive sleep apnea and the metabolic syndrome

PURPOSE OF REVIEW: Patients with obstructive sleep apnea are often overweight or obese, and they frequently exhibit metabolic aberrations, collectively known as the metabolic syndrome, an established cardiovascular risk factor. We review recent data on the relationship between obstructive sleep apnea and metabolic syndrome or its components, including abdominal obesity, insulin resistance, hypertension, and dyslipidemia. RECENT FINDINGS: There is accumulating evidence for an independent association between obstructive sleep apnea and metabolic syndrome or its components. Recent epidemiologic and clinical data suggest a causal role of severe obstructive sleep apnea in development of hypertension, but findings for insulin resistance and dyslipidemia are controversial. Visceral obesity remains a confounding issue in analyses. Animal models and translational studies indicate that obstructive sleep apnea may promote metabolic dysfunction through cycles of intermittent hypoxia; proposed underlying pathophysiologic mechanisms include oxidative stress, sympathetic activation, and inflammation. SUMMARY: There is suggestive evidence, but independent associations between obstructive sleep apnea and metabolic syndrome or its components are not fully established because of the confounding effect of obesity. Large randomized interventional trials are needed to identify any cause-effect relationship. Long-term follow-up studies would help to clarify the role of treatment of sleep apnea in reducing cardio-metabolic morbidity.     

Interactions between obstructive sleep apnea and the metabolic syndrome

The metabolic syndrome, an emerging public health problem, represents a constellation of cardiovascular risk factors. It has been suggested that the presence of obstructive sleep apnea (OSA) may increase the risk of developing some of the features of the metabolic syndrome, including hypertension, insulin resistance, and type 2 diabetes. In this article, we discuss the parallels between the metabolic syndrome and obstructive sleep apnea and describe possible OSA-related factors that may contribute to the metabolic syndrome, specifically the roles of obesity, hypertension, dyslipidemia, sex hormones, inflammation, vascular dysfunction, leptin, insulin resistance, and sleep deprivation.     

Update on Obstructive Sleep Apnea and Its Associated Metabolic Abnormalities: Insulin Resistance,Metabolic Syndrome,and Type 2 Diabetes Mellitus

Obstructive sleep apnea is characterized by repeated episodes of upper airway collapse during sleep, leading to apneic and hypopneic episodes, oxygen desaturation, and sleep fragmentation. This condition is closely associated with features of “metabolic syndrome” as well as overt diabetes. Although the association of metabolic abnormalities clearly portend increased cardiovascular risk, it remains unclear to what extent obesity confounds these associations. Attempts to demonstrate a causal relationship between obstructive sleep apnea and insulin resistance have yielded conflicting results. Although several recent studies have demonstrated a relationship between obstructive sleep apnea and diabetes mellitus independent of obesity, there are currently limited data demonstrating a strong causative link. The currently proposed pathophysiology involves intermittent hypoxia, sleep fragmentation, sympathetic activation, oxidative stress, an increase in proinflammatory adipocytokines, and hyperleptinemia and leptin resistance. Although continuous positive airway pressure has shown promise in treating obstructive sleep apnea and its associated metabolic derangements, two recent large, randomized controlled trials have redoubled the emphasis on weight loss in treating the triad of metabolic syndrome, diabetes, and obstructive sleep apnea. Weight loss and aggressive lifestyle intervention remain a common treatment modality for all of these conditions and should always be considered first-line treatment for this clinical construct.     

Obesity and obstructive sleep apnea-hypopnea syndrome

Obstructive sleep apnea-hypopnea syndrome involves recurring episodes of total obstruction (apnea) or partial obstruction (hypopnea) of airways during sleep. Obstructive sleep apnea-hypopnea syndrome affects mainly obese individuals and it is defined by an apnea-hypopnea index of five or more episodes per hour associated with daytime somnolence. In addition to anatomical factors and neuromuscular and genetic factors, sleep disorders are also involved in the pathogenesis of sleep apnea. Obesity affects upper airway anatomy because of fat deposition and metabolic activity of adipose tissue. Obstructive sleep apnea-hypopnea syndrome and metabolic syndrome have several characteristics such as visceral obesity, hypertension and insulin resistance. Inflammatory cytokines might be related to the pathogenesis of sleep apnea and metabolic syndrome. Sleep apnea treatment includes obesity treatment, use of equipment such as continuous positive airway pressure, drug therapy and surgical procedures in selected patients. Currently, there is no specific drug therapy available with proven efficacy for the treatment of obstructive sleep apnea-hypopnea syndrome. Body-weight reduction results in improvement of sleep apnea, and obesity treatment must be emphasized, including lifestyle changes, anti-obesity drugs and bariatric surgery.     

Is sleep-disordered breathing an additional risk factor for the metabolic syndrome in obese children and adolescents?

Sleep-disordered breathing is highly prevalent in childhood obesity. Two recent cross-sectional studies have demonstrated an independent association between the severity of sleep-disordered breathing and the metabolic syndrome. A limited number of studies have also addressed the correlation between sleep-disordered breathing and insulin resistance, the core factor of the metabolic syndrome. Cross-sectional reports in modestly obese children are in favor of an association between sleep apnea and insulin resistance. However, these findings were not confirmed in studies of normal-weight children and of morbidly obese children. Only one out of three treatment studies before and after adenotonsillectomy confirmed the association between sleep apnea and insulin resistance, but only in obese children. Although statistical power issues and differences in patient characteristics might partially explain these contradicting results, the evidence to date is far from establishing a causal link between sleep-disordered breathing and insulin resistance. Longitudinal studies and randomized control trials are therefore warranted to investigate a possible causal link between sleep-disordered breathing and insulin resistance.     

Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.     

Obstructive sleep apnea syndrome and fatty liver: Association or causal link?

Obstructive sleep apnea (OSA) is a complex disorder that consists of upper airway obstruction, chronic intermittent hypoxia and sleep fragmentation. OSA is well known to be associated with hypoxia, insulin resistance and glucose intolerance, and these factors can occur in the presence or absence of obesity and metabolic syndrome. Although it is well established that insulin resistance, glucose intolerance and obesity occur frequently with non-alcoholic fatty liver disease (NAFLD), it is now becoming apparen...     

Obesity, hypertension and the metabolic syndrome

The prevalence of obesity in both developed and developing countries has increased dramatically in recent years.1Many people who are obese develop metabolic changes that increase the risk of diabetes mellitus and adverse cardiovascular outcomes. Obesity leads to the development of insulin resistance, lipid abnormalities and increased blood pressure.……     

Disturbed sleep as risk factor for metabolic syndrome

Sleep disorders, sleep fragmentation, and chronically reduced sleep duration are increasingly common in western societies. In parallel, incidence of the metabolic syndrome and its key components, i.e. type 2 diabetes and obesity, is rapidly increasing. A huge number of epidemiological studies has shown a robust association between disturbed sleep quality, reduced sleep duration and the development of components of the metabolic syndrome. Moreover, there is growing evidence from experimental studies proving a causal link between sleep loss and disturbed human energy homeostasis. Short term sleep loss has been shown to reduce insulin sensitivity and glucose tolerance, increase feelings of hunger by modulating orexigenic/anorexigenic hormonal signaling, and disturb physical activity behavior. This review attempts to present an overview of the presently available literature on the link between sleep loss and disturbed human energy homeostasis, as well as on potential pathophysiological mechanisms.     

Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome.

AIMS: Obstructive sleep apnoea (OSA) is associated with increased cardiovascular morbidity and mortality. Although it was previously assumed that this was due to its relation with obesity, recent data suggest that OSA is independently associated with the cardiovascular risk factors that comprise metabolic syndrome, including hypertension, insulin resistance, impaired glucose tolerance, and dyslipidaemia. However, as previous studies have only considered these variables individually, it has not been possible to determine the overall association of OSA with this syndrome. METHODS AND RESULTS: We recruited 61 male subjects with OSA and 43 controls. Glucose, insulin, lipids, and blood pressure (BP) were measured following an overnight fast. Insulin resistance was estimated using homeostasis model assessment (HOMA). Metabolic syndrome was diagnosed according to National Cholesterol Education Program (NCEP) criteria. Subjects with OSA were more obese, had higher BP and fasting insulin, were more insulin resistant, had lower HDL cholesterol, and an increased incidence of metabolic syndrome (87% vs. 35%, p<0.0001). In order to determine whether these associations were independent of obesity and other known covariates, a regression analysis adjusted for age, BMI, smoking, and alcohol consumption was performed. This demonstrated that OSA was independently associated with increased systolic and diastolic blood pressure, higher fasting insulin and triglyceride concentrations, decreased HDL cholesterol, increased cholesterol:HDL ratio, and a trend towards higher HOMA values. Metabolic syndrome was 9.1 (95% confidence interval 2.6, 31.2: p<0.0001) times more likely to be present in subjects with OSA. CONCLUSIONS: OSA is independently associated with an increase in the cardiovascular risk factors that comprise the metabolic syndrome and its overall prevalence. This may help explain the increased cardiovascular morbidity and mortality associated with this condition.     

阻塞性睡眠呼吸暂停低通气综合征与胰岛素抵抗关系的研究进展

有研究表明,中心性肥胖是阻塞性睡眠呼吸暂停低通气综合征(OSAHS)的主要危险因素,可导致胰岛素抵抗.OSAHS患者存在胰岛素抵抗,中心性肥胖可能是联系OSAHS和胰岛素抵抗的中间环节.早期开展经鼻持续气道正压通气治疗OSAHS,可提高组织对胰岛素的敏感性,促进组织对葡萄糖摄取利用,从而减轻或避免产生胰岛素抵抗.     

Adipose tissue in obesity and obstructive sleep apnoea

A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.     

Ectopic fat accumulation and metabolic syndrome

The recent escalation of obesity from an individual health problem to a major public health issue reaching epidemic proportions has drawn attention to a constellation of abnormalities (abdominal obesity, hypertension and dyslipidaemia) collectively referred to as metabolic syndrome. As an indicator of insulin resistance and a harbinger of diabetes, this syndrome has been associated with major cardiovascular mortality and morbidity. Yet, the exact pathophysiological events leading to the development of metabolic syndrome remain unknown. We review some of the current literature on the pathogenesis of metabolic syndrome with an emphasis on the role of ectopic lipid accumulation.     

Relationship between the cardiometabolic syndrome and obstructive sleep apnea

Obstructive sleep apnea (OSA), characterized by cessation of air flow for a minimum of 10 seconds despite continuous respiratory effort, is a prevalent condition in our society. Recent studies demonstrate that OSA is an independent risk factor for insulin resistance and the cardiometabolic syndrome. Hypoxemia and sleep fragmentation from OSA appear to produce autonomic activation, alterations in neuroendocrine function, and increased amounts of inflammatory cytokines (interleukin 6 and tumor necrosis factor alpha). These variables have important roles in the pathogenesis of insulin resistance and the cardiometabolic syndrome. It can be concluded that insulin sensitivity, a key contributor to the pathogenesis of the cardiometabolic syndrome, is mainly determined by the extent of obesity and, to a lesser extent, by OSA. The authors review OSA and summarize recent discoveries and proposed mechanisms of the causal relationship that OSA has with insulin resistance and the cardiometabolic syndrome independent of many confounding comorbidities.     

阻塞性睡眠呼吸暂停低通气综合征与代谢综合征的关系

阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)是由多种致病因素引起的发病率高、危险性大的一种慢性睡眠呼吸疾病.OSAHS患者常常与代谢综合征(metabolic syndrome,MS)大家族中的多种疾病,如肥胖、胰岛素抵抗、高血压、糖尿病等伴发或先后出现.其最终结果导致心血管事件发生和死亡的危险性增加.本文对OSAHS和MS的相互关系作一综述.     

Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance

Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNF alpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNF alpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNF alpha, leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.     

Sleep disturbances and insulin resistance

The causes and risk factors of insulin resistance remain insufficiently understood. After taking into account the important roles of adiposity, age, sex and race/ethnicity, up to 50% of the individual variability in insulin resistance remains unexplained. In recent years, evidence has accumulated to support a role for sleep disturbances, including insufficient sleep, poor sleep quality and insomnia, and obstructive sleep apnoea, as independent risk factors for the development and exacerbation of insulin resistance. The present review summarizes the evidence. We will start with a brief introduction to sleep and its disorders and then examine in succession the role of the three major types of sleep disturbances of modern society, namely insufficient sleep, poor sleep quality and/or insomnia and obstructive sleep apnoea. Insulin resistance is a hallmark of the polycystic ovary syndrome, the most common endocrine pathology in women, and the last section of this review will discuss the role of obstructive sleep apnoea in the insulin resistance and metabolic disturbances of polycystic ovary syndrome.     

Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea

The metabolic syndrome shows a variable prevalence in obstructive sleep apnoea (OSA), and its association with insulin resistance or excessive daytime sleepiness in OSA is unclear. This study assessed the following in consecutive patients with newly diagnosed OSA: 1) the prevalence of metabolic syndrome; and 2) its association with insulin resistance and daytime sleepiness. Metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria), insulin resistance (Homeostatic Model Assessment (HOMA) index, n = 288) and daytime sleepiness (Epworth Sleepiness Scale) were assessed in 529 OSA patients. The prevalence of metabolic syndrome was 51.2%, which increased with OSA severity. Each metabolic syndrome component correlated with apnoea/hypopnoea index, but only blood pressure retained significance after correction for confounders. Both obesity and OSA contributed to metabolic abnormalities, with different sex-related patterns, since diagnosis of metabolic syndrome was significantly associated with neck circumference, age, body mass index and lowest arterial oxygen saturation in males, and with age and arousal index in females. The number of metabolic syndrome components increased with HOMA index (p<0.001). Prevalence of sleepiness was the same in patients with and without metabolic syndrome. The metabolic syndrome occurs in about half of "real-life" OSA patients, irrespective of daytime sleepiness, and is a reliable marker of insulin resistance.     

Hypothalamische Entzündung und metabolisches Syndrom

Overweight and obesity are two key factors in development of the metabolic syndrome. In recent years the major focus was directed towards elucidating how impairment of the central nervous system affects food intake and the development of obesity and insulin resistance. It has been shown in animal models and in humans that overconsumption of an energy-dense, high-fat diet leads to fundamental structural and functional changes of hypothalamic nuclei which govern eating behavior. Several recent scientific studies suggested that these nutritionally induced hypothalamic effects and changes, i.e. apoptosis of hypothalamic neurons and glial cells and subsequent local inflammatory processes, modulate eating behavior and metabolism in a defined way paving the way for development of obesity and eventually also the metabolic syndrome. This article summarizes findings from current related studies, introduces some of the underlying molecular mechanisms and shows how this knowledge might be used to develop novel treatment options for patients suffering from obesity and the metabolic syndrome.     

代谢综合征与结直肠腺瘤的研究进展

近年许多研究表明代谢综合征与结直肠腺瘤关系密切。多项流行病学研究评估了肥胖、血糖异常、血脂异常和高血压等代谢综合征组分与结直肠腺瘤的风险。这种关系的潜在机制尚不清楚,胰岛素抵抗和慢性炎症是可能的影响因素。本文就代谢综合征与结直肠腺瘤的关系作一综述。