Diabetes and metabolic aspects of OSA.pdf

Chapter 12Diabetes and metabolic aspects of OSA J. C-M. Lam, M. M-S. Lui and M. S-M. Ip Summary Obstructive sleep apnoea (OSA) is increasingly recognised as a risk factor for cardiometabolic dysfunction. Obesity is the most common risk factor in OSA, and various obesity-related cardiometabolic disorders, including a spectrum of glucose disorders from insulin resistance to overt type 2 diabetes mellitus, hypertension, dyslipidaemia and the metabolic syndrome, have all been found to be highly associated with sleepdisordered breathing. Current evidence on the magnitude of the impact on ultimate morbidity or mortality attributable to OSA-induced metabolic dysfunction is scarce. Given the known pathophysiology of intermittent hypoxia and sleep disturbance/loss in OSA, it is postulated that OSA independently contributes towards metabolic dysfunction through various downstream intermediary pathways of sympathetic activation, neurohumoral changes, inflammation and oxidative stress. Human and animal/cell experiments are providing clues to these mechanistic pathways. Regardless of any independent role in the causation of metabolic dysfunction, awareness of the concurrence of OSA and metabolic disorders, and the modifying roles of diet and lifestyle behaviour on metabolic function cannot be over emphasised. Keywords: Glucose metabolism, lipid metabolism, metabolic function, metabolic syndrome, obesity, obstructive sleep apnoea Dept of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China. Correspondence: M.S-M. Ip, Room 409, 4/F., Professorial Block, Dept of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China, Email [email protected] Eur Respir Mon 2010. 50, 189–215. Printed in UK – all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024809 O bstructive sleep apnoea (OSA) is highly associated with cardiometabolic disorders [1, 2]. There is increasing evidence to suggest that OSA poses an independent risk for metabolic dysfunction [3] but, to date, the data remain controversial. Due to the common presence of obesity in those with OSA, it is not easy to irrefutably demonstrate independent effects of OSA on various metabolic derangements which are highly driven by obesity. Many epidemiological or clinical studies have shown that untreated OSA has an independent association with various 189 J. C-M. LAM ET AL. metabolic derangements, including impaired glucose tolerance/insulin resistance/diabetes mellitus (DM), dyslipidaemia and the metabolic syndrome. However, a causal role of OSA in metabolic dysfunction cannot be firmly established with data from cross-sectional studies, and definitive evidence requires longitudinal cohort studies and rigorously designed interventional trials. Other than causality, many further questions on clinical outcomes, which result from complex interactions of multiple biological and environmental factors, are also being pursued. In OSA, recurrent intermittent hypoxia-reoxygenation occurs during sleep, as well as disruption of sleep architecture, over a period of years. It is postulated that these direct pathophysiological consequences of sleep-disordered breathing (SDB) act as triggers for various pathological cascades which involve sympathetic over activity, neurohumoral activation, systemic inflammation and oxidative stress, which may individually, collectively or interactively lead to adverse cardiometabolic function [2–4]. These mediating mechanisms for metabolic dysfunction are being investigated through clinical and translational studies, as well as in vitro and in vivo experimental models of intermittent hypoxia or arousals [3–5]. This chapter will give a comprehensive review of the current state of knowledge of various metabolic aspects of OSA, focusing on glucose metabolism, lipid metabolism and obesity. OSA and impaired glucose metabolism DM is a metabolic disorder associated with long-term microvascular and macrovascular complications [6]. The International Diabetes Federation estimates that 246 million adults worldwide suffer from this chronic disease, the incidence of which is escalating with the pandemic of obesity, and it is expected to reach 380 million by the year 2025. DM accounts for 6% of the total global mortality, with 50% of DM-associated deaths being attributed to cardiovascular disease [7]. There is compelling evidence that OSA is highly associated with impaired glucose metabolism, in a spectrum of insulin resistance, glucose intolerance and type 2 DM (table 1) [8]. This association brings out further research questions of clinically relevant outcomes. Does OSA per se predispose to the development or aggravation of adverse glucose metabolism? If it does, is there any additional/synergistic burden on atherosclerosis and other cardiovascular complications seen in DM? Recent studies show that the prevalence of OSA in type 2 diabetic patients range from 23% to 75% in different ethnic groups [9], and such figures obviously implicate a significant magnification of any negative influence which OSA may have on glucose metabolism, no matter how small this may be in an individual. Table 1. Disease definitions of altered glucose metabolism Abnormal glucose metabolism Fasting plasma glucose o100 mg?dL-1 or 5.6 mmol?L-1 Impaired fasting glucose Fasting plasma glucose 100–125 mg?dL-1 or 5.6–6.9 mmol?L-1 Impaired glucose tolerance Oral glucose tolerance test is performed after fasting for at least 8 h, 2 h after drinking 75 g anhydrous glucose dissolved in water: 2 h post-load glucose 140–199 mg?dL-1 or 7.8–11.1 mmol?L-1 Diabetes Fasting plasma glucose o126 mg?dL-1 or 7 mmol?L-1 Or Symptoms of hyperglycaemia and random plasma glucose o200 mg?dL-1 or 11.1 mmol?L-1 Or 2-h plasma glucose o200 mg?dL-1 or 11.1 mmol?L-1 during an oral glucose tolerance test 190 OSA AND METABOLIC DYSFUNCTION Similarly. Our group has recently studied Chinese diabetics in Hong Kong. DM was found to be present in 30% of subjects while glucose intolerance affected another 30%. In a study of 129 Japanese middle-aged adults with OSA. and the presence of OSA in addition to obesity contributed further to the risk of DM [10]. was estimated to be .387).7 yrs [26]. defined as . subjects and methodology to investigate the relationship between OSA and glucose metabolism. However. which was much higher than that of 6% which was reported from their general population [17].23%.Cross-sectional/longitudinal studies on OSA and disorders of glucose metabolism Reported studies in the literature have used a variety of designs. and the frequency of DM and glucose intolerance was higher among patients with increasing severity of OSA [22]. or worse glycaemic control in those with established DM. OSA and type 2 DM Common occurrence of OSA in diabetic subjects or vice versa can be anticipated since both diseases share the same risk factor of obesity. Another Japanese study found that the prevalence of DM in 629 obstructive sleep apnoea syndrome (OSAS) patients was higher than that of the control group (25. . China. The very severe OSAS group (AHI o45 events?h-1) had significantly higher homeostasis model assessment for estimating insulin resistance (HOMA) than those with milder OSA and the control group [31]. but no independent increase in incident DM was found at 4 yrs follow-up [15]. rapid eye movement (REM) AHI and oxygen desaturation index. the prevalence of OSA.L. Male sex and AHI were identified to be the predictors of impaired glucose metabolism. Lam. Queen Mary Hospital. However. SAR. the Sleep Ahead Study from the USA reported that OSA (AHI o5 events?h-1) affected as many as 86% of very obese type 2 diabetic adults (mean body mass index (BMI) 36 kg?m-2) and increasing waist circumference was the predictor for OSA. in contrast to the US study [29]. Most of the recently published cross-sectional studies supported an independent association between OSA and disorders of glucose metabolism (table 2). LAM ET AL. Recently.10 events?h-1 oxygen saturation dips of o4% on overnight oximetry. recruited from a diabetic clinic in the USA also showed a very high prevalence of OSA (77%) [29]. the risk of DM was elevated two-fold in subjects with OSA (defined by an apopnoea/hyponoea index (AHI) o15 events?h-1) after adjustment for known confounders on cross-sectional analysis at baseline. 191 J. a sample of 60 type 2 diabetics with a mean BMI of 33. The risk was attenuated by effective continuous positive airway pressure (CPAP) treatment with mean duration of follow-up being 2. Studies reported from various countries have also addressed the occurrence of OSA in diabetic populations of different ethnicities.668 males with hypertension. Hong Kong. contrary to the findings for hypertension [30]. p. free of recent/unstable/severe organ damage such as renal failure.0. insulin or glycosylated haemoglobin (HbA1c) to the laborious hyperinsulinaemic euglycaemic clamp studies. C-M. The University of Hong Kong. the prevalence of moderate-to-severe OSA (AHI o20 events?h-1) was significantly higher in the diabetic group compared to the normoglycaemic group (36% versus 14%). In a Swedish cohort of 2. ranging from simple assays of blood glucose. In a UK study among 240 male subjects with type 2 DM recruited from a tertiary hospital centre and five primary care centres. and found an OSA (AHI o5 events?h-1) prevalence of . In the Wisconsin Sleep Cohort study (n51.9% versus 8.2%. stroke or cardiac events. we were unable to identify an independent association between severity of OSA and glycaemic control (HbA1c) (C.001). including AHI.8 kg?m-2 [28]. There is a spectrum of measurement tools for glucose metabolism. unpublished data). Apart from comorbid existence. The authors further demonstrated that measures of OSA severity. studies have attempted to address whether the presence of OSA would confer any independent risk of developing DM. a recent study including 544 nondiabetic subjects in the USA reported a dose– dependent relationship between the severity of OSA and the risk of developing incident DM.23% of males and 10% of females with type 2 DM. were positively correlated with increasing HbA1c levels after adjustment for confounders. 33 HbA1c OSA (. HOMA SDB was associated with insulin resistance independent of visceral obesity M AKINO [18] 25–28 192 . OGTT R ESNICK [13] OSA AND METABOLIC DYSFUNCTION Community-based 28–31 from the Sleep Heart Health Study. glucose and HbA1c AHI and minimum Sa.90% Sa. 4-yr followup in 987 subjects 29 S ULIT [16] 394 subjects from Cleveland Family Study 32 W EST [17] 240 diabetics from a hospital clinic and five primary care clinics in the UK Clinic-based. 2656 subjects from the USA 27 Self-report Severe OSA was more common in diabetic subjects Significant relationship between variables of SDB and fasting insulin. sex and habitus No independent relationship between incident diabetes mellitus and OSA at 4-yr follow-up OGTT Threshold dose response for measures of hypoxic stress (o2% time with . 116 hypertensive males with or without diabetes mellitus I P [11] M ESLIER [12] Clinic-based.O2) and glucose intolerance. adjusted OR 2.O2 are independent predictors of insulin resistance Both diabetes mellitus and IGT were more common in OSA subjects compared to non-apnoeic snorers Insulin sensitivity decreased with increasing severity of OSA Significant difference between diabetic and nondiabetic in RDI.O2 were associated with both fasting and 2-h glucose levels FG Diabetes mellitus was more common in OSA (AHI o15). CAI and periodic breathing Statistical significance was lost after adjustment for obesity P UNJABI [14] R EICHMUTH [15] Wisconsin Sleep Cohort. HOMA Degree of insulin resistance was independently associated with severity of OSA AHI and minimum Sa.90% Sa. 1387 subjects.11) after adjustment for age. 5874 subjects with or without diabetes mellitus Sleep Heart Health Study.6 OGTT. 491 27–31 males with or without OSA Fasting insulin.O2 dips?h-1 and HbA1c FG and insulin.10 dips?h-1 of o4% desaturation) was estimated to be present in 23% No correlation between number of Sa.O2 saturation.] Study sample Average Tools BMI assessing glucose metabolism 27–30 FG and insulin.28–4. 270 26 non-diabetic Chinese with or without OSA Clinic-based. HOMA FG and insulin. OR 2. HbA1c Findings E LMASRY [10] Population-based. 213 OSA subjects 29. Cross-sectional/longitudinal studies on sleep-disordered breathing (SDB) and glucose metabolism in adults First author [Ref. sleep time .3 (95% CI 1.Table 2. fasting insulin.] Study sample Average Tools BMI assessing glucose metabolism HOMA FG.5% had moderate OSA. C-M.Table 2. .86% had OSA with AHI 5 events?h-1. and pancreatic b-cell function FG An independent association between OSA and incident diabetes after mean duration of follow-up for 2. HOMA OGTT F OSTER [28] 306 subjects from 16 diabetes mellitus centres in the USA 36. 26–33 118 nondiabetic subjects with or without SDB 544 nondiabetics 33–34 from a sleep centre in the USA R ONKSLEY [27] Sleep clinic-based. Continued First author [Ref. 22. 67 nondiabetic males with or without OSA 29–31 P UNJABI [25] B OTROS [26] Population-based. glucose effectiveness. 23 42 with OSA and 52 without OSA.O2 was associated with decreased insulin sensitivity HOMA Insulin resistance was not associated with sleep apnoea severity after adjustment for obesity FSIVGTT SDB is associated with impairments in insulin sensitivity. 30. after adjusting for confounders Self-reported The prevalence of diabetes history of mellitus increased with diabetes increasing OSA severity Severe OSA was independently mellitus associated with diabetes mellitus exclusively in sleepy subjects HbA1c . 129 24–27 Japanese with OSA Insulin resistance correlated significantly with AHI FG and HOMA were significantly higher in those with OSA AHI was a predictor of number of metabolic syndrome parameters OSA was not associated with insulin resistance T HEORELL¨ W [23] H AGLO 400 females from a Swedish city 25–31 K APSIMALIS [24] Clinic-based.5 193 J. 2149 subjects 31 Diabetes mellitus and IGT were more common in those with severe OSA AHI was independently associated with diabetes mellitus and IGT OGTT AHI was associated with increased fasting and 2-h insulin levels after adjusting for confounders Low nocturnal minimal Sa.6% had severe OSA Waist circumference was a significant predictor of the presence of OSA FG. matched for age. BMI and visceral fat 40 obese OSA 30 40 obese non-OSA 29 40 non-obese control 21 Clinic-based.7 yrs. HOMA Findings P ELED [19] K ONO [20] S HARMA [21] T AMURA [22] Clinic-based. 98 with 25–31 suspected OSA 94 Japanese males. LAM ET AL. whereby only OSA subjects who had excessive daytime sleepiness but not the nonsleepy ones. The evidence for the presence of untreated OSA as a risk factor for poor glycaemic control is controversial.8 HbA1c Findings A RONSOHN [29] Clinic based. 33]. the overall higher rates of OSA in diabetics compared with the relevant general population were consistent [13. had worse insulin resistance compared to controls without OSA [35]. The presence of such pre-diabetic status provides an imperative opportunity to prevent the upcoming complications associated with the development of frank DM. Continued First author [Ref. Findings from a diabetic sample were in line. after adjustment for multiple confounders in stratified analyses [27]. duration of DM and antidiabetic medications which.656) found that respiratory disturbance index (RDI) and hypoxaemia were associated with severity of insulin resistance and glucose intolerance. if timely effective treatment can be implemented. 3. although the findings were inconsistent other studies [21. In a cohort of 400 Swedish females. OSA: obstructive sleep apnoea. notably lifestyle variations. In children.Table 2. These confounding factors are not easily controlled or adequately accounted for in statistical adjustments. should be closely titrated to the level of HbA1c as an index of therapeutic control. CAI: central apnoea index. theoretically. FG: fasting glucose. a gradual decrease in insulin sensitivity. sex. RDI: respiratory disturbance index.] Study sample Average Tools BMI assessing glucose metabolism 33. while the role of obesity is relatively minor as compared to adults. Sa. OGTT: oral glucose tolerance test. HbA1c: glycosylated haemoglobin. The Sleep Heart Health Study including a large sample of community-dwelling subjects not on any diabetic medications (n52. 12. The presence of excessive sleepiness has been suggested to be a phenotypic marker for the development of hypertension in OSA [34]. The association of OSA and glucose intolerance/insulin resistance has been consistently shown in numerous studies involving different ethnicities and study design [2. HOMA: homeostatic model assessment. AHI: apnoea/hypopnoea index. HOMA in subjects with OSA of moderate severity was higher compared to age and weight matched Caucasian control subjects [32]. OSA and glucose intolerance/insulin resistance Glucose intolerance is clinically managed as pre-diabetes while insulin resistance is one of the major pathophysiological phenomena leading to clinical DM. Similar associations independent of obesity were also observed in a few studies [11. 60 diabetic subjects 77% had OSA with AHI 5 events?h-1 Increasing OSA severity was associated with poorer glucose control. 27–29]. based on the glucose/insulin ratios before and after an oral glucose tolerance test. 17. OSA AND METABOLIC DYSFUNCTION Although the reported OSA prevalence among diabetics varied widely in the published studies. independent of confounders [23]. FSIVGTT: frequently sampled intravenous glucose tolerance test. 9]. Paediatric subjects with SDB have 194 . 19. Similar observation of the impact of sleepiness on glucose metabolism in OSA subjects has been reported. Diabetic control across individuals is well known to be subjected to many influencing factors. 20. BMI and waist circumference [14]. the presence of enlarged adenotonsillar tissue is conventionally considered as the major factor contributing to OSA.O2: arterial oxygen saturation. In a case–control study. was seen with increasing AHI. 24]. independent of age. after controlling for adiposity and other confounders BMI: body mass index. observing that the association between severe OSA and DM took place exclusively in sleepy patients. IGT: impaired glucose intolerance. C-M. children with SDB had a six-fold increased odds of metabolic syndrome compared to those without SDB. [55] used the short insulin tolerance test to measure insulin sensitivity in a randomised controlled trial of CPAP treatment involving 61 non-diabetic Chinese males with and without OSA. However.9 yrs [52]. was also reduced in those with moderate-to-severe OSA. There have been data to support an independent association between OSA and adverse glucose metabolism in children and adolescents [37–39]. In the Cleveland Cohort. The same group of investigators also found improvement in insulin sensitivity in diabetic OSA subjects with usage of CPAP for 3 months [43]. Another randomised controlled trial with two parallel treatment arms using therapeutic or sham CPAP for 3 months was conducted in diabetic males with OSA. about half of whom were obese. In adult studies. However. which reflect glucose utilisation in peripheral tissue in response to insulin. The latter finding suggested that insulin secretion may be affected by OSA. Other than a progressive reduction in insulin sensitivity with increasing severity of SDB. Treatment of OSA and insulin resistance/sensitivity Table 3 focuses on published studies in the past decade. and the severity of OSA was not a significant predictor of insulin resistance in another study involving non-obese children [41]. after adjusting for age. sex. This beneficial effect persisted at 3 months of CPAP treatment. despite a significant decrease in blood pressure [47]. and adequately powered randomised controlled trials have been scarce. and was more prominent in the non-obese subgroup with a mean BMI of 28 kg?m-2 [42]. the intervention was almost exclusively CPAP. In a randomised controlled crossover trial of 34 obese nondiabetic males with moderate-to-severe OSA. Such beneficial effects of CPAP were not seen in other prospective observational studies [46. Pancreatic b-cells. with a wide range of treatment durations of one night to 6 months. and insulin resistance improved with CPAP treatment for 3 months. respectively [48]. the epidemic of obesity is also increasingly affecting the paediatric population. LAM et al. although most of the studies were observational with small sample sizes. Using the hyperinsulinaemic euglycaemic clamp to evaluate insulin sensitivity. the disposition index. There have only been a few randomised controlled studies on the effects of CPAP treatment on insulin sensitivity/resistance in either diabetic or nondiabetic subjects. 54]. no change in fasting glucose levels or HOMA could be demonstrated with either therapeutic or sham CPAP for 6 weeks. In a study of 135 children from the USA. The frequently sampled intravenous glucose tolerance test was used to evaluate the dynamic relationship between insulin sensitivity and insulin secretion in 118 subjects with a range of SDB severity [25]. The improvement was sustained at further follow-up of nine subjects at 2. and evidence is increasing to support the growing importance of obesity as a causative factor of OSA [36]. insulin resistance and dyslipidaemia were determined primarily by the degree of adiposity rather than the severity of SDB among those with OSA [40]. ethnicity and pre-term status [39]. are also subject to the detrimental effects of sleep apnoea and intermittent hypoxia. A number of interventional studies have examined the effects of OSA treatment on glucose metabolism. while no response was seen in the nonsleepy group who had similar HOMA as the non-OSA controls at baseline [35]. Recently. Impact of intervention in OSA on glucose metabolism J.previously provided a desirable model for research on cardiometabolic effects of OSA. Most studies have focused on the impact of SDB on insulin sensitivity/resistance. 53. while adenotonsillectomy was the predominant treatment in children. a measure of pancreatic b-cell function. A Spanish group reported that sleepy OSA subjects were more resistant to insulin than nonsleepy OSA subjects at baseline. Again. 195 . no change was demonstrated in insulin sensitivity/resistance as measured by the hyperinuslinaemic euglycaemic clamp and HOMA. without obesity or established comorbidities as confounding factors. like any other tissues in the body. such findings were not consistently reported. CPAP for 2 days in 40 nondiabetic OSA males was shown to promptly improve insulin sensitivity. LAM ET AL. HbA1c for 2 days. 10 HOMA resistance after CPAP for irregular CPAP 12 weeks" # C OUGHLIN [47] RCT (crossover. No change after CPAP CPAP): 42 diabetic males hyperinsulinaemic for 3 months" with OSA euglycaemic clamp B ARCELO [35] 44 nondiabetic subjects HOMA Sleepy subjects had higher with OSA (22 with and 22 glucose/insulin level and without EDS matched for HOMA index compared with age.8¡1. 23 healthy CPAP for 3 months reduced controls insulin and HOMA index in patients with sleepiness.3%) 29 OSA subjects: 19 FG. Interventional studies about the effects of continuous positive airway pressure (CPAP) on glucose metabolism in adults First author [Ref. Retrospective study post-CPAP 7.7% 38 diabetic subjects HbA1c HbA1c decreased after CPAP for H ASSABALLA [45] and severe OSA .3¡1.4 months (baseline 7. but not in the nonsleepy group 14 subjects with severe CGMS Reduction of nocturnal glucose P ALLAYOVA [49] OSA and diabetes mellitus variability and improved overnight glucose control on CPAP 20 diabetic subjects CGMS Mean sleeping glucose D AWSON [50] with OSA decreased after treatment with CPAP for an average of 41 days No change in HbA1c 32 subjects with severe D ORKOVA [51] HOMA Compliant with CPAP OSA and metabolic (o4 h?night-1) for 8 weeks led to improved HOMA and global syndrome (16 compliant to CVD risk CPAP. fasting insulin. HbA1c.4%. BMI and OSA nonsleepy patients and controls severity).] H ARSCH [42] Design/sample Tools assessing glucose metabolism Hyperinsulinaemic euglycaemic clamp Findings Insulin sensitivity improved after CPAP for 2 days and after 3 months.Table 3. CPAP/ FG.9 yrs of clamp CPAP treatment 40 nondiabetic males with OSA 196 OSA AND METABOLIC DYSFUNCTION . HbA1c Post-prandial glucose improved B ABU [44] and OSA after CPAP for 3 months HbA1c also improved in those with HbA1c . but was significantly improved after 3 months Glycaemic control and leptin were unchanged after 3 months 24 diabetic subjects CGMS. 16 noncompliant) 9 nondiabetic Hyperinsulinaemic Improvement in insulin sensitivity S CHAHIN [52] subjects with OSA euglycaemic maintained after 2. CPAP/sham HOMA. more pronounced in non-obese subjects 9 obese diabetic Hyperinsulinaemic Insulin sensitivity was H ARSCH [43] males with OSA euglycaemic unchanged after CPAP clamp. No change in insulin T RENELL [46] regular CPAP. HOMA No change after CPAP sham CPAP): 34 nonfor 6 weeks" diabetic subjects with OSA W EST [48]# RCT (parallel. 13 months" non-obese controls CUHADAROGLU [54] 44 nondiabetic subjects HOMA Good CPAP compliance for 8 with moderate–severe weeks reduced leptin levels and OSA (31 compliant to cholesterol. lifestyle variations and the duration of DM. Data from paediatric subjects were also conflicting. those with SDB had increased sympathetic nervous system activity and nocturnal leptin levels but not worse insulin sensitivity. Interestingly. Treatment of OSA and glycaemic control in diabetes mellitus For studies involving subjects with established DM.] V GONTZAS [53] Design/sample Tools assessing glucose metabolism Findings 16 with OSA. but not insulin resistance RCT: 61 OSA subjects Short insulin Therapeutic nCPAP for 1 week L AM [55]# free of comorbid tolerance test. RCT: randomised controlled trial. Continued First author [Ref. CGMS: continuous glucose monitoring system. . the beneficial effect appeared to be more prominent and sustainable in those who were moderately obese by Asian ethnic criteria (mean BMI 28 kg?m-2) compared to the non-obese subjects. C-M. 15 FG.Table 3. LAM ET AL. while the beneficial effect on HbA1c was confined to those who had higher baseline HbA1c levels of . BMI: body mass index. and a few were retrospective analyses [44. Using a similar glucose monitoring system. The small numbers of subjects and suboptimal compliance to CPAP posed further limitations in the interpretation of findings in some of these studies. HbA1c. improved glucose disappearance conditions (31 CPAP. #: indicates an RCT. nCPAP: nasal CPAP. ": negative findings. 30 HOMA rate. the study included few nonobese subjects. such as anti-diabetic medications. and reduction of nocturnal glucose variability with improved overnight glucose control during CPAP treatment was demonstrated [49]. compared to the sham CPAP group. 45. In contrast to the findings of a German group [42]. and the improvement was sham CPAP) maintained after 12 weeks of CPAP in those with moderate obesity No change in HOMA" OSA: obstructive sleep apnoea. HOMA: homeostatic model assessment. Using the continuous glucose monitoring system to measure interstitial glucose in 24 diabetic subjects with OSA. 49. 14 obese subjects with severe OSA and type 2 DM were evaluated. and increased insulin CPAP) secretion capacity. EDS: excessive daytime sleepiness.7% [44]. no change in HOMA was seen. 197 J. glycosylated haemoglobin. and CPAP treatment for 3 months in 11 subjects reduced noradrenalin and leptin levels but did not change the insulin sensitivity index [59]. However. HOMA No change after CPAP for 3 obese controls. 58]. 50]. limiting further definitive conclusion. insulin. two other studies did not find any difference in insulin resistance before and after adenotonsillectomy [57. In contrast to such positive findings. FG: fasting glucose. In 34 children with the metabolic syndrome. Most of these studies were observational. CVD: cardiovascular disease. A brisk increase in fasting levels of insulin and insulin/glucose ratio after adenotonsillectomy for OSA was seen only in the obese children but not the non-obese group [56]. the effect of OSA treatment on glycaemic control may be highly influenced by other factors. a significant reduction in post-prandial interstitial glucose was seen after using CPAP for 3 months. highlighting the impact of difference in evaluative tools on study results. Therapeutic CPAP for 1 week improved insulin sensitivity. one in three adults is overweight and one in 10 is obese [61]. is an established risk factor for a number of cardiometabolic diseases including hypertension and type 2 DM. Both gaining and losing weight are associated with deterioration and improvement of sleep apnoea. Therefore. and it is one defining component of the metabolic syndrome [62]. a 2. another study also reported a reduction in mean sleeping glucose after treatment with CPAP for an average of 41 days. mean BMI was significantly reduced from 56¡1 kg?m-2 to 38¡1 kg?m-2 and mean RDI from 51¡4 to 15¡2 events?h-1.3 months treatment duration needed for assessing any change in HbA1c levels [50]. their minimum oxygen saturation. Given the impact of obesity on OSA. while there was no change in HbA1c.10 kg weight gain over the follow-up period had a five-fold risk of increasing their AHI to . 70]. sleep efficiency and REM latency improved [73]. Weight loss should be recommended for all overweight or obese patients with sleep apnoea. The overall incidence of moderate-to-severe OSA over a 5-yr period was 11. Both the Wisconsin Sleep Cohort Study [68] and the Sleep Heart Health Study [70] demonstrated the impact of changes in body weight on the ‘‘natural course’’ of sleep apnoea. Obesity. a serotonin/noradrenalin re-uptake inhibitor. By 2015. and is becoming a global health burden this century [60]. In a prospective study of 101 OSA patients who underwent bariatric surgery for weight reduction.10. Average CPAP usage was . daytime sleepiness in the therapeutic CPAP group was significantly improved. In contrast. surgically and medically induced weight loss can significantly improve obesity-related OSA. obesity is a major risk factor for the development of OSA in adults [63–67]. in particular visceral obesity. The only randomised controlled study in diabetic OSA subjects reported to date found no change in either HbA1c or insulin sensitivity in those receiving therapeutic CPAP compared to those receiving sham CPAP for 3 months [48]. which is equivalent to the combined populations of China. has also been shown to lead to improvement in OSA severity and daytime sleepiness with weight reduction [74]. Europe and the USA [61]. the average change of BMI in the 1. as its beneficial effects embrace other obesity-related health problems. In addition. but despite the less than ideal CPAP compliance.1% in males and 4. However.9% in females. it is generally accepted that global rise in obesity has a major impact on the prevalence and severity of sleep apnoea. which was probably not an appropriate outcome measure to use. the prevalence of OSA was reported as 45% [73]. Regardless of ethnicity. and this could have reduced any positive effect on metabolic control. The significant weight reduction in the bariatric surgery group was accompanied by marked improvement in sleep apnoea symptoms and a lower 2-yr incidence of type 2 DM and hypertriglyceridaemia.729 subjects in the bariatric surgical group was -9. In a study of OSA subjects with the metabolic syndrome. In a case–control longitudinal study of obese subjects in Sweden. The rise in obesity coincides with increased modernisation and a worldwide explosion in the availability of highly processed foods.7¡5 kg?m-2 compared to 0¡3 kg?m-2 for the 1. Alternatively. Males with . Sibutramine for 6 months was also efficacious 198 OSA AND METABOLIC DYSFUNCTION . sibutramine. WHO estimates the number of overweight adults will increase to 2. given the . Weight reduction also has many beneficial effects on the metabolic profile in OSA subjects. it is well appreciated that it takes time to lose weight and only a minority of patients will successfully maintain it. The World Health Organization (WHO) declared obesity as the alarming ‘‘globesity’’ problem in 2009.748 subjects in the control group [75]. for the same degree of weight gain in females. respectively [69.In keeping with this finding.5-fold risk of a similar increment in their severity of sleep apnoea was seen [70]. Preoperative BMI correlated with the severity of OSA after adjustment for age and sex.4 h?night-1 in both treatment groups. an anti-obesity drug. notably cardiometabolic diseases [71. 72]. compliant CPAP therapy for 2 months reduced insulin resistance (HOMA) [51]. OSA and obesity Obesity is highly prevalent in modern western societies. At a median of 11 months after bariatric surgery. and it was also estimated to increase the risk of sleep apnoea by . At present.to 14-fold in children [68].15 events?h-1.3 billion worldwide. this hypothesis remains to be proven. A more recently recognised consequence of obesity and insulin resistance is nonalcoholic fatty liver disease (NAFLD) [87. especially in terms of its pathogenetic role in metabolic dysfunction.4¡13. DM. and that it is a metabolically active tissue which participates in many systemic metabolic processes [82]. when assessed at 17. In a multicentre study of atherosclerosis of different ethnic groups. It has been hypothesised that a stress reaction activating the hypothalamic-pituitary-adrenal axis leading to release of cortisol and other hormones may trigger mechanisms generating insulin resistance and preferential abdominal fat accumulation [78]. 96–98. and the prevalence of dyslipidaemia was similar among different ethnic groups [91]. By inducing neurohumoral changes.6¡34 to 13. along with reduction of RDI by 30% as well as improvement in insulin resistance and lipid profile [76]. insulin resistance and lipid peroxidation [84–86]. Obesity/visceral obesity are the most common risk factors in OSA. There is a high prevalence of dyslipidaemia in the general population. It is possible that hypoxia and sleep interruption in OSA would contribute to changes in body composition over time [53]. It is now recognised that adipose tissue is much more than a warehouse of energy. thus. 79. hypertriglyceridaemia and hypertension have been identified as risk factors for the progression of NAFLD [87]. The increased obesity would in turn result in progressive deterioration of sleep apnoea. 20 (80%) of these subjects fulfilled the criteria of the metabolic syndrome. which probably make a substantial contribution to the adverse lipid profile.800 subjects aged 45–84 yrs had dyslipidaemia. Insulin resistance is thought to be a driving force of abnormal lipid metabolism through promoting increased assembly and secretion of very LDL-cholesterol and triglycerides via the complex post-translational regulation pathway of apolipoprotein B. age . Adiposity in OSA carries another dimension.7¡10 months after the surgery [77]. and this was drastically reduced to three (12%) subjects at the post-operative reassessment. laparoscopic adjustable gastric banding resulted in an average weight loss of 44. ranging from steatosis without inflammation to nonalcoholic steatohepatitis and liver cirrhosis [88. OSA and lipid metabolism Abnormal lipid metabolism is a major risk factor in the development of coronary artery disease. possibly through promoting the mediators of atherosclerosis: endothelial dysfunction. there is suggestive evidence of an independent contribution of OSA towards insulin resistance and hence potentially. Tissue hypoxia in OSA may also contribute to the progression of NAFLD. insulin resistant. . 92–94. Dyslipidaemia is present in many OSA subjects. Their fasting plasma glucose. 199 J.in reducing weight in 93 nondiabetic males with moderate-to-severe OSA. and an independent association between the two was observed in a number of studies (table 4) [22. the downstream sequelae of dyslipidaemia. C-M. Obesity. 89]. and inflammation is well known to be in close association with cardiometabolic dysfunction. At baseline. LAM ET AL.3% of 6. and thus sleep apnoea and metabolic disturbances may run into a vicious cycle [81]. and the increased ratios of low-density lipoprotein (LDL)-cholesterol/HDL-cholesterol and total cholesterol/HDL-cholesterol are indicative of increased cardiovascular risk [90]. which in turn leads to reduced HDL-cholesterol levels [102]. but as previously presented.45 yrs. OSA subjects tend to be obese and. mean BMI was 52. It was recently proposed that adipose tissue hypoxia may be a trigger of inflammation in obesity [83]. 101].7 kg?m-2. 80]. 88]. OSA could promote the development of central obesity directly or indirectly through increasing insulin resistance [53. serum insulin and triglycerides were decreased and high-density lipoprotein (HDL)-cholesterol was significantly increased. in a spectrum of disease severity. Some theoretical mechanisms have been postulated for the association between OSA and metabolic processes that influence fat accumulation and deposition. 29.9¡22 kg and a significant fall in AHI from 61. As yet. although there is cumulating evidence to support some of the individual mechanisms in this complex network. In an Australian study of 25 severely obese patients with moderate-to-severe OSA. OSA: BMI.5): lipoprotein A group 2 compared to n532 controls separately Controls (AHI . TG. S HARMA [21] No difference females HDL-C. n530 Apo-B. TG. TG HDL-C was inversely Health Study: females: n54991 related to AHI. TG TC/HDL-C Controls: n530 TG decreased Matched for age. males TC. Elevated TC. while longitudinal RDI in quartiles TG was positively study associated with AHI. TC/ between OSA Apnoeic obese. HDL-C. sex. lipoprotein A. in those aged . independent of obesity. males LDL-C Severe OSA had B ARCELO [93] CPAP treatment Severe OSA: n514 Lipid abnormal lipid for 1 yr Healthy controls: n513 peroxidation peroxidation and Matched for age improved with CPAP Sleep Heart USA. Apo-AI. TG. males and TC. C AN [97] Group 1 (AHI o5): LDL-C. diabetes and treatment n586 lipid-lowering drugs HDL-C increased significantly by 5. HDL-C. CPAP treatment Non-OSA: n539 and its concentration was increased after treatment Case–control Australia. HDL-C. significantly after sex and menopausal treatment status Case–control: Spain. CPAP/BiPAP After treatment. OSA subjects had M CA RDLE [32] OSA: n521 LDL-C. TG increased TC and Non-OSA: n521 LDL-C Matched for age. TG TC was significantly R OBINSON [95] from two RCTs: OSA: n5220 reduced within CPAP 4 weeks of CPAP: n5108 group but no CPAP versus Sham CPAP: n5112 difference between sham CPAP two groups Longitudinal Germany. LDL-C. Apo-B in group 1/ Group 2 (AHI . AHI was associated B ORGEL [96] study: females LDL-C with HDL-C after 6 months of OSA: n5366 adjusting for age. TG.Table 4. males TC. LDL-C. males and TC. OSA subjects had males and females LDL-C. TC/ increased TG and OSA: n530 HDL-C. HDL-C. LDL-C/ subjects and obese OSA: n540 HDL-C controls 200 OSA AND METABOLIC DYSFUNCTION .8% after treatment Cross-sectional Turkey. Chinese TC.1): n530 Cross-sectional: Japan: n5194 LPL LPL concentration I ESATO [98] 3 months of OSA: n5155 decreased with AHI. HDL-C. Clinical studies of obstructive sleep apnoea (OSA) and lipid metabolism First author [Ref. BMI and current smoking status Case–control India. HDL-C. BMI. males TC.] Ip [92] Design Case–control: CPAP treatment for 6 months Sample Lipid profile Findings Hong Kong.65 yrs only Pooled data UK. males and N EWMAN [94] TC. TG and Apo-B D ORKOVA [51] Cross-sectional: Slovakia. TC. Apo-B levels were reduced CPAP treatment OSA: n529 after treatment for 3 months CPAP: continuous positive airway pressure. TC: total cholesterol. Continued First author [Ref. which are more atherogenic. Data on effects of treatment of OSA on lipid metabolism has been controversial. Apo-AI: apolipoprotein AI. and increased oxidation of lipids. and there were both positive [55. Chinese TC. controls: of metabolic n540 abnormalities Cross-sectional Hong Kong. HDL-C. males and LDL-C. COMONDORE No improvement [100] crossover: females LDL-C within CPAP group 4 weeks of Moderate-to-severe or between two CPAP versus no OSA: n513 groups treatment Longitudinal Hong Kong. HDL oxidised LDL in OSA OSA: n5128 dysfunction. T AN [99] Increased HDL males and females: LDL-C. LDL-C: low-density lipoprotein cholesterol. In a randomised study with a cross-over design for 6 weeks of therapeutic versus sham CPAP treatment. TG. dysfunction and n5210 Apo-B. 92. males RCT with TC. TG.4 h?night-1): n516 RCT with Canada. there were no changes in the lipid profiles compared to sham CPAP but the short duration of treatment may be a limiting factor [47]. Apo-B compliance group and for 8 weeks Severe OSA: n532 TC. males and TC. HDL-C: high-density lipoprotein cholesterol. TG. In another study of CPAP treatment for 8 weeks.] Design Sample Lipid profile Findings Non-apnoeic obese. TC. TG: triglycerides. AHI: apnoea/hypopnoea index. OSA may also affect the quality of the lipids. 98] and negative [48. HDL-C. TG. TG and Apo-B L AM [55] study: males LDL-C. triglycerides and apolipoprotein B levels without significant changes in BMI [55]. lipid profile improved significantly in those with good CPAP compliance of o4 h?night-1 compared to those using CPAP for less time [51]. Apo AI. TAN et al. has been demonstrated in OSA and was taken to reflect a state of enhanced oxidative stress [86]. C-M.Table 4. In a prospective longitudinal follow-up. No improvement C OUGHLIN [47] OSA: n535 crossover: LDL-C after treatment CPAP: n535 6 weeks of Sham CPAP: n534 CPAP versus sham CPAP TC. we observed that 3 months of CPAP treatment significantly reduced total cholesterol. TG. improved within CPAP CPAP treatment females Apo AI. 201 J. BMI: body mass index. and the severity of OSA accounted for 30% of the variance in HDL dysfunction in sleep apnoea. 95. HDL-C. 100] studies (table 4). . LDL-C and Good CPAP compliance Apo-B improved (o4 h?night-1): n516 Poor compliance between two groups (. HDL-C. LPL: lipoprotein lipase. LAM ET AL. TG. Chinese TC. [99] have also shown that HDLcholesterol in OSA subjects was less effective in preventing LDL oxidation. RDI: respiratory disturbance index. BiPAP: bilevel positive airway pressure. HDL-C. 51. RCT: randomised controlled trial. 93. Obesity was the controls: n540 major determinant Normal weight. subjects Controls: n582 oxidised LDL AHI was the major determinant of HDL dysfunction UK. Apo-B: apolipoprotein B. the metabolic syndrome was found to be a better predictor of nocturnal desaturation than AHI in those with sleep apnoea [117]. in a study of 195 patients with cardiovascular diseases. 202 OSA AND METABOLIC DYSFUNCTION . it has been proposed that OSA may well be considered as a manifestation of an expanded metabolic syndrome [81. This finding may indicate that treatment of OSA could be effective in reducing inflammatory responses and ameliorating lipid metabolism. and 3 months of CPAP treatment significantly increased its concentration [98]. It was reported that enzyme levels decreased with the severity of OSA. with insulin resistance as the central pathophysiological feature. Interestingly. In an interventional study of 38 OSA patients with metabolic syndrome. and was labelled as ‘‘syndrome X’’ [106]. hypercholesterolaemia and lipid peroxidation developed in the absence of obesity. the metabolic syndrome is associated with cardiovascular mortality [108]. Reduced lipoprotein lipase activity provokes early inflammatory responses central to atherosclerosis. who were expectedly obese. those who suffered from OSA and the metabolic syndrome had higher levels of carotid intima media thickness. metabolic syndrome is defined as a group of inter-related risk features of metabolic origin. 33. they are also well known cardiovascular risk factors. The cause of the syndrome remains unknown. The frequent clustering of OSA and metabolic syndrome or its components has led to the description of ‘‘syndrome Z’’ [121]. There is increasing interest in exploring the relationship between sleep apnoea and the metabolic syndrome and its defining components [109–111]. Data from animal models of intermittent hypoxia also support a causal role of OSA in the pathogenesis of abnormal lipid metabolism. 104]. and led to lipid peroxidation in the liver in a dose-dependent manner [103. Not surprisingly. OSA and metabolic syndrome The metabolic syndrome was first described as a cluster of metabolic abnormalities. and the degree of metabolic dysregulation was dependent on the severity of the hypoxic stimulus [105]. and this was consistent across different ethnic samples (table 5) [19. Many studies have investigated the relationship of OSA and individual cardiometabolic parameters. In another experiment of lean mice exposed to different levels of intermittent hypoxia (21%. OSA was present in 68% of them. Therefore. insulin resistance. and lipoprotein lipase is one of the step-limiting enzymes. including hypertension. given its defining components which are all risk factors for atherosclerosis. 112–120]. In a study of subjects with newly diagnosed metabolic syndrome. Currently. Given these closely interwoven relationships between OSA and the metabolic syndrome or its defining components. presence of OSA was associated with higher fasting glucose level and glycosylated haemoglobin but not with BMI [119]. Insulin resistance and central obesity have been acknowledged as key driving forces for the metabolic syndrome and.Lipid metabolism involves a series of enzymatic interactions. 120]. In a cross-sectional study of 81 patients with multiple comorbidities recruited from a heart institute. a figure which was similar to that for other established individual components of metabolic syndrome [119]. carotid-femoral pulse wave velocity and carotid diameter compared to those without metabolic syndrome [123]. dyslipidaemia and obesity/visceral obesity as its major components [107]. In subjects with metabolic syndrome who were not yet overtly diabetic. Snoring or OSA has been shown to be strongly associated with the metabolic syndrome. independently. OSA also demonstrated independent associations with many of the other individual components as well as the syndromic entity in many of these studies (table 5). 10% and 5% oxygen nadir) for 4 weeks. The syndrome is associated with a three-fold and two-fold increase in type 2 DM and cardiovascular diseases respectively. Exposure to intermittent hypoxia in genetically obese ob/ob mice models caused an upregulation of lipid biosynthesis and dyslipidaemia. It is logical to surmise that the coexistence of OSA and the metabolic syndrome may lead to worse cardiometabolic outcomes than either condition alone. A recent study from India suggested sequential development of metabolic syndrome and OSA [122]. the concurrent presence of metabolic syndrome in OSA patients may have an additive effect on atherosclerosis. UK. males: n535 SBP. insulin.7–9. males and females: HDL-C. Obese controls: n543 HDL-C. WC. not improve MS but SBP. OSA (21) Severe OSA: n553 serum amyloid Severe OSA (30) Clinic-based BMI. insulin. MBP 6 weeks of CPAP HOMA-IR. Mild OSA The prevalence of Snorers: n59 FBS.2) OSA (58) OSA was associated with L AM [113] Mild OSA all metabolic components (54) in MS Moderate MS: OR 5. SBP. OSA (80) CPAP treatment did C OUGHLIN [47] UK. and BRS in those CPAP: n518+17 TC. DBP. Moderate with OSA severity Moderate OSA: n527 TG. WC. n579 HDL-C. males and females: DBP.6) Clinic-based WC. had a OSA: n589 higher AHI but did not increase the risk of cardiovascular events after 22¡10 months of CPAP treatment compared to those OSA subjects without MS Clinic-based BMI. on CPAP for Sham CPAP: n517+17 LDL-C. MS in males: OR 5. FBS and MS were females younger. . TC. FBS.9 (95% CI 2–17.1 Controls: 89 TC.Table 5.5 h?night-1 P ELED [19] Clinic based: n598 BMI. RCT with crossover insulin. HDL-C. (37) independent Obese OSA: n538 FBS.8) Clinic-based BMI. TC/HDL Community-based BMI. DBP. MBP. OSA (73) Insulin resistance was not G RUBER [114] UK. males and TG. SBP. (22) In severe OSA: OSA: n5819 HOMA-IR.] C OUGHLIN [112] Sample Metabolic parameters MS (%) Findings OSA (87) OSA was associated with Non-OSA multiple (35) metabolic risk factors MS: OR 9. TG o3. TG. LAM ET AL. OSA (53) Subjects with OSA A MBROSETTI [111] Italy. BP. TC. Chinese DBP. n5907 FBS. HDL-C.6–31.1 (95% CI 2. OSA: n595 FBS Non-OSA: n5160 203 J. TG. C-M. SBP. Controls with severity of OSA females. Clinical studies of obstructive sleep apnoea (OSA) and metabolic syndrome (MS) First author [Ref. HDL-C. TC. (11) MS increased Mild OSA: n59 TC. Obese OSA: n561 HOMA-IR. LDL-C.9–66. WC. (95% CI 2. insulin. Hs-CRP. TG Controls associated with OSA. Hong Kong. DBP. of obesity Obese controls: n541 HOMA-IR MS: OR 5. LDL-C. WC. males DBP. FBS.3 (95% CI OSA (56) 3. TG.26) Severe OSA (70) Non-OSA (21) Clinic-based BMI. HDL-C. males and SBP. WC. WC. insulin.03–9. b-cell MS in females: OR 14 function (95% CI 2. LDL-C. BRS. n5255 TC/HDL-C.7) LDL-C. OSA (50) MS was associated S ASANABE [115] Japan. insulin. TC. males and DBP. SBP. FBS with OSA+MS: n520 Longitudinal study of 1 yr CPAP treatment Clinic-based BMI. HDL-C.5–28) Mild-to-moderate OSA: OR 1. AHI . HDL-C. females LDL-C. MBP (77) Hospitalised inpatients WC. TC. BNP Non-MS: n5139 Clinic-based WC. TG.6–6) MS was a strong predictor of nocturnal desaturations . Non-OSA USA. insulin. Non-OSA: n530 IMT. DBP. FBS. SBP. TG. leptin. (46) females: n598 LDL-C.8 (95% CI 0. CD AHI was the predictor of the number of metabolic components in MS OSA was associated with multiple cardiometabolic risk factors MS was associated with OSA severity O KTAY [118] MS was associated with OSA severity Severe OSA: OR 8. HOMA-IR MS (%) OSA (43) Non-OSA (16) Findings MS may constitute an additive cardiovascular risk in OSA K ONO [20] M CA RDLE [32] P ARISH [116] OSA AND METABOLIC DYSFUNCTION T KACOVA [109] T AKAMA [117] Clinic-based OSA (19) Case–control Non-OSA Japan.4 (95% CI 2. FBS.] S HIINA [110] Sample Clinic-based Japan. OSA (63) Brazil. BMI TNF-a. AHI o5 to AHI . Controls: n521 IGF-1.30 (51) AHI o5 to .Table 5. OSA (77) with cardiovascular SBP.5: n528 Apo-AI. TC. urine status catecholamines Clinic-based MS. SBP.5 Slovakia. LDL-C. TC. MS: n556 HDL-C. OSA: n521 HDL-C. HDL-C. SFA. TG. males and TG. OSA (63) with MS: n581 TC. . TG. TG. Apo-B. DBP. SBP.90% in patients with cardiovascular diseases The prevalence of MS was reduced by 45% after 1 yr of CPAP treatment D RAGER [119] OSA increased cardiovascular risk in patients with MS 204 . Controls (4) Australia. TG. males and females DBP. (40) n5228 diabetes OSA: n5146 Non-OSA: n582 Clinic-based BMI. TC. PWV. WC. SBP.30: n539 FBS. WC. males and females: n5184 OSA: n594 Non-OSA: n590 Metabolic parameters BMI. SBP. LDL-C. TC. brachial– ankle PWV BMI. VFA. Continued First author [Ref. diseases: n5195 FBS. Turkey. MBP. OSA: n551 HDL-C. HDL-C. FBS. AHI o30 AHI o30: n531 DBP. OSA (23) Case–control DBP. males FBS. BMI and VFA Clinic-based BMI. Matched for age. WC. males and females: hyperlipidaemia. and current smoking adiponectin. males (4) OSA: n542 Non-OSA: n552 Matched for age. BMI. OSA (60) Retrospective review hypertension. DBP. BMI. 6–6. short sleep duration was associated with significant weight gain. SFA: subcutaneous fat accumulation. SBP: systolic blood pressure. independent of sympathetic and neuroendocrine activation MS In mild OSA: OR 4. the prevalence of metabolic syndrome was decreased by 45% [118]. HDL-C. irrespective of SDB.8) WC. Continued First author [Ref. Hs-CRP: highsensitivity C-reactive protein. There are epidemiological and clinical data to suggest that short sleep duration may lead to weight gain [125–127]. HOMA. In a retrospective study of 1. Apo-B: apolipoprotein B. . Apo-AI: apolipoprotein AI. particularly in the young age groups [126]. insulin. TNF-a: tumour necrosis factor-a. These data give rise to the attractive notion that early CPAP treatment in otherwise ‘‘healthy’’ OSA subjects may help to prevent the development of overt cardiometabolic diseases.3) Ms in moderate/ severe OSA: OR 5. urinary cortisol and adrenalin RCT: randomised controlled trial.25) [127]. IMT: carotid intima–media thickness. C-M. FBS. sleep fragmentation or even sleep loss. LAM ET AL. BMI: body mass index.] N IETO [120] Sample Community-based USA. BP: blood pressure. which act in parallel as metabolic counterparts for body weight control through different mechanisms on feeding. 20 of whom were evaluated after receiving 1 yr of CPAP treatment. Sleep duration is believed to regulate leptin and ghrelin levels in humans. TC: total cholesterol. and the overweight (BMI o25) and obese patients (BMI o30) slept less than the patients with normal weight (BMI .0 (95% CI 2. OSA (32) DBP. females were shown to sleep more than males. provided that the baseline sleeping duration was 8 h as self-reported in their sleep questionnaires [125]. DBP: diastolic blood pressure.Table 5. males and females: n5546 OSA: n5 253 Non-OSA: n5293 Metabolic parameters MS (%) Findings OSA is associated with the prevalence of MS. In addition. HDL-C: high-density lipoprotein cholesterol. BNP: brain natriuretic peptide. CPAP: continuous positive airway pressure. BMI. may adversely affect glucose metabolism [128. 129]. WC: waist circumference. MBP: mean BP. TG. In the Wisconsin Sleep cohort study. Sleep duration and sleep quality play a major role in hormonal regulation in human physiological systems. Mechanistic links between OSA and metabolic disorders Sleep fragmentation and altered sleep architecture OSA is characterised by disrupted sleep architecture with repetitive arousals. in a recent systematic review of 36 observational studies in children and adults from 1966 to January 2007. AHI: apnoea/hypopnoea index. a 3-h sleep loss was associated with a 4–5% weight gain. In the Massachusetts Male 205 J. Evidence from epidemiological and in-laboratory studies suggest that sleep loss or poor sleep quality.2–8. resulting in daytime sleepiness. IGF-1: insulin growth factor-1. FBS: fasting blood sugar. HOMA-IR: homeostasis model assessment for estimating insulin resistance. TG: triglycerides.000 patients from four different family practice groups in the USA. wakefulness and energy expenditure [124]. SBP. LDL-C: lowdensity lipoprotein cholesterol. PWV: pulse wave velocity. VFA: visceral fat accumulation.3 (95% CI 3. CD: carotid diameter. although it is still a long way before this can be proven. BRS: baroreceptor sensitivity. Mechanically induced sleep fragmentation can also produce acute adverse effects on glucose homeostasis. In addition to the reduction in sleep duration.90% O2 saturation) was the strongest polysomnographic index associated with glucose intolerance [16]. it is proposed that the associated sleep loss and sleep disturbance may be one primary trigger for promoting obesity and DM in OSA. 143] In a Canadian study of 10 young healthy males subjected to intermittent hypoxia for 6 h?day-1 for 4 days to simulate the situation in OSA. an appetite-stimulating peptide. without a change in sleep duration. Reduced insulin sensitivity. the disturbance in oxygenation in OSA is unique with recurrent intermittent hypoxia and reoxygenation alternating in rapid cycles. might also adversely affect the glucose metabolism. In leptin-deficient obese mice. increased production of reactive oxygen species without a compensatory increase in anti-oxidant activity was found [144]. The same predisposition to glucose intolerance and DM were observed across various ethnic populations in a number of prospective studies investigating the adverse impact from shortened sleep duration or poor sleep quality for 7–32 yrs [132–136]. measures of hypoxic stress (time spent with . All-night suppression of slow-wave sleep. The decrease in the anorexigenic hormone leptin and increase in ghrelin. possibly through complex hormonal regulations in the body. most commonly reduced slow-wave sleep.398 communitydwelling Japanese followed up for a median of 3 yrs showed that those with moderate-to-severe nocturnal intermittent hypoxia (3% oxygen saturation dips o15 per hour) on pulse oximetry at baseline had a 1. was shown to result in dramatic worsening in insulin sensitivity in young healthy adults [137]. was also demonstrated in lean mice exposed to intermittent hypoxia. the culprit of oxidative stress. repeated exposure to intermittent hypoxia (30 s hypoxia alternating with 30 s normoxia for 12 h?day-1) for 12 weeks led to a time-dependent increase in fasting insulin level and deterioration in glucose tolerance and insulin resistance [146].Aging Study. were associated with higher prevalence of impaired glucose tolerance and DM [131]. after thorough adjustment for multiple confounders [145]. and this developed independent of autonomic nervous system activity [147]. respectively. In the Sleep Heart Health Study (n51. A study of 4. with a discernible dose–response relationship of incident DM with the desaturation index. suggested that sleep loss could predispose to overeating with consequent weight gain and dysregulation of glucose metabolism [139]. In the Cleveland Family study. with adjustment for body habitus and AHI.10–15 yrs of follow-up [130]. certain changes in sleep architecture in OSA.486). males free of DM at baseline had a two and three-fold increase in the risk of developing incident diabetes for both short and long sleep duration. The rapid reoxygenation of transiently ischaemic tissues could lead to tissue injury and release of reactive oxygen species. With these data. including reduced insulin sensitivity and impaired insulin secretion [140]. The pathogentic role of OSA in metabolic derangements has also been investigated using animal/ cell models of intermittent hypoxia. after . self-reported sleep durations of f6 h or o9 h. It has also been shown in the laboratory that sleep curtailment for 2 days led to adverse glucose profile and increase in appetite for high caloric carbohydrates when compared to extended sleep [138]. An in vitro study of the effect of 206 . Most epidemiological studies were based on subjective self-reporting of sleep duration and quality. compared to the groups with normal and o6 h sleep duration [136]. from inflammatory cells [142. the risk of having DM was three-fold higher in individuals with f5 h sleep duration. In contrast to other chronic respiratory diseases. In a population study using objective measurement of sleep duration by in-laboratory monitoring. as measured by hyperinsulinemic euglycemic clamp. OSA AND METABOLIC DYSFUNCTION Intermittent hypoxia and oxidative stress Increased oxidative stress has been shown to be a key mechanism for insulin resistance and diabetes [141]. The intermittent hypoxia and resultant oxidative stress have been proposed to be a pathogenetic link between OSA and disturbance of glucose homesostasis [142].7-fold risk of incident DM compared to those without significant hypoxia. Many of these markers have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and. LAM ET AL. 207 .intermittent hypoxia on b-cells showed that it led to increased b-cell proliferation and cell death. Inflammatory cytokines. a marker of inflammation. Some of these have been investigated in relation to OSA. play a role in the mediation of vascular inflammation and adverse glucose metabolism [149. 160]. and these markers were positively correlated with excessive daytime sleepiness [152]. and the cell death response appeared to be due to oxidative stress [148]. this mechanism may be involved in the development of insulin-resistant state in obesity [154]. HeLa cells exposed to intermittent hypoxia demonstrated selective activation of the pro-inflammatory transcription factor nuclear factor-kB whereas the adaptive regulator hypoxia inducible factor (HIF)-1 was not activated. Its levels are decreased with obesity and visceral obesity. Adiponectin is a key promoter of insulin sensitivity. 161]. is a potential pathogenetic mechanism promoting inflammation and leading to sleep apnoea [152]. Adipocyte-derived hormones/proteins Fat tissue produces many biomolecules which have regulatory effects on various metabolic processes [80]. In relation to inflammation and insulin resistance. 158]. C-M. the regulation of inflammatory and adaptive pathways on hypoxic stimulation was mapped [153]. LUI et al. Overall. 150]. [156] have demonstrated an independent association between severity of OSA and elevated CRP level in males free of comorbidities. it has been suggested that visceral obesity and insulin resistance. creating a state of insulin resistance. suggesting that selective activation of inflammatory over adaptive pathways with intermittent hypoxia might be an important molecular mechanism of cardiometabolic dysfunction in OSA. after careful consideration of the confounding effect from visceral obesity measured by magnetic resonance imaging. in both human and murine adipocytes. in addition. hypoadiponectinaemia was significantly associated with visceral adiposity and insulin resistance but not with any of the sleep indices [18]. In a Japanese study of 200 male patients with cardiovascular diseases. Elevated levels of C-reactive protein (CRP). correlated positively with worsening HOMA in a general population followed up for 5 yrs [155]. hypoxia inhibits insulin signalling through HIF transcription factor expression. probably related to the confounding effects of obesity and presence of comorbidities. 157. Intermittent hypoxia and sleep fragmentation in OSA are postulated to be triggers of the cascade of inflammation in adipose tissue and vascular compartment and. and it has anti-inflammatory and protective vascular effects [81. In a study using an in vitro model of intermittent hypoxia/ reoxygenation and HeLa cells. Hypoadiponectinaemia has been demonstrated to be closely associated with endothelial dysfunction and cardiovascular morbidity in clinical studies [159. pose deleterious effects on the cardiovascular system [151]. the data are still controversial regarding the role of OSA. such as tumour necrosis factor-a and interleukin (IL)-6 were found to be elevated in subjects with OSA. in the generation of the inflammatory state seen in OSA subjects. The association between OSA and an elevated level of CRP has been investigated in many studies with conflicting results. Studies on serum adiponectin levels in OSA have been controversial [18. Inflammation and cytokine release Many cytokines. 32. independent of obesity. an array of inflammatory products may be released. J. In another study of 68 subjects with no known comorbidity undergoing sleep studies. It has been postulated that OSA may down regulate adiponectin expression in adipose tissue. In addition. Hence. thus. in particular adipokines. Adiponectin Adiponectin is produced in white adipose tissues and is found in high circulating levels in humans. and inhibiting glucose transport as well as inducing IL-6 secretion. suggesting that sympathetic activation is a pathway through which SDB may contribute to the determination of adiponectin levels. 171–173]. LAM et al. and the level of these hormones may be affected in OSA. Alterations of the neuroendocrine and autonomic system Neuroendocrine factors and autonomic activity are important in glucose regulation [84]. but most obese subjects have high circulating leptin levels. The evidence for enhanced leptin resistance attributable to OSA is controversial. indicating that obesity is a leptin-resistant state [166]. energy intake and expenditure. In animal experiments. Leptin is functionally a ‘‘thrifty’’ hormone. In a recent large population-based genetic study. Increased serum leptin levels were related to endothelial dysfunction [168. the impact was more pronounced in patients with a BMI . OSA AND METABOLIC DYSFUNCTION Adipocyte fatty acid-binding protein Fatty acid-binding proteins are a family of small intracellular lipid-binding proteins. there was no difference in adiponectin levels between OSA and BMI-matched non-OSA subjects. hyperglycaemia. LAM et al. Leptin levels increase exponentially with increasing fat mass [167]. In a case– control study of 28 otherwise healthy subjects with moderate OSA. 170]. Adipocyte fatty acid-binding protein (A-FABP) is abundantly present in adipocytes and regulates intracellular fatty acid trafficking and glucose metabolism [177]. the lack of control group is a major limitation due to potentially significant confounding effect from changes in body weight. Several observational studies showed a reduction of serum leptin levels after weeks or months of CPAP treatment [92. Visceral obesity accounted for the increase in leptin levels in OSA in some studies [32. though significant differences were seen in other metabolic parameters [32]. However. [162] found that serum adiponectin levels was suppressed in OSA and independently associated with sympathetic activity and severity of sleep apnoea.OSA subjects actually had a higher level of adiponectin compared to BMI-matched non-OSA subjects. there was a reduced risk for hypertriglyceridaemia. This was supported by previous work which showed that adiponectin gene expression in pre-adipocyte cell lines was severely suppressed by the synthetic b-adrenergic agonist isoproterenol [163]. while others reported that serum leptin levels were significantly higher in OSA subjects than in BMI-matched controls [92. insulin resistance and the metabolic syndrome have been reported in cross-sectional and longitudinal studies [180]. Heightened sympathetic activity has been convincingly 208 . 175] and in one study. 179]. The use of CPAP treatment for 2–3 months has been reported to increase serum adiponectin levels significantly in OSA subjects in a few observational studies [164. A study found that leptin levels correlated with cardiac sympathetic activity in OSA subjects [174]. Leptin Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate neuroendocrine function. type 2 DM and coronary artery disease in subjects who carried a functional genetic variant of the A-FABP gene that resulted in reduced adipose tissue A-FABP gene expression [181]. and its level significantly correlated with insulin resistance. 165] but not in a randomised controlled study of diabetics with OSA [48]. These findings suggested that A-FABP levels may be upregulated by severe OSA and may be one of the mediators which propagate metabolic dysfunction in sleep apnoea. the apparent functions of A-FABP were mediation of insulin resistance independent of the effects of obesity and the promotion of atherosclerosis [178. Positive associations between serum A-FABP levels and adiposity. leptin may contribute to the pathogenesis of cardiovascular complications in OSA.30 [176]. but their blood samples were taken in a nonfasting state in the evening [161]. 169]. [182] demonstrated that A-FABP level was elevated in severe OSA subjects compared to non-OSA or less severe OSA subjects. thus. Adrenalin and cortisol are counter-regulatory hormones of insulin. Australia). 373: 82–93. intermittent hypoxaemia and sleep fragmentation have been identified as major triggering factors that lead to downstream pathophysiological cascades which may result in metabolic dysfunction. 2. M. although. S-M. Floras JS. which supported a working group meeting of the International Diabetes Panel on OSA and diabetes mellitus in February 2007 (Sydney. LAM ET AL. Obesity/ visceral obesity. Eur Respir J 2007. Lam has received a university grant for HK$150. Eur Respir J 2009. M-S. 15: 207–217. Conclusions Many OSA subjects have an adverse metabolic profile. Obstructive sleep apnea and metabolic syndrome: alterations in glucose metabolism and inflammation. C-M. Apart from disease states. . and this occurred independent of autonomic nervous system activity [147]. There is also substantial evidence that activation of the sympathetic nervous system and increased adrenalin levels promote insulin resistance and are associated with abnormalities in glucose metabolism [184–186]. sleep-disordered breathing and metabolic consequences. Ip has received reimbursement from ResMed for attending a symposium. and from Celki for attending the Sleep Course organised by the University of Hong Kong in 2008 and 2009. hormones and binding proteins believed to be players in the pathogenesis of cardiometabolic complications at the molecular level. CPAP therapy was reported to alleviate the disordered adrenocorticotrophic hormone and cortisol secretory dynamics in subjects with moderate-to-severe OSA [187]. 2009). South Korea. 4. Studies of cortisol secretion in OSA have shown inconsistent results [3]. In the complex human biological system. J. ´ vy P. Recently. 2009). Ip was a working group member invited by the International Diabetes Foundation and has also received a fee from Respironics for speaking at a satellite symposium (World Congress of Sleep Apnea. the role of this mechanistic pathway in the metabolic regulation in OSA has not been well studied. is likely to be multifactorial and inter-crossed with various feedback signals. References 1. It has been demonstrated that intermittent hypoxia resulted in impaired insulin sensitivity in lean mice. and may act in concert with OSA in the generation of metabolic aberrations. Management Committee of EU COST ACTION B26. Tasali E. Lam received sponsorships for travel and accommodation to overseas conferences in 2008 (for APSR from GSK) and 2009 (for the World Congress of Sleep Apnea from Celki and for ERS from Boehringer Ingelheim). Le 34: 243–260. Current data suggest that SDB may contribute to adverse glucose and lipid metabolism. inflammatory cytokines and oxidative stress mediators. C-M. M. adipokines. 209 J. Proc Am Thorac Soc 2008. 29: 156–178. Bonsignore MR. Bradley TD. which contributes significantly to the elevation of blood pressure [183]. Ip MS. He has also received a grant of HK$800. are significant sources of inflammatory biomarkers.000 from GSK for a clinical randomised controlled trial on asthma in 2008. Obstructive sleep apnoea and its cardiovascular consequences. McNicholas WT. but pieces of the huge jigsaw puzzle of OSA and metabolic function are just beginning to appear. In relation to OSA. Sleep. present in the majority of OSA subjects.000 for a clinical trial on patients with diabetes mellitus and OSA from the University of Hong Kong in 2008. 3. body metabolism is also influenced by endogenous factors of genetics and exogenous factors of lifestyle behaviour.demonstrated in OSA. Statement of Interest J. Lancet 2009. the regulation of hormones. C-M. South Korea. Seoul. Bonsignore MR. 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