Diabetes and Metabolic Aspects of OSA PDF

Chapter 12
Diabetes 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 msmip@hkucc.hku.hk
Eur Respir Mon 2010. 50, 189215. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024809
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
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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 [24]. 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 [35]. 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 100125 mg?dL-1 or 5.66.9 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 140199 mg?dL-1 or 7.811.1 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
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OSA AND METABOLIC DYSFUNCTION
Cross-sectional/longitudinal studies on OSA and disorders of glucose metabolism

Reported studies in the literature have used a variety of designs, subjects and methodology to investigate the relationship between OSA and glucose metabolism. There is a spectrum of measurement tools for glucose metabolism, ranging from simple assays of blood glucose, insulin or glycosylated haemoglobin (HbA1c) to the laborious hyperinsulinaemic euglycaemic clamp studies. Most of the recently published cross-sectional studies supported an independent association between OSA and disorders of glucose metabolism (table 2).
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. Apart from comorbid existence, studies have attempted to address whether the presence of OSA would confer any independent risk of developing DM, or worse glycaemic control in those with established DM. In the Wisconsin Sleep Cohort study (n51,387), 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, but no independent increase in incident DM was found at 4 yrs follow-up [15], contrary to the findings for hypertension [30]. However, 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. The risk was attenuated by effective continuous positive airway pressure (CPAP) treatment with mean duration of follow-up being 2.7 yrs [26]. In a study of 129 Japanese middle-aged adults with OSA, DM was found to be present in 30% of subjects while glucose intolerance affected another 30%, and the frequency of DM and glucose intolerance was higher among patients with increasing severity of OSA [22]. Male sex and AHI were identified to be the predictors of impaired glucose metabolism. 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 (25.9% versus 8.2%; p,0.001). 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]. Studies reported from various countries have also addressed the occurrence of OSA in diabetic populations of different ethnicities. In a Swedish cohort of 2,668 males with hypertension, 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%), and the presence of OSA in addition to obesity contributed further to the risk of DM [10]. In a UK study among 240 male subjects with type 2 DM recruited from a tertiary hospital centre and five primary care centres, the prevalence of OSA, defined as .10 events?h-1 oxygen saturation dips of o4% on overnight oximetry, was estimated to be ,23%, which was much higher than that of 6% which was reported from their general population [17]. Recently, 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. Similarly, a sample of 60 type 2 diabetics with a mean BMI of 33.8 kg?m-2 [28], recruited from a diabetic clinic in the USA also showed a very high prevalence of OSA (77%) [29]. The authors further demonstrated that measures of OSA severity, including AHI, rapid eye movement (REM) AHI and oxygen desaturation index, were positively correlated with increasing HbA1c levels after adjustment for confounders. Our group has recently studied Chinese diabetics in Hong Kong, and found an OSA (AHI o5 events?h-1) prevalence of ,23% of males and 10% of females with type 2 DM, free of recent/unstable/severe organ damage such as renal failure, stroke or cardiac events. However, in contrast to the US study [29], we were unable to identify an independent association between severity of OSA and glycaemic control (HbA1c) (C.L. Lam, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China; unpublished data).
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Table 2. Cross-sectional/longitudinal studies on sleep-disordered breathing (SDB) and glucose metabolism in

adults
First author [Ref.]
Study sample
Average Tools BMI assessing glucose metabolism 2730 FG and insulin, HbA1c
Findings
E LMASRY [10]
Population-based, 116 hypertensive males with or without diabetes mellitus
I P [11]
M ESLIER [12]
Clinic-based, 270 26 non-diabetic Chinese with or without OSA Clinic-based, 491 2731 males with or without OSA
Fasting insulin, HOMA FG and insulin, OGTT
R ESNICK [13]
Community-based 2831 from the Sleep Heart Health Study, 5874 subjects with or without diabetes mellitus Sleep Heart Health Study, 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, glucose and HbA1c AHI and minimum Sa,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, sleep time ,90% Sa,O2 saturation, CAI and periodic breathing Statistical significance was lost after adjustment for obesity
P UNJABI [14]
R EICHMUTH [15]
Wisconsin Sleep Cohort, 1387 subjects, 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, 213 OSA subjects
29.6
OGTT, HOMA Degree of insulin resistance was independently associated with severity of OSA AHI and minimum Sa,O2 were associated with both fasting and 2-h glucose levels FG Diabetes mellitus was more common in OSA (AHI o15), OR 2.3 (95% CI 1.284.11) after adjustment for age, 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 ,90% Sa,O2) and glucose intolerance; adjusted OR 2.33 HbA1c OSA (.10 dips?h-1 of o4% desaturation) was estimated to be present in 23% No correlation between number of Sa,O2 dips?h-1 and HbA1c FG and insulin, HOMA SDB was associated with insulin resistance independent of visceral obesity
M AKINO [18]
2528
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Table 2. Continued First author [Ref.] Study sample Average Tools BMI assessing glucose metabolism HOMA FG, HOMA Findings
P ELED [19] K ONO [20]
S HARMA [21]
T AMURA [22]
Clinic-based, 98 with 2531 suspected OSA 94 Japanese males, 23 42 with OSA and 52 without OSA, matched for age, BMI and visceral fat 40 obese OSA 30 40 obese non-OSA 29 40 non-obese control 21 Clinic-based, 129 2427 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
2531
K APSIMALIS [24]
Clinic-based, 67 nondiabetic males with or without OSA
2931
P UNJABI [25]
B OTROS [26]
Population-based, 2633 118 nondiabetic subjects with or without SDB 544 nondiabetics 3334 from a sleep centre in the USA
R ONKSLEY [27]
Sleep clinic-based, 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,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, glucose effectiveness, and pancreatic b-cell function FG An independent association between OSA and incident diabetes after mean duration of follow-up for 2.7 yrs, 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 .86% had OSA with AHI 5 events?h-1, 30.5% had moderate OSA, 22.6% had severe OSA Waist circumference was a significant predictor of the presence of OSA
FG, fasting insulin, HOMA OGTT
F OSTER [28]
306 subjects from 16 diabetes mellitus centres in the USA
36.5
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Table 2. Continued First author [Ref.] Study sample Average Tools BMI assessing glucose metabolism 33.8 HbA1c Findings
A RONSOHN [29]
Clinic based, 60 diabetic subjects
77% had OSA with AHI 5 events?h-1 Increasing OSA severity was associated with poorer glucose control, after controlling for adiposity and other confounders
BMI: body mass index; OSA: obstructive sleep apnoea; FG: fasting glucose; HbA1c: glycosylated haemoglobin; HOMA: homeostatic model assessment; OGTT: oral glucose tolerance test; FSIVGTT: frequently sampled intravenous glucose tolerance test; AHI: apnoea/hypopnoea index; Sa,O2: arterial oxygen saturation; IGT: impaired glucose intolerance; RDI: respiratory disturbance index; CAI: central apnoea index.
Although the reported OSA prevalence among diabetics varied widely in the published studies, the overall higher rates of OSA in diabetics compared with the relevant general population were consistent [13, 17, 2729]. The evidence for the presence of untreated OSA as a risk factor for poor glycaemic control is controversial. Diabetic control across individuals is well known to be subjected to many influencing factors, notably lifestyle variations, duration of DM and antidiabetic medications which, theoretically, should be closely titrated to the level of HbA1c as an index of therapeutic control. These confounding factors are not easily controlled or adequately accounted for in statistical adjustments.
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. The presence of such pre-diabetic status provides an imperative opportunity to prevent the upcoming complications associated with the development of frank DM, if timely effective treatment can be implemented. The association of OSA and glucose intolerance/insulin resistance has been consistently shown in numerous studies involving different ethnicities and study design [2, 3, 9]. The Sleep Heart Health Study including a large sample of community-dwelling subjects not on any diabetic medications (n52,656) found that respiratory disturbance index (RDI) and hypoxaemia were associated with severity of insulin resistance and glucose intolerance, independent of age, sex, BMI and waist circumference [14]. In a casecontrol study, HOMA in subjects with OSA of moderate severity was higher compared to age and weight matched Caucasian control subjects [32]. In a cohort of 400 Swedish females, a gradual decrease in insulin sensitivity, based on the glucose/insulin ratios before and after an oral glucose tolerance test, was seen with increasing AHI, independent of confounders [23]. Similar associations independent of obesity were also observed in a few studies [11, 12, 19, 20, 33], although the findings were inconsistent other studies [21, 24]. The presence of excessive sleepiness has been suggested to be a phenotypic marker for the development of hypertension in OSA [34]. Similar observation of the impact of sleepiness on glucose metabolism in OSA subjects has been reported, whereby only OSA subjects who had excessive daytime sleepiness but not the nonsleepy ones, had worse insulin resistance compared to controls without OSA [35]. Findings from a diabetic sample were in line, observing that the association between severe OSA and DM took place exclusively in sleepy patients, after adjustment for multiple confounders in stratified analyses [27]. In children, the presence of enlarged adenotonsillar tissue is conventionally considered as the major factor contributing to OSA, while the role of obesity is relatively minor as compared to adults. Paediatric subjects with SDB have
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previously provided a desirable model for research on cardiometabolic effects of OSA, without obesity or established comorbidities as confounding factors. However, the epidemic of obesity is also increasingly affecting the paediatric population, and evidence is increasing to support the growing importance of obesity as a causative factor of OSA [36]. There have been data to support an independent association between OSA and adverse glucose metabolism in children and adolescents [3739]. In the Cleveland Cohort, children with SDB had a six-fold increased odds of metabolic syndrome compared to those without SDB, after adjusting for age, sex, ethnicity and pre-term status [39]. However, such findings were not consistently reported. In a study of 135 children from the USA, about half of whom were obese, insulin resistance and dyslipidaemia were determined primarily by the degree of adiposity rather than the severity of SDB among those with OSA [40], and the severity of OSA was not a significant predictor of insulin resistance in another study involving non-obese children [41]. Most studies have focused on the impact of SDB on insulin sensitivity/resistance, which reflect glucose utilisation in peripheral tissue in response to insulin. Pancreatic b-cells, like any other tissues in the body, are also subject to the detrimental effects of sleep apnoea and intermittent hypoxia. 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]. Other than a progressive reduction in insulin sensitivity with increasing severity of SDB, the disposition index, a measure of pancreatic b-cell function, was also reduced in those with moderate-to-severe OSA. The latter finding suggested that insulin secretion may be affected by OSA.
Impact of intervention in OSA on glucose metabolism

J. C-M. LAM ET AL.
A number of interventional studies have examined the effects of OSA treatment on glucose metabolism, although most of the studies were observational with small sample sizes, and adequately powered randomised controlled trials have been scarce. In adult studies, the intervention was almost exclusively CPAP, with a wide range of treatment durations of one night to 6 months, while adenotonsillectomy was the predominant treatment in children.
Treatment of OSA and insulin resistance/sensitivity

Table 3 focuses on published studies in the past decade. Using the hyperinsulinaemic euglycaemic clamp to evaluate insulin sensitivity, CPAP for 2 days in 40 nondiabetic OSA males was shown to promptly improve insulin sensitivity. This beneficial effect persisted at 3 months of CPAP treatment, and was more prominent in the non-obese subgroup with a mean BMI of 28 kg?m-2 [42]. The improvement was sustained at further follow-up of nine subjects at 2.9 yrs [52]. The same group of investigators also found improvement in insulin sensitivity in diabetic OSA subjects with usage of CPAP for 3 months [43]. A Spanish group reported that sleepy OSA subjects were more resistant to insulin than nonsleepy OSA subjects at baseline, and insulin resistance improved with CPAP treatment for 3 months, while no response was seen in the nonsleepy group who had similar HOMA as the non-OSA controls at baseline [35]. Such beneficial effects of CPAP were not seen in other prospective observational studies [46, 53, 54].
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. In a randomised controlled crossover trial of 34 obese nondiabetic males with moderate-to-severe OSA, no change in fasting glucose levels or HOMA could be demonstrated with either therapeutic or sham CPAP for 6 weeks, despite a significant decrease in blood pressure [47]. Another randomised controlled trial with two parallel treatment arms using therapeutic or sham CPAP for 3 months was conducted in diabetic males with OSA. Again, no change was demonstrated in insulin sensitivity/resistance as measured by the hyperinuslinaemic euglycaemic clamp and HOMA, respectively [48]. Recently, LAM et al. [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.
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Table 3. Interventional studies about the effects of continuous positive airway pressure (CPAP) on glucose
metabolism in adults
First author [Ref.] 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, more pronounced in non-obese subjects 9 obese diabetic Hyperinsulinaemic Insulin sensitivity was H ARSCH [43] males with OSA euglycaemic unchanged after CPAP clamp, HbA1c for 2 days, but was significantly improved after 3 months Glycaemic control and leptin were unchanged after 3 months 24 diabetic subjects CGMS, HbA1c Post-prandial glucose improved B ABU [44] and OSA after CPAP for 3 months HbA1c also improved in those with HbA1c .7% 38 diabetic subjects HbA1c HbA1c decreased after CPAP for H ASSABALLA [45] and severe OSA ,4 months (baseline 7.81.4%, Retrospective study post-CPAP 7.31.3%) 29 OSA subjects: 19 FG, fasting insulin, No change in insulin T RENELL [46] regular CPAP, 10 HOMA resistance after CPAP for irregular CPAP 12 weeks" # C OUGHLIN [47] RCT (crossover, CPAP/ FG, HOMA No change after CPAP sham CPAP): 34 nonfor 6 weeks" diabetic subjects with OSA W EST [48]# RCT (parallel, CPAP/sham HOMA, HbA1c, 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, BMI and OSA nonsleepy patients and controls severity), 23 healthy CPAP for 3 months reduced controls insulin and HOMA index in patients with sleepiness, 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, 16 noncompliant) 9 nondiabetic Hyperinsulinaemic Improvement in insulin sensitivity S CHAHIN [52] subjects with OSA euglycaemic maintained after 2.9 yrs of clamp CPAP treatment
40 nondiabetic males with OSA
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Table 3. Continued First author [Ref.] V GONTZAS [53] Design/sample Tools assessing glucose metabolism Findings
16 with OSA; 15 FG, insulin, HOMA No change after CPAP for 3 obese controls; 13 months" non-obese controls CUHADAROGLU [54] 44 nondiabetic subjects HOMA Good CPAP compliance for 8 with moderatesevere weeks reduced leptin levels and OSA (31 compliant to cholesterol, and increased insulin CPAP) secretion capacity, but not insulin resistance RCT: 61 OSA subjects Short insulin Therapeutic nCPAP for 1 week L AM [55]# free of comorbid tolerance test, improved glucose disappearance conditions (31 CPAP, 30 HOMA rate, 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; RCT: randomised controlled trial; EDS: excessive daytime sleepiness; BMI: body mass index; HbA1c; glycosylated haemoglobin; CGMS: continuous glucose monitoring system; FG: fasting glucose; HOMA: homeostatic model assessment; CVD: cardiovascular disease; nCPAP: nasal CPAP. #: indicates an RCT; ": negative findings.
Data from paediatric subjects were also conflicting. 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]. In contrast to such positive findings, two other studies did not find any difference in insulin resistance before and after adenotonsillectomy [57, 58]. In 34 children with the metabolic syndrome, those with SDB had increased sympathetic nervous system activity and nocturnal leptin levels but not worse insulin sensitivity, and CPAP treatment for 3 months in 11 subjects reduced noradrenalin and leptin levels but did not change the insulin sensitivity index [59].
Treatment of OSA and glycaemic control in diabetes mellitus

For studies involving subjects with established DM, the effect of OSA treatment on glycaemic control may be highly influenced by other factors, such as anti-diabetic medications, lifestyle variations and the duration of DM. Most of these studies were observational, and a few were retrospective analyses [44, 45, 49, 50]. The small numbers of subjects and suboptimal compliance to CPAP posed further limitations in the interpretation of findings in some of these studies. Using the continuous glucose monitoring system to measure interstitial glucose in 24 diabetic subjects with OSA, a significant reduction in post-prandial interstitial glucose was seen after using CPAP for 3 months, while the beneficial effect on HbA1c was confined to those who had higher baseline HbA1c levels of .7% [44]. Using a similar glucose monitoring system, 14 obese subjects with severe OSA and type 2 DM were evaluated, and reduction of nocturnal glucose variability with improved overnight glucose control during CPAP treatment was demonstrated [49].
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Therapeutic CPAP for 1 week improved insulin sensitivity, compared to the sham CPAP group. Interestingly, no change in HOMA was seen, highlighting the impact of difference in evaluative tools on study results. In contrast to the findings of a German group [42], 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. However, the study included few nonobese subjects, limiting further definitive conclusion.
In keeping with this finding, another study also reported a reduction in mean sleeping glucose after treatment with CPAP for an average of 41 days, while there was no change in HbA1c, which was probably not an appropriate outcome measure to use, given the ,3 months treatment duration needed for assessing any change in HbA1c levels [50]. In a study of OSA subjects with the metabolic syndrome, compliant CPAP therapy for 2 months reduced insulin resistance (HOMA) [51]. 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]. Average CPAP usage was ,4 h?night-1 in both treatment groups, and this could have reduced any positive effect on metabolic control, but despite the less than ideal CPAP compliance, daytime sleepiness in the therapeutic CPAP group was significantly improved.
OSA and obesity

Obesity is highly prevalent in modern western societies, and is becoming a global health burden this century [60]. The World Health Organization (WHO) declared obesity as the alarming globesity problem in 2009. The rise in obesity coincides with increased modernisation and a worldwide explosion in the availability of highly processed foods. At present, one in three adults is overweight and one in 10 is obese [61]. By 2015, WHO estimates the number of overweight adults will increase to 2.3 billion worldwide, which is equivalent to the combined populations of China, Europe and the USA [61]. Obesity, in particular visceral obesity, is an established risk factor for a number of cardiometabolic diseases including hypertension and type 2 DM, and it is one defining component of the metabolic syndrome [62]. Regardless of ethnicity, obesity is a major risk factor for the development of OSA in adults [6367], and it was also estimated to increase the risk of sleep apnoea by ,10- to 14-fold in children [68]. Both gaining and losing weight are associated with deterioration and improvement of sleep apnoea, respectively [69, 70]. 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. The overall incidence of moderate-to-severe OSA over a 5-yr period was 11.1% in males and 4.9% in females. Males with .10 kg weight gain over the follow-up period had a five-fold risk of increasing their AHI to .15 events?h-1. In contrast, for the same degree of weight gain in females, a 2.5-fold risk of a similar increment in their severity of sleep apnoea was seen [70]. Given the impact of obesity on OSA, it is generally accepted that global rise in obesity has a major impact on the prevalence and severity of sleep apnoea. Weight loss should be recommended for all overweight or obese patients with sleep apnoea, as its beneficial effects embrace other obesity-related health problems, notably cardiometabolic diseases [71, 72]. However, it is well appreciated that it takes time to lose weight and only a minority of patients will successfully maintain it. In a prospective study of 101 OSA patients who underwent bariatric surgery for weight reduction, the prevalence of OSA was reported as 45% [73]. Preoperative BMI correlated with the severity of OSA after adjustment for age and sex. At a median of 11 months after bariatric surgery, mean BMI was significantly reduced from 561 kg?m-2 to 381 kg?m-2 and mean RDI from 514 to 152 events?h-1. In addition, their minimum oxygen saturation, sleep efficiency and REM latency improved [73]. Alternatively, an anti-obesity drug, sibutramine, a serotonin/noradrenalin re-uptake inhibitor, has also been shown to lead to improvement in OSA severity and daytime sleepiness with weight reduction [74]. Therefore, surgically and medically induced weight loss can significantly improve obesity-related OSA. Weight reduction also has many beneficial effects on the metabolic profile in OSA subjects. In a casecontrol longitudinal study of obese subjects in Sweden, the average change of BMI in the 1,729 subjects in the bariatric surgical group was -9.75 kg?m-2 compared to 03 kg?m-2 for the 1,748 subjects in the control group [75]. 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. Sibutramine for 6 months was also efficacious
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in reducing weight in 93 nondiabetic males with moderate-to-severe OSA, along with reduction of RDI by 30% as well as improvement in insulin resistance and lipid profile [76]. In an Australian study of 25 severely obese patients with moderate-to-severe OSA, mean BMI was 52.7 kg?m-2, laparoscopic adjustable gastric banding resulted in an average weight loss of 44.922 kg and a significant fall in AHI from 61.634 to 13.413, when assessed at 17.710 months after the surgery [77]. Their fasting plasma glucose, serum insulin and triglycerides were decreased and high-density lipoprotein (HDL)-cholesterol was significantly increased. At baseline, 20 (80%) of these subjects fulfilled the criteria of the metabolic syndrome, and this was drastically reduced to three (12%) subjects at the post-operative reassessment. Some theoretical mechanisms have been postulated for the association between OSA and metabolic processes that influence fat accumulation and deposition. It is possible that hypoxia and sleep interruption in OSA would contribute to changes in body composition over time [53]. 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]. By inducing neurohumoral changes, OSA could promote the development of central obesity directly or indirectly through increasing insulin resistance [53, 79, 80]. The increased obesity would in turn result in progressive deterioration of sleep apnoea, and thus sleep apnoea and metabolic disturbances may run into a vicious cycle [81]. As yet, this hypothesis remains to be proven, although there is cumulating evidence to support some of the individual mechanisms in this complex network. Adiposity in OSA carries another dimension, especially in terms of its pathogenetic role in metabolic dysfunction. It is now recognised that adipose tissue is much more than a warehouse of energy, and that it is a metabolically active tissue which participates in many systemic metabolic processes [82]. It was recently proposed that adipose tissue hypoxia may be a trigger of inflammation in obesity [83], and inflammation is well known to be in close association with cardiometabolic dysfunction, possibly through promoting the mediators of atherosclerosis: endothelial dysfunction, insulin resistance and lipid peroxidation [8486]. A more recently recognised consequence of obesity and insulin resistance is nonalcoholic fatty liver disease (NAFLD) [87, 88]. Obesity, age .45 yrs, DM, hypertriglyceridaemia and hypertension have been identified as risk factors for the progression of NAFLD [87]. Tissue hypoxia in OSA may also contribute to the progression of NAFLD, in a spectrum of disease severity, ranging from steatosis without inflammation to nonalcoholic steatohepatitis and liver cirrhosis [88, 89].
OSA and lipid metabolism

Abnormal lipid metabolism is a major risk factor in the development of coronary artery disease, and the increased ratios of low-density lipoprotein (LDL)-cholesterol/HDL-cholesterol and total cholesterol/HDL-cholesterol are indicative of increased cardiovascular risk [90]. There is a high prevalence of dyslipidaemia in the general population. In a multicentre study of atherosclerosis of different ethnic groups, 29.3% of 6,800 subjects aged 4584 yrs had dyslipidaemia, and the prevalence of dyslipidaemia was similar among different ethnic groups [91]. Dyslipidaemia is present in many OSA subjects, and an independent association between the two was observed in a number of studies (table 4) [22, 9294, 9698, 101]. Obesity/visceral obesity are the most common risk factors in OSA, which probably make a substantial contribution to the adverse lipid profile. 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, which in turn leads to reduced HDL-cholesterol levels [102]. OSA subjects tend to be obese and, thus, insulin resistant, but as previously presented, there is suggestive evidence of an independent contribution of OSA towards insulin resistance and hence potentially, the downstream sequelae of dyslipidaemia.
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Table 4. Clinical studies of obstructive sleep apnoea (OSA) and lipid metabolism First author [Ref.] Ip [92] Design Casecontrol: CPAP treatment for 6 months Sample Lipid profile Findings
Hong Kong, Chinese TC, HDL-C, OSA subjects had males and females LDL-C, TC/ increased TG and OSA: n530 HDL-C, TG TC/HDL-C Controls: n530 TG decreased Matched for age, BMI, significantly after sex and menopausal treatment status Casecontrol: Spain, 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, males and N EWMAN [94] TC, HDL-C, TG HDL-C was inversely Health Study: females: n54991 related to AHI, while longitudinal RDI in quartiles TG was positively study associated with AHI, independent of obesity, in those aged ,65 yrs only Pooled data UK, males TC, 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, males and TC, TG, HDL-C, AHI was associated B ORGEL [96] study: females LDL-C with HDL-C after 6 months of OSA: n5366 adjusting for age, sex, CPAP/BiPAP After treatment, OSA: BMI, diabetes and treatment n586 lipid-lowering drugs HDL-C increased significantly by 5.8% after treatment Cross-sectional Turkey, males TC, TG, HDL-C, Elevated TC, TG, C AN [97] Group 1 (AHI o5): LDL-C, Apo-AI, LDL-C, lipoprotein A, n530 Apo-B, Apo-B in group 1/ Group 2 (AHI ,5): lipoprotein A group 2 compared to n532 controls separately Controls (AHI ,1): n530 Cross-sectional: Japan: n5194 LPL LPL concentration I ESATO [98] 3 months of OSA: n5155 decreased with AHI, CPAP treatment Non-OSA: n539 and its concentration was increased after treatment Casecontrol Australia, males TC, HDL-C, OSA subjects had M CA RDLE [32] OSA: n521 LDL-C, TG increased TC and Non-OSA: n521 LDL-C Matched for age, BMI and current smoking status Casecontrol India, males and TC, LDL-C, S HARMA [21] No difference females HDL-C, TG, TC/ between OSA Apnoeic obese, HDL-C, LDL-C/ subjects and obese OSA: n540 HDL-C controls
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Table 4. Continued First author [Ref.] Design Sample Lipid profile Findings
Non-apnoeic obese, Obesity was the controls: n540 major determinant Normal weight, controls: of metabolic n540 abnormalities Cross-sectional Hong Kong, Chinese TC, TG, HDL-C, T AN [99] Increased HDL males and females: LDL-C, Apo AI, dysfunction and n5210 Apo-B, HDL oxidised LDL in OSA OSA: n5128 dysfunction, subjects Controls: n582 oxidised LDL AHI was the major determinant of HDL dysfunction UK, males RCT with TC, TG, HDL-C, 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, HDL-C, TC, TG and Apo-B D ORKOVA [51] Cross-sectional: Slovakia, males and LDL-C, TG, improved within CPAP CPAP treatment females Apo AI, Apo-B compliance group and for 8 weeks Severe OSA: n532 TC, TG, LDL-C and Good CPAP compliance Apo-B improved (o4 h?night-1): n516 Poor compliance between two groups (,4 h?night-1): n516 RCT with Canada, males and TC, TG, HDL-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, Chinese TC, TG, HDL-C. TC, TG and Apo-B L AM [55] study: males LDL-C, Apo-B levels were reduced CPAP treatment OSA: n529 after treatment for 3 months
CPAP: continuous positive airway pressure; RCT: randomised controlled trial; BiPAP: bilevel positive airway pressure; BMI: body mass index; RDI: respiratory disturbance index; AHI: apnoea/hypopnoea index; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglycerides; Apo-AI: apolipoprotein AI; Apo-B: apolipoprotein B; LPL: lipoprotein lipase.
Data on effects of treatment of OSA on lipid metabolism has been controversial, and there were both positive [55, 51, 92, 93, 98] and negative [48, 95, 100] studies (table 4). In a randomised study with a cross-over design for 6 weeks of therapeutic versus sham CPAP treatment, there were no changes in the lipid profiles compared to sham CPAP but the short duration of treatment may be a limiting factor [47]. In a prospective longitudinal follow-up, we observed that 3 months of CPAP treatment significantly reduced total cholesterol, triglycerides and apolipoprotein B levels without significant changes in BMI [55]. In another study of CPAP treatment for 8 weeks, lipid profile improved significantly in those with good CPAP compliance of o4 h?night-1 compared to those using CPAP for less time [51]. OSA may also affect the quality of the lipids, and increased oxidation of lipids, which are more atherogenic, has been demonstrated in OSA and was taken to reflect a state of enhanced oxidative stress [86]. TAN et al. [99] have also shown that HDLcholesterol in OSA subjects was less effective in preventing LDL oxidation, and the severity of OSA accounted for 30% of the variance in HDL dysfunction in sleep apnoea.
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Lipid metabolism involves a series of enzymatic interactions, and lipoprotein lipase is one of the step-limiting enzymes. Reduced lipoprotein lipase activity provokes early inflammatory responses central to atherosclerosis. It was reported that enzyme levels decreased with the severity of OSA, and 3 months of CPAP treatment significantly increased its concentration [98]. This finding may indicate that treatment of OSA could be effective in reducing inflammatory responses and ameliorating lipid metabolism. Data from animal models of intermittent hypoxia also support a causal role of OSA in the pathogenesis of abnormal lipid metabolism. Exposure to intermittent hypoxia in genetically obese ob/ob mice models caused an upregulation of lipid biosynthesis and dyslipidaemia, and led to lipid peroxidation in the liver in a dose-dependent manner [103, 104]. In another experiment of lean mice exposed to different levels of intermittent hypoxia (21%, 10% and 5% oxygen nadir) for 4 weeks, hypercholesterolaemia and lipid peroxidation developed in the absence of obesity, and the degree of metabolic dysregulation was dependent on the severity of the hypoxic stimulus [105].
OSA and metabolic syndrome

The metabolic syndrome was first described as a cluster of metabolic abnormalities, with insulin resistance as the central pathophysiological feature, and was labelled as syndrome X [106]. Currently, metabolic syndrome is defined as a group of inter-related risk features of metabolic origin, including hypertension, insulin resistance, dyslipidaemia and obesity/visceral obesity as its major components [107]. The cause of the syndrome remains unknown. Insulin resistance and central obesity have been acknowledged as key driving forces for the metabolic syndrome and, independently, they are also well known cardiovascular risk factors. The syndrome is associated with a three-fold and two-fold increase in type 2 DM and cardiovascular diseases respectively. Not surprisingly, given its defining components which are all risk factors for atherosclerosis, the metabolic syndrome is associated with cardiovascular mortality [108]. Many studies have investigated the relationship of OSA and individual cardiometabolic parameters. There is increasing interest in exploring the relationship between sleep apnoea and the metabolic syndrome and its defining components [109111]. Snoring or OSA has been shown to be strongly associated with the metabolic syndrome, and this was consistent across different ethnic samples (table 5) [19, 33, 112120]. The frequent clustering of OSA and metabolic syndrome or its components has led to the description of syndrome Z [121]. In a study of subjects with newly diagnosed metabolic syndrome, who were expectedly obese, OSA was present in 68% of them, a figure which was similar to that for other established individual components of metabolic syndrome [119]. 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). Interestingly, in a study of 195 patients with cardiovascular diseases, the metabolic syndrome was found to be a better predictor of nocturnal desaturation than AHI in those with sleep apnoea [117]. A recent study from India suggested sequential development of metabolic syndrome and OSA [122]. Given these closely interwoven relationships between OSA and the metabolic syndrome or its defining components, it has been proposed that OSA may well be considered as a manifestation of an expanded metabolic syndrome [81, 120]. It is logical to surmise that the coexistence of OSA and the metabolic syndrome may lead to worse cardiometabolic outcomes than either condition alone. In a cross-sectional study of 81 patients with multiple comorbidities recruited from a heart institute, those who suffered from OSA and the metabolic syndrome had higher levels of carotid intima media thickness, carotid-femoral pulse wave velocity and carotid diameter compared to those without metabolic syndrome [123]. Therefore, the concurrent presence of metabolic syndrome in OSA patients may have an additive effect on atherosclerosis. In subjects with metabolic syndrome who were not yet overtly diabetic, presence of OSA was associated with higher fasting glucose level and glycosylated haemoglobin but not with BMI [119]. In an interventional study of 38 OSA patients with metabolic syndrome,
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Table 5. Clinical studies of obstructive sleep apnoea (OSA) and metabolic syndrome (MS) First author [Ref.] C OUGHLIN [112] Sample Metabolic parameters MS (%) Findings
OSA (87) OSA was associated with Non-OSA multiple (35) metabolic risk factors MS: OR 9.1 (95% CI 2.631.2) OSA (58) OSA was associated with L AM [113] Mild OSA all metabolic components (54) in MS Moderate MS: OR 5.3 (95% CI OSA (56) 3.039.26) Severe OSA (70) Non-OSA (21) Clinic-based BMI, WC, SBP, OSA (73) Insulin resistance was not G RUBER [114] UK, males and females: DBP, TC, TG Controls associated with OSA, n579 HDL-C, LDL-C, (37) independent Obese OSA: n538 FBS, insulin, of obesity Obese controls: n541 HOMA-IR MS: OR 5.9 (95% CI 217.6) Clinic-based WC, HDL-C, OSA (53) Subjects with OSA A MBROSETTI [111] Italy, males and TG, BP, FBS and MS were females younger, had a OSA: n589 higher AHI but did not increase the risk of cardiovascular events after 2210 months of CPAP treatment compared to those OSA subjects without MS Clinic-based BMI, WC, BRS, OSA (80) CPAP treatment did C OUGHLIN [47] UK, males: n535 SBP, DBP, MBP, not improve MS but SBP, RCT with crossover insulin, FBS, DBP, MBP 6 weeks of CPAP HOMA-IR, and BRS in those CPAP: n518+17 TC, HDL-C, on CPAP for Sham CPAP: n517+17 LDL-C, TG o3.5 h?night-1 P ELED [19] Clinic based: n598 BMI, WC, Mild OSA The prevalence of Snorers: n59 FBS, insulin, (11) MS increased Mild OSA: n59 TC, HDL-C, Moderate with OSA severity Moderate OSA: n527 TG, Hs-CRP, OSA (21) Severe OSA: n553 serum amyloid Severe OSA (30) Clinic-based BMI, WC, OSA (50) MS was associated S ASANABE [115] Japan, males and SBP, DBP, Controls with severity of OSA females, n5907 FBS, insulin, (22) In severe OSA: OSA: n5819 HOMA-IR, MS in males: OR 5.1 Controls: 89 TC, TG, HDL-C, (95% CI 2.79.7) LDL-C, b-cell MS in females: OR 14 function (95% CI 2.966.8)
Clinic-based BMI, WC, SBP, UK, males DBP, FBS, insulin, Obese OSA: n561 HOMA-IR, TC, TG, Obese controls: n543 HDL-C, LDL-C, TC/HDL Community-based BMI, WC, SBP, Hong Kong, Chinese DBP, TC, TG, males and females: HDL-C, LDL-C, n5255 TC/HDL-C, OSA: n595 FBS Non-OSA: n5160
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Table 5. Continued First author [Ref.] S HIINA [110] Sample Clinic-based Japan, males and females: n5184 OSA: n594 Non-OSA: n590 Metabolic parameters BMI, SBP, DBP, MBP, TC, HDL-C, TG, FBS, brachial ankle PWV BMI, VFA, SFA, SBP, DBP, TC, HDL-C, TG, insulin, FBS, 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]
T KACOVA [109]
T AKAMA [117]
Clinic-based OSA (19) Casecontrol Non-OSA Japan, males (4) OSA: n542 Non-OSA: n552 Matched for age, BMI and VFA Clinic-based BMI, WC, SBP, OSA (23) Casecontrol DBP, insulin, Controls (4) Australia, males FBS, TC, LDL-C, OSA: n521 HDL-C, TG, Controls: n521 IGF-1, leptin, Matched for age, BMI TNF-a, and current smoking adiponectin, urine status catecholamines Clinic-based MS, OSA (60) Retrospective review hypertension, Non-OSA USA, males and females: hyperlipidaemia, (40) n5228 diabetes OSA: n5146 Non-OSA: n582 Clinic-based BMI, WC, TC, AHI ,5 Slovakia, males and TG, HDL-C, (46) females: n598 LDL-C, AHI o5 to AHI ,5: n528 Apo-AI, Apo-B, ,30 (51) AHI o5 to ,30: n539 FBS, SBP, AHI o30 AHI o30: n531 DBP, MBP (77) Hospitalised inpatients WC, BMI, OSA (77) with cardiovascular SBP, DBP, diseases: n5195 FBS, TC, TG, MS: n556 HDL-C, BNP Non-MS: n5139 Clinic-based WC, BMI, SBP, Turkey, males and DBP, TC, HDL-C, females LDL-C, TG, FBS with OSA+MS: n520 Longitudinal study of 1 yr CPAP treatment Clinic-based BMI, WC, SBP, OSA (63) Brazil, males and females DBP, FBS, OSA (63) with MS: n581 TC, LDL-C, OSA: n551 HDL-C, TG, Non-OSA: n530 IMT, PWV, 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 8.4 (95% CI 2.528) Mild-to-moderate OSA: OR 1.8 (95% CI 0.66) MS was a strong predictor of nocturnal desaturations ,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
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Table 5. Continued First author [Ref.] N IETO [120] Sample Community-based USA, males and females: n5546 OSA: n5 253 Non-OSA: n5293 Metabolic parameters MS (%) Findings OSA is associated with the prevalence of MS, independent of sympathetic and neuroendocrine activation MS In mild OSA: OR 4.0 (95% CI 2.66.3) Ms in moderate/ severe OSA: OR 5.3 (95% CI 3.28.8)
WC, BMI, SBP, OSA (32) DBP, insulin, FBS, HOMA, TG, HDL-C, urinary cortisol and adrenalin
RCT: randomised controlled trial; CPAP: continuous positive airway pressure; BMI: body mass index; VFA: visceral fat accumulation; AHI: apnoea/hypopnoea index; WC: waist circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBS: fasting blood sugar; HOMA-IR: homeostasis model assessment for estimating insulin resistance; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: lowdensity lipoprotein cholesterol; BP: blood pressure; BRS: baroreceptor sensitivity; MBP: mean BP; Hs-CRP: highsensitivity C-reactive protein; PWV: pulse wave velocity; SFA: subcutaneous fat accumulation; IGF-1: insulin growth factor-1; TNF-a: tumour necrosis factor-a; Apo-AI: apolipoprotein AI; Apo-B: apolipoprotein B; BNP: brain natriuretic peptide; IMT: carotid intimamedia thickness; CD: carotid diameter.
20 of whom were evaluated after receiving 1 yr of CPAP treatment, the prevalence of metabolic syndrome was decreased by 45% [118]. 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, although it is still a long way before this can be proven.
Mechanistic links between OSA and metabolic disorders

Sleep fragmentation and altered sleep architecture
OSA is characterised by disrupted sleep architecture with repetitive arousals, sleep fragmentation or even sleep loss, resulting in daytime sleepiness. Sleep duration and sleep quality play a major role in hormonal regulation in human physiological systems. Sleep duration is believed to regulate leptin and ghrelin levels in humans, which act in parallel as metabolic counterparts for body weight control through different mechanisms on feeding, wakefulness and energy expenditure [124]. There are epidemiological and clinical data to suggest that short sleep duration may lead to weight gain [125127]. In the Wisconsin Sleep cohort study, a 3-h sleep loss was associated with a 45% weight gain, provided that the baseline sleeping duration was 8 h as self-reported in their sleep questionnaires [125]. In a retrospective study of 1,000 patients from four different family practice groups in the USA, females were shown to sleep more than males, and the overweight (BMI o25) and obese patients (BMI o30) slept less than the patients with normal weight (BMI ,25) [127]. In addition, in a recent systematic review of 36 observational studies in children and adults from 1966 to January 2007, short sleep duration was associated with significant weight gain, particularly in the young age groups [126]. Evidence from epidemiological and in-laboratory studies suggest that sleep loss or poor sleep quality, irrespective of SDB, may adversely affect glucose metabolism [128, 129]. In the Massachusetts Male
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Aging Study, 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, respectively, after ,1015 yrs of follow-up [130]. In the Sleep Heart Health Study (n51,486), self-reported sleep durations of f6 h or o9 h, with adjustment for body habitus and AHI, were associated with higher prevalence of impaired glucose tolerance and DM [131]. 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 732 yrs [132136]. Most epidemiological studies were based on subjective self-reporting of sleep duration and quality. In a population study using objective measurement of sleep duration by in-laboratory monitoring, the risk of having DM was three-fold higher in individuals with f5 h sleep duration, compared to the groups with normal and o6 h sleep duration [136]. In addition to the reduction in sleep duration, certain changes in sleep architecture in OSA, most commonly reduced slow-wave sleep, might also adversely affect the glucose metabolism. All-night suppression of slow-wave sleep, without a change in sleep duration, was shown to result in dramatic worsening in insulin sensitivity in young healthy adults [137]. 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]. The decrease in the anorexigenic hormone leptin and increase in ghrelin, an appetite-stimulating peptide, suggested that sleep loss could predispose to overeating with consequent weight gain and dysregulation of glucose metabolism [139]. Mechanically induced sleep fragmentation can also produce acute adverse effects on glucose homeostasis, including reduced insulin sensitivity and impaired insulin secretion [140]. With these data, it is proposed that the associated sleep loss and sleep disturbance may be one primary trigger for promoting obesity and DM in OSA, possibly through complex hormonal regulations in the body.
Intermittent hypoxia and oxidative stress

Increased oxidative stress has been shown to be a key mechanism for insulin resistance and diabetes [141]. In contrast to other chronic respiratory diseases, the disturbance in oxygenation in OSA is unique with recurrent intermittent hypoxia and reoxygenation alternating in rapid cycles. The rapid reoxygenation of transiently ischaemic tissues could lead to tissue injury and release of reactive oxygen species, the culprit of oxidative stress, from inflammatory cells [142, 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, increased production of reactive oxygen species without a compensatory increase in anti-oxidant activity was found [144]. The intermittent hypoxia and resultant oxidative stress have been proposed to be a pathogenetic link between OSA and disturbance of glucose homesostasis [142]. A study of 4,398 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 1.7-fold risk of incident DM compared to those without significant hypoxia, with a discernible doseresponse relationship of incident DM with the desaturation index, after thorough adjustment for multiple confounders [145]. In the Cleveland Family study, measures of hypoxic stress (time spent with ,90% O2 saturation) was the strongest polysomnographic index associated with glucose intolerance [16]. The pathogentic role of OSA in metabolic derangements has also been investigated using animal/ cell models of intermittent hypoxia. In leptin-deficient obese mice, 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]. Reduced insulin sensitivity, as measured by hyperinsulinemic euglycemic clamp, was also demonstrated in lean mice exposed to intermittent hypoxia, and this developed independent of autonomic nervous system activity [147]. An in vitro study of the effect of
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intermittent hypoxia on b-cells showed that it led to increased b-cell proliferation and cell death, and the cell death response appeared to be due to oxidative stress [148].
Inflammation and cytokine release

Many cytokines, in particular adipokines, play a role in the mediation of vascular inflammation and adverse glucose metabolism [149, 150]. Intermittent hypoxia and sleep fragmentation in OSA are postulated to be triggers of the cascade of inflammation in adipose tissue and vascular compartment and, thus, an array of inflammatory products may be released. Many of these markers have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, pose deleterious effects on the cardiovascular system [151]. Inflammatory cytokines, such as tumour necrosis factor-a and interleukin (IL)-6 were found to be elevated in subjects with OSA, and these markers were positively correlated with excessive daytime sleepiness [152]. In relation to inflammation and insulin resistance, it has been suggested that visceral obesity and insulin resistance, is a potential pathogenetic mechanism promoting inflammation and leading to sleep apnoea [152]. In a study using an in vitro model of intermittent hypoxia/ reoxygenation and HeLa cells, the regulation of inflammatory and adaptive pathways on hypoxic stimulation was mapped [153]. 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; suggesting that selective activation of inflammatory over adaptive pathways with intermittent hypoxia might be an important molecular mechanism of cardiometabolic dysfunction in OSA. In addition, in both human and murine adipocytes, hypoxia inhibits insulin signalling through HIF transcription factor expression, creating a state of insulin resistance, and inhibiting glucose transport as well as inducing IL-6 secretion. Hence, this mechanism may be involved in the development of insulin-resistant state in obesity [154]. Elevated levels of C-reactive protein (CRP), a marker of inflammation, correlated positively with worsening HOMA in a general population followed up for 5 yrs [155]. The association between OSA and an elevated level of CRP has been investigated in many studies with conflicting results, probably related to the confounding effects of obesity and presence of comorbidities. LUI et al. [156] have demonstrated an independent association between severity of OSA and elevated CRP level in males free of comorbidities, after careful consideration of the confounding effect from visceral obesity measured by magnetic resonance imaging. Overall, the data are still controversial regarding the role of OSA, independent of obesity, in the generation of the inflammatory state seen in OSA subjects.
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Adipocyte-derived hormones/proteins
Fat tissue produces many biomolecules which have regulatory effects on various metabolic processes [80]. Some of these have been investigated in relation to OSA.
Adiponectin
Adiponectin is produced in white adipose tissues and is found in high circulating levels in humans. Its levels are decreased with obesity and visceral obesity. Adiponectin is a key promoter of insulin sensitivity, and it has anti-inflammatory and protective vascular effects [81, 157, 158]. Hypoadiponectinaemia has been demonstrated to be closely associated with endothelial dysfunction and cardiovascular morbidity in clinical studies [159, 160]. It has been postulated that OSA may down regulate adiponectin expression in adipose tissue. Studies on serum adiponectin levels in OSA have been controversial [18, 32, 161]. In a Japanese study of 200 male patients with cardiovascular diseases, hypoadiponectinaemia was significantly associated with visceral adiposity and insulin resistance but not with any of the sleep indices [18]. In another study of 68 subjects with no known comorbidity undergoing sleep studies,
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OSA subjects actually had a higher level of adiponectin compared to BMI-matched non-OSA subjects, but their blood samples were taken in a nonfasting state in the evening [161]. In a case control study of 28 otherwise healthy subjects with moderate OSA, there was no difference in adiponectin levels between OSA and BMI-matched non-OSA subjects, though significant differences were seen in other metabolic parameters [32]. LAM et al. [162] found that serum adiponectin levels was suppressed in OSA and independently associated with sympathetic activity and severity of sleep apnoea, suggesting that sympathetic activation is a pathway through which SDB may contribute to the determination of adiponectin levels. 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]. The use of CPAP treatment for 23 months has been reported to increase serum adiponectin levels significantly in OSA subjects in a few observational studies [164, 165] but not in a randomised controlled study of diabetics with OSA [48].
Leptin
Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate neuroendocrine function, energy intake and expenditure. Leptin is functionally a thrifty hormone, but most obese subjects have high circulating leptin levels, indicating that obesity is a leptin-resistant state [166]. Leptin levels increase exponentially with increasing fat mass [167]. Increased serum leptin levels were related to endothelial dysfunction [168, 169], thus, leptin may contribute to the pathogenesis of cardiovascular complications in OSA. The evidence for enhanced leptin resistance attributable to OSA is controversial. Visceral obesity accounted for the increase in leptin levels in OSA in some studies [32, 170], while others reported that serum leptin levels were significantly higher in OSA subjects than in BMI-matched controls [92, 171173]. A study found that leptin levels correlated with cardiac sympathetic activity in OSA subjects [174]. Several observational studies showed a reduction of serum leptin levels after weeks or months of CPAP treatment [92, 175] and in one study, the impact was more pronounced in patients with a BMI ,30 [176]. However, the lack of control group is a major limitation due to potentially significant confounding effect from changes in body weight.
Adipocyte fatty acid-binding protein

Fatty acid-binding proteins are a family of small intracellular lipid-binding proteins. Adipocyte fatty acid-binding protein (A-FABP) is abundantly present in adipocytes and regulates intracellular fatty acid trafficking and glucose metabolism [177]. In animal experiments, the apparent functions of A-FABP were mediation of insulin resistance independent of the effects of obesity and the promotion of atherosclerosis [178, 179]. Positive associations between serum A-FABP levels and adiposity, hyperglycaemia, insulin resistance and the metabolic syndrome have been reported in cross-sectional and longitudinal studies [180]. In a recent large population-based genetic study, there was a reduced risk for hypertriglyceridaemia, 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]. LAM et al. [182] demonstrated that A-FABP level was elevated in severe OSA subjects compared to non-OSA or less severe OSA subjects, and its level significantly correlated with insulin resistance. 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.
Alterations of the neuroendocrine and autonomic system

Neuroendocrine factors and autonomic activity are important in glucose regulation [84]. Adrenalin and cortisol are counter-regulatory hormones of insulin, and the level of these hormones may be affected in OSA. Heightened sympathetic activity has been convincingly
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demonstrated in OSA, which contributes significantly to the elevation of blood pressure [183]. 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 [184186]; although, the role of this mechanistic pathway in the metabolic regulation in OSA has not been well studied. It has been demonstrated that intermittent hypoxia resulted in impaired insulin sensitivity in lean mice, and this occurred independent of autonomic nervous system activity [147]. Studies of cortisol secretion in OSA have shown inconsistent results [3]. Recently, CPAP therapy was reported to alleviate the disordered adrenocorticotrophic hormone and cortisol secretory dynamics in subjects with moderate-to-severe OSA [187].
Conclusions
Many OSA subjects have an adverse metabolic profile. In relation to OSA, intermittent hypoxaemia and sleep fragmentation have been identified as major triggering factors that lead to downstream pathophysiological cascades which may result in metabolic dysfunction. Obesity/ visceral obesity, present in the majority of OSA subjects, are significant sources of inflammatory biomarkers, hormones and binding proteins believed to be players in the pathogenesis of cardiometabolic complications at the molecular level, and may act in concert with OSA in the generation of metabolic aberrations. In the complex human biological system, the regulation of hormones, adipokines, inflammatory cytokines and oxidative stress mediators, is likely to be multifactorial and inter-crossed with various feedback signals. Apart from disease states, body metabolism is also influenced by endogenous factors of genetics and exogenous factors of lifestyle behaviour. Current data suggest that SDB may contribute to adverse glucose and lipid metabolism, but pieces of the huge jigsaw puzzle of OSA and metabolic function are just beginning to appear.
Statement of Interest
J. C-M. Lam has received a university grant for HK$150,000 for a clinical trial on patients with diabetes mellitus and OSA from the University of Hong Kong in 2008. He has also received a grant of HK$800,000 from GSK for a clinical randomised controlled trial on asthma in 2008. J. C-M. 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). M. M-S. Lui received financial support (including travel, accommodation and registration fees) from ResMed for attending the World Congress of Sleep Apnea (Seoul, South Korea; 2009), and from Celki for attending the Sleep Course organised by the University of Hong Kong in 2008 and 2009. M. S-M. Ip has received reimbursement from ResMed for attending a symposium, which supported a working group meeting of the International Diabetes Panel on OSA and diabetes mellitus in February 2007 (Sydney, Australia). M. S-M. 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, Seoul, South Korea; 2009).
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Chapter 12

Diabetes and metabolic aspects of OSA

J. C-M. LAM ET AL.

OSA and impaired glucose metabolism

OSA AND METABOLIC DYSFUNCTION

Cross-sectional/longitudinal studies on OSA and disorders of glucose metabolism

OSA and type 2 DM

J. C-M. LAM ET AL.

Table 2. Cross-sectional/longitudinal studies on sleep-disordered breathing (SDB) and glucose metabolism in

First author [Ref.]

Population-based, 116 hypertensive males with or without diabetes mellitus

Fasting insulin, HOMA FG and insulin, OGTT

OSA AND METABOLIC DYSFUNCTION

Wisconsin Sleep Cohort, 1387 subjects, 4-yr followup in 987 subjects

394 subjects from Cleveland Family Study

P ELED [19] K ONO [20]

T HEORELL W [23] H AGLO

400 females from a Swedish city

Clinic-based, 67 nondiabetic males with or without OSA

Sleep clinic-based, 2149 subjects

FG, fasting insulin, HOMA OGTT

306 subjects from 16 diabetes mellitus centres in the USA

J. C-M. LAM ET AL.

Clinic based, 60 diabetic subjects

OSA AND METABOLIC DYSFUNCTION

OSA and glucose intolerance/insulin resistance

Impact of intervention in OSA on glucose metabolism

Treatment of OSA and insulin resistance/sensitivity

First author [Ref.] H ARSCH [42]

Tools assessing glucose metabolism Hyperinsulinaemic euglycaemic clamp

40 nondiabetic males with OSA

OSA AND METABOLIC DYSFUNCTION

Treatment of OSA and glycaemic control in diabetes mellitus

J. C-M. LAM ET AL.

OSA and obesity

OSA AND METABOLIC DYSFUNCTION

OSA and lipid metabolism

J. C-M. LAM ET AL.

OSA AND METABOLIC DYSFUNCTION

J. C-M. LAM ET AL.

OSA and metabolic syndrome

OSA AND METABOLIC DYSFUNCTION

J. C-M. LAM ET AL.

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

OSA increased cardiovascular risk in patients with MS

Mechanistic links between OSA and metabolic disorders

J. C-M. LAM ET AL.

Intermittent hypoxia and oxidative stress

Inflammation and cytokine release

OSA AND METABOLIC DYSFUNCTION

Adipocyte fatty acid-binding protein

Alterations of the neuroendocrine and autonomic system

J. C-M. LAM ET AL.

OSA AND METABOLIC DYSFUNCTION

21. 22. 23. 24.

J. C-M. LAM ET AL.

OSA AND METABOLIC DYSFUNCTION

J. C-M. LAM ET AL.

OSA AND METABOLIC DYSFUNCTION

J. C-M. LAM ET AL.

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