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Abstract

Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss.

Keywords

Sleep-disordered breathing obstructive sleep apnoea type 2 diabetes metabolic syndrome

Introduction

Sleep-disordered breathing (SDB) encompasses a range of conditions in which repeated apnoeas or hypopnoeas occur during sleep, including snoring, upper airway resistance syndrome and obstructive sleep apnoea (OSA) that can result in perturbations in sleep homeostasis.¹ SDB is associated with hypertension, cardiovascular disease, type 2 diabetes and metabolic impairment.² There is also evidence linking disrupted sleep patterns to other adverse health consequences such as neurocognitive deficits, impaired quality of life and an increased risk of accidents.³ In recent years, progress has been made in understanding how SDB can affect the cardiovascular system, especially blood pressure regulation and why it is associated with dyslipidaemia and abnormal glucose homeostasis.

OSA is the most common form of SDB. In OSA, repeated episodes of apnoeas and hypopnoeas occur during sleep with subsequent daytime hypersomnolence.⁴ These episodes are characterized by recurrent upper airway obstruction causing intermittent hypoxia, with frequent sleep arousals and fragmented sleep.⁵ The severity of OSA may be assessed by the number of apnoeas and hypopnoeas per hour during sleep, termed the apnoea–hypopnoea index (AHI). Besides the AHI, the frequency of oxygen desaturation episodes and severity of somnolence symptoms are also used.⁶ The AHI measures the frequency of reduction in airflow associated with collapse or narrowing of the airways.⁷ The index classifies the severity of OSA based on the number of obstructive breathing episodes per hour during sleep as: mild AHI: 5–15 events per hour, moderate OSA: 15–30 events per hour and severe AHI: OSA > 30 events per hour.⁸

The prevalence of OSA has been increasing, and it has been estimated that 13% of men and 6% of women between the ages of 30 and 70 have moderate to severe forms of OSA (AHI > 15 events per hour of sleep).⁹ This may be related to the growing obesity prevalence, as it is known that obesity is a risk factor for OSA.¹⁰ Obesity may be classified according to the body mass index (BMI), which is calculated as weight (in kilogram)/height (in square metre). According to World Health Organization guidance, adults with a BMI of 25–30 kg/m² are classed as ‘overweight’, those with a BMI of 30 kg/m² or more may be referred to as having obesity and those with a BMI of 40 kg/m² or more may be referred to as having severe (termed ‘morbid’) obesity. It should be noted that the threshold values for the definition of obesity may differ among populations,¹¹ with Asian populations in particular having lower BMI cut-offs. Prevalence estimates of OSA in severe obesity were between 40% and 90%;¹² furthermore, OSA severity worsens with increasing levels of obesity.¹³

OSA severity is correlated with the degree of perturbation in glucose homeostasis, an effect that is independent of obesity.^1,14 The prevalence of OSA in type 2 diabetes has been reported with different rates in several population-based studies that are not directly comparable due to differences in populations studied and how OSA was assessed. This has been found to range from 18% of patients in primary care based on an assessment of electronic records,¹⁵ 23% in a mixed primary and secondary care population of patients with type 2 diabetes who had overnight oximetry testing,¹⁶ to as high as 86% in the Sleep Action for Health in Diabetes (AHEAD) study cohort comprising obese subjects with type 2 diabetes who had polysomnography.¹⁷

One of the major implications of the global rise in obesity has been an associated rise in the prevalence of the metabolic syndrome.¹⁸ The metabolic syndrome, also known as the insulin resistance syndrome, or ‘syndrome X’¹⁹ has been variably defined based on clustering of abnormalities of factors including insulin resistance, dyslipidaemia (low high-density lipoprotein (HDL) cholesterol and raised triglycerides), hyperglycaemia and blood pressure,²⁰ with the most recent definition of the syndrome requiring central adiposity as a key feature (Table 1).²⁵ There is also evidence that OSA is associated with the metabolic syndrome, independently of adiposity.^2,26 The term ‘syndrome Z’ reflects the close interaction between OSA and cardiovascular disease risk.²⁷ In a study of 529 newly diagnosed OSA patients who had polysomnography, metabolic syndrome based on the National Cholesterol Education Program Adult Treatment Panel definition occurred in about half of the patients; prevalence rates of metabolic syndrome in OSA have previously been reported to be between 23% and 87% using this definition.²⁸

Table 1.

Definitions of metabolic syndrome.

World Health Organization (1999)	European Group for the Study of Insulin Resistance (1999)	US National Cholesterol Education Program: Adult Treatment Panel III (2001)	International Diabetes Federation (2005)	International Diabetes Federation (2009)
Alberti and Zimmet²¹	Balkau and Charles²²	Cleeman and Grundy²³	Alberti and Zimmet²⁴	Alberti and Eckel²⁵
Impaired glucose regulation or diabetes mellitus and/or insulin resistance together with two or more of: raised arterial pressure (≥160/90 mmHg) raised plasma triglycerides (≥1.7 mmol/L; 150 mg/dL) and/or low HDL cholesterol (<0.9 mmol/L, 35 mg/dL males; <1.0 mmol/L, 39 mg/dL females); central obesity (males: waist to hip ratio >0.90; females: waist to hip ratio >0.85 and/or BMI >30 kg/m²) microalbuminuria (urinary albumin excretion rate ≥ 20 µg/min) or albumin:creatinine ratio ≥ 20 mg/g	Excluding people with diabetes, presence of insulin resistance or fasting hyperinsulinaemia and two of: hyperglycaemia (fasting plasma glucose and 6.1 mmol/L, but without diabetes); hypertension (systolic/diastolic blood pressures ≥140/90 mmHg or treated for hypertension); dyslipidaemia (triglycerides > 2.0 mmol/L or HDL cholesterol < 1.0 mmol/L or treated for dyslipidaemia); central obesity (waist circumference ≥94 cm in males and ≥80 cm in females). Hyperglycaemia was defined as fasting plasma glucose ≥6.1 mmol/L or impaired fasting glucose in individuals without diabetes.	Presence of any three of: central obesity (waist circumference) males > 102 cm females > 88 cm raised blood pressure ≥130/≥85); Raised triglycerides ≥1.7 mmol/L; 150 mg/dL; Low HDLcholesterol (males < 1.03 mmol/L; 40 mg/dL, females < 1.29 mmol/L; 50 mg/dL); fasting hyperglycaemia (≥6.1 mmol/L; 110 mg/dL).	Central obesity waist circumference according to ethnicity and any two: raised triglycerides >1.7 mmol/L; 150 mg/dL or on treatment for this reduced HDL cholesterol (males < 1.03 mmol/L; 40 mg/dL, females < 1.29 mmol/L; 50 mg/dL or on treatment for this) raised blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg or on treatment for previously diagnosed hypertension) raised fasting plasma glucose (fasting plasma glucose ≥ 5·6 mmol/L; 100 mg/dL or known type 2 diabetes)	Presence of any three of: waist circumference according to specific population and country definitions elevated triglycerides (≥1.7 mmol/L; 150 mg/dL or on treatment for elevated triglycerides) reduced HDL cholesterol (<1.0 mmol/L; 40 mg/dL in males; <1.3 mmol/l; 50 mg/dL in females or on treatment for reduced HDL cholesterol) elevated blood pressure (systolic ≥130 mmHg and/or diastolic ≥ 85 mmHg or on antihypertensive drug treatment) elevated fasting glucose (≥5.6 mmol/L; 100 mg/dL or on treatment for elevated glucose)

HDL: high-density lipoprotein; BMI: body mass index.

The reduction in time spent sleeping that is typical of OSA may have profound effects on glucose regulation, insulin resistance, appetite and energy balance.²⁹ OSA may induce fatigue and with increasing daytime somnolence, weight-reducing activities are pursued less often with a decrease in energy expenditure that may lead to weight gain, insulin resistance and further worsening of SDB.

Understanding the potential influence of OSA on the components of the metabolic syndrome and the mechanisms by which such interactions may contribute to metabolic dysregulation is important because such knowledge may define appropriate targets and lead to more precisely administered preventive actions in addressing health outcomes such as cardiovascular disease, obesity and type 2 diabetes.

Whilst there are different forms of SDB, the majority of research studies have focused on OSA and the potential interactions with diabetes, metabolic syndrome and its components. In this article, we review OSA and its association with diabetes as well as components of the metabolic syndrome. We discuss the underlying pathophysiology and also review the effects of OSA treatment on both conditions.

Search strategy

A search of Web of Science electronic database for relevant articles was performed using the search terms ‘obstructive sleep apnoea’, ‘sleep-disordered breathing’ with relevant phrases including ‘diabetes’, ‘metabolic syndrome’, ‘type 2 diabetes’ and ‘CPAP’. Only articles published in English were used. Publications referred to in the identified articles were also reviewed and were cited if they provided important data not addressed in subsequent articles.

Compromised metabolism

Insulin resistance and type 2 diabetes

There is substantial evidence for the association between OSA, insulin resistance and type 2 diabetes. OSA is independently associated with alterations in glucose metabolism and an increased risk of type 2 diabetes.^1,14 SDB as assessed by AHI was observed to be independently correlated with insulin resistance; this association was seen in both obese and non-obese subjects.³⁰ Punjabi et al. found that SDB based on the AHI was associated with glucose intolerance and insulin resistance in mildly obese men without diabetes or cardiopulmonary disease and that increasing AHI was associated with worsening insulin resistance independent of obesity.³¹ The Sleep Heart Health study showed that OSA was associated with impaired glucose tolerance and insulin resistance,³² and in the Wisconsin Sleep study cohort, there was an association between OSA and type 2 diabetes.³³ Botros et al. found that OSA increased the risk of type 2 diabetes in a cohort of 544 patients referred for evaluation of SDB after adjusting for age, gender, ethnicity, blood glucose, BMI and weight change.³⁴ Tamura et al. observed that OSA-induced hypoxia was associated with increases in glycated haemoglobin regardless of glucose tolerance status.³⁵ In a longitudinal study, men without diabetes were followed up for a mean of 11 years, and it was demonstrated that OSA was independently related to the development of insulin resistance.³⁶ In a cross-sectional analysis in the European Sleep Apnoea Cohort study, the prevalence of type 2 diabetes and poorer glycaemic control was observed to be associated with increasing severity of OSA assessed by the oxygen desaturation index (ODI).³⁷ Another study that retrospectively analysed health data in a cohort of OSA patients found that the initial severity of OSA was associated with subsequent risk of diabetes.³⁸ It should be noted that these studies have been based on observational data that can only suggest an association and not causality. Vgontzas et al. evaluated obese males with symptomatic sleep apnoea with age- and BMI-matched controls and found that mean fasting blood glucose and insulin levels were higher in OSA than in obese controls suggesting that SDB is an independent risk factor for hyperinsulinaemia.³⁹ Conversely, two studies did not find an independent association between OSA and insulin resistance.^40,41

The relation of OSA with type 2 diabetes has important implications for improving health outcomes given the substantial increase in the worldwide prevalence of diabetes mellitus in recent years; estimates indicate that this may reach 7.7% and patient numbers expected to reach 439 million adults by 2030.⁴² With cardiovascular disease risk increased in OSA, targeting patients with type 2 diabetes who are at risk of SDB may be a means to address this risk. The International Diabetes Federation Taskforce on Epidemiology and Prevention has recommended that patients with type 2 diabetes and SDB should be assessed for each condition.¹

Several potential mechanisms could explain the pathophysiological links between OSA and impaired glucose metabolism (Figure 1). These include intermittent hypoxia and sleep fragmentation that may alter sympathetic activity,⁵⁷ effects on endocrine⁶¹ and hypothalamic–pituitary–adrenal (HPA) axes,⁶² oxidative stress and inflammatory responses^63,77 and changes in adipokines that may alter glucose metabolism.^47,48

Figure 1.

Interacting pathophysiological pathways in OSA, type 2 diabetes and metabolic syndrome. Selected references are in parentheses. OSA: obstructive sleep apnoea.

Animal studies of intermittent hypoxia have demonstrated glucose intolerance and insulin resistance in lean mice with acute intermittent hypoxia⁴⁹ and in obese mice exposed to chronic intermittent hypoxia for 12 weeks.⁵⁰ Human volunteers exposed to acute sustained hypoxia for 30 min⁵³ and acute intermittent hypoxia simulating moderate OSA for 5 h⁶⁴ also demonstrated impaired glucose tolerance.

Autonomic function

Several studies have found autonomic abnormalities in OSA that are attenuated with CPAP therapy.^57,65 During sleep in OSA, intermittent hypoxia and recurrent arousals stimulate sympathetic responses by mechanisms that include chemoreflex and baroreflex changes, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction.^66,67 Sympathetic activation increases hepatic glycogenolysis and gluconeogenesis.⁴⁸ The stimulation of lipolysis increases circulating free fatty acid metabolites that inhibit insulin signalling and reduce insulin-mediated glucose uptake, contributing to insulin resistance.⁶⁸

HPA axis

Activation of the HPA axis may provide a further mechanistic link between OSA and diabetes. There is evidence for potential OSA effects on the HPA axis as several studies have reported enhanced cortisol secretion in OSA.⁶⁹ Increased cortisol levels may contribute to hyperglycaemia by reducing insulin secretion and glycogen synthesis and increasing gluconeogenesis.⁷⁰ It should be noted that an increased cortisol secretion in OSA has not been consistently reported in the literature.⁶⁹ For example, Dadoun et al. found no association in cortisol profiles and OSA in obese men.⁴⁴ This may reflect an interaction between OSA and the HPA axis that may involve different mechanisms. Alterations in HPA axis activity may potentially be induced by intermittent hypoxia or by altered neural control of corticotroph function.^47,69 Obese patients with OSA were found to have an increased adrenocorticotrophin hormone response to corticotrophin releasing hormone compared with obese controls.⁷¹ Additionally, sleep deprivation has been associated with increased HPA axis activity that can potentially affect insulin resistance and may also predispose to obesity and metabolic syndrome.^72,73

Several studies have examined the effects of OSA treatment on the HPA axis. The results have been mixed in terms of effects of CPAP treatment on cortisol production. Meston et al. found no relation between cortisol and OSA severity and no measurable response to nasal CPAP treatment.⁶¹ Vgontzas et al. demonstrated that OSA in obese men is associated with increased nocturnal cortisol levels, compared with controls, that were corrected after the use of CPAP for 3 months.⁶² Consistent with this, another study found that 3 months of CPAP therapy decreased evening salivary cortisol concentrations in severe OSA patients.⁷⁴

Oxidative stress and activation of inflammatory pathways

Repeated episodes of intermittent hypoxia and reoxygenation in OSA may cause oxidative stress with increased production of reactive oxygen species that may contribute to altered glucose homeostasis. The formation of reactive oxygen species may impair pancreatic beta cell function and insulin secretion.⁴⁸ This may be due to increased pancreatic β cell proliferation and apoptosis with mitochondrial oxidative stress.⁷⁵ Hypoxia-inducible factor-1 is upregulated in many tissues during hypoxia and modulate the expression of proteins that mediate adaptive responses to hypoxia, some of which may influence glucose metabolism.^48,76,63

Additionally, reactive oxygen species formation may have an important role in activating inflammatory responses and have been implicated in the upregulation of transcription factors, such as nuclear factor-κB, and activator protein 1 with increased expression of proinflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-8.⁷⁷ TNF-α and IL-6 are increased in patients with OSA,³⁹ and there is evidence that these cytokines may have a role in insulin resistance.⁷⁸ Expression of TNF-α and plasma IL-6 are higher in subjects with insulin resistance.⁷⁹ TNF-α may downregulate genes required for normal insulin action and the peroxisomal proliferator-activated receptor-γ – an insulin-sensitizing nuclear receptor – and may have direct effects on insulin signalling and induction of elevated free fatty acids via stimulation of lipolysis.⁸⁰ IL-6 levels have been found to be correlated with insulin resistance in adipose tissue.⁵¹

Changes in adipokine profiles

There is evidence that OSA may be associated with altered adipokine levels. The adipokines leptin and adiponectin are hormones produced mainly by adipocytes that have a range of effects on physiological processes. The main function of leptin is its role in regulation of appetite and energy, but it also influences glucose regulation.⁸¹ Adiponectin has roles in fat distribution, inflammation and insulin sensitivity.⁸² It acts as an insulin-sensitizing hormone, and low levels are found in type 2 diabetes.⁸³ One study found elevated serum leptin levels in OSA that are reduced following CPAP treatment,⁸⁴ consistent with the observation that intermittent hypoxia increases leptin expression and inhibits insulin secretion.⁴⁷ However, other studies on leptin levels and OSA have shown no effect independent of adiposity.⁸⁵ Insulin resistance is associated with low levels of adiponectin,⁸⁶ although the mechanism remains unclear; intermittent hypoxia has been proposed as a putative mechanism so adiponectin concentrations have been studied in OSA, with equivocal findings.^55,83

Sleep duration/fragmented sleep

Shortened sleep duration from fragmented sleep may be associated with altered glucose regulation and insulin resistance.^52,87 Short sleep duration is associated with impaired glucose regulation and an increased prevalence of diabetes.⁵⁴ Potential mechanisms underlying this effect may include sympathetic activity which may impair glucose regulation via lipolysis, alterations in the HPA axis, reduced growth hormone secretion, appetite changes and inflammatory responses that may influence glucose and insulin homeostasis. Other mechanisms include upregulation of orexin neurons and altered cerebral glucose metabolism.^52,54

Diabetes complications

A number of studies have shown that OSA may be associated with increased risk of the complications of diabetes independent of glucose control. These studies were not randomized controlled trials and were based on observational findings at a point in time from the populations examined. It may be possible that control group comparisons were difficult, given the nature of the complications necessitating treatment. West et al. showed that in males with type 2 diabetes, the presence of OSA is associated with diabetic retinopathy.⁵⁶ Mason et al. found a high prevalence of SDB in patients with type 2 diabetes and diabetic macular oedema, although no relationship was observed between the severity of SDB as defined by ODI and macular oedema.⁴⁶ Proposed mechanisms that may influence retinal damage include increases in blood pressure and sympathetic activation, oxygen desaturation causing retinal hypoxia with production of vascular growth factors and autonomic dysregulation.⁴⁶ Tahrani et al. reported an association between OSA and peripheral neuropathy in patients with type 2 diabetes and proposed increased oxidative stress and microvascular changes as potential mechanisms.⁸⁸

In relation to diabetes nephropathy, a prospective study to evaluate the OSA and microalbuminuria found no correlation between urinary albumin excretion and OSA in a cohort with type 2 diabetes, although this may have been due to the small study sample size.⁴⁵ In another study of Japanese subjects, nocturnal intermittent hypoxia was found to be associated with microalbuminuria in females with type 2 diabetes.⁸⁹

Metabolic syndrome

The association between OSA and the metabolic syndrome may influence cardiometabolic dysregulation.⁹⁰ OSA patients are more likely to have abnormalities in components characterizing the metabolic syndrome, and conversely, there may be a higher prevalence of OSA in patients with metabolic syndrome.⁹¹

Many studies have demonstrated relationships between OSA and metabolic syndrome (Figure 1). In patients well matched for total adiposity, it was found that OSA was independently associated with metabolic syndrome components including increased blood pressure, higher fasting insulin and dyslipidaemia and increased insulin resistance (higher Homeostasis Model Assessment values).²⁶ In another study, this association was found to be independent of obesity mainly from increased triglyceride, glucose but not insulin resistance.⁴¹ In Chinese OSA subjects, there was a fivefold risk of having metabolic syndrome that was associated with waist circumference, diastolic blood pressure and fasting glucose.⁹² Such effects may be independent of obesity, for example, the severity of OSA as measured by the AHI was found to be a strong predictor of metabolic syndrome parameters that included hypertension, dyslipidaemia and hyperglycaemia.⁹³ Another study demonstrated that non-obese OSA subjects had metabolic abnormalities associated with dyslipidaemia and hypertension.⁴³ Thus, the coexistence of metabolic syndrome and OSA may have detrimental effects on cardiovascular risk and glycaemia. The extent to which OSA has direct effects on components of the metabolic syndrome was found to be dependent on the severity of OSA⁹³ and was correlated with insulin resistance and inflammatory markers.⁹⁴ It is conceivable that OSA itself may represent a complex marker of adverse metabolic and cardiovascular factors. OSA may simply be a marker for upper body obesity, as most of the studies did not measure this directly; however, those studies that controlled for total body fat and fat distribution, for example, using bioimpedance,²⁶ computed tomography⁹³ and waist–hip ratio,⁹¹ still show a striking excess of metabolic syndrome in OSA patients. It seems unlikely that small residual differences in body composition explain the entire clinical picture; furthermore, there are a number of plausible biological mechanisms that link OSA itself to components of the metabolic syndrome.

There have been advances in our understanding of the important contributions of OSA to metabolism with findings from studies on the components of the metabolic syndrome and the influence of OSA, with potential interactions that may influence predisposition to cardiometabolic dysregulation. The parameters defining metabolic syndrome may be important in determining susceptibility to cardiovascular mortality. In an observational study, a significant trend was noted between all-cause or cardiovascular mortality and the number of risk factors and that risk was increased with the number of metabolic syndrome components.⁹⁵ In another study, it was found that metabolic syndrome did not predict cardiovascular mortality independently of the individual variables.⁹⁶ Further longitudinal studies are needed to elucidate the prognostic implications of metabolic syndrome parameters in OSA.²⁸

Obesity

In OSA patients, many factors may contribute to the effects on metabolism. OSA patients were found to have greater visceral adiposity compared with BMI-matched obese controls, and there was a strong association between visceral obesity and OSA.³⁹ Intra-abdominal and visceral adiposity has been closely associated with insulin resistance with increased lipolysis and fatty acid availability⁹⁷ as well as dyslipidaemia, hypertension and hyperglycaemia.⁹³

Obesity is associated with mechanical effects that may predispose to upper airway obstruction. The mechanisms causing upper airway obstruction in obesity are only partly understood.¹² Suggested mechanisms include adiposity in the neck leading to increased neck circumference, with pharyngeal airway narrowing and enlargement of tissue in the upper airways such as the lateral pharyngeal wall and posterior tongue. Lung volumes are also reduced due to the effects of central obesity in recumbency that may decrease tracheal traction forces and pharyngeal wall tension.⁹⁸ Upper airway collapsibility is increased and lung volumes may be decreased.¹² Other reported mechanisms include neuromechanical changes such as adipokines and inflammatory cytokines that may modulate upper airway patency⁹⁹ and ventilatory stability.^12,100

Hypertension

It is known that OSA has an adverse effect on blood pressure and OSA patients have an increased risk of hypertension, independent of obesity and age.^101,102 Furthermore, untreated patients with proven OSA have been found to have an increased risk of hypertension.¹⁰³ This may be attributable to increased sympathetic activity, with chemoreflex activation, oxidative stress, systemic inflammation and endothelial dysfunction from repeated arousals and intermittent hypoxia.^104,105 There may be a role for vasoactive hormones such as renin–angiotensin–aldosterone system activation in OSA-related hypertension with evidence of increased angiotensin II and aldosterone levels in OSA although this remains to be clarified.^105,106 Additionally, the effects of reduced slow wave sleep on vascular function in OSA may affect cardiorespiratory function by increasing sympathetic activation and pressor responses.¹⁰⁷

Dyslipidaemia

In patients with metabolic syndrome, it was observed that patients with OSA had higher triglycerides, cholesterol, low-density lipoprotein (LDL), cholesterol (HDL) and triglycerides(HDL ratios); furthermore, OSA severity (AHI) was independently associated with increased triglycerides and cholesterol/HDL ratio.¹⁰⁸ In the Sleep Heart Health study, alterations in lipid profiles were found in relation to the respiratory disturbance index (RDI) in different subject groups. For example, HDL cholesterol levels were inversely related to the RDI in women and in men aged less than 65 years; triglyceride levels were associated with the level of RDI only in younger men and women. Total cholesterol level did not vary across quartiles of RDI, although there was a trend towards higher cholesterol in those with higher RDI in the men aged less than 65 years.¹⁰⁹ Another study of OSA patients observed a significant association between the AHI and HDL cholesterol that was independent of age, gender, BMI, diabetes and lipid-lowering medication; at 6 months, there were improvements in lipid levels with CPAP therapy.¹¹⁰

The link between severity of OSA and lipid metabolism is not fully understood and may involve activation of the inflammatory cascade⁷⁸ and intermittent hypoxia.¹¹¹ Several murine studies have provided evidence for potential mechanisms. Chronic intermittent hypoxia may induce dyslipidaemia through increased triglyceride and phospholipid synthesis⁵⁸ and may lead to upregulation of expression of pathways involved in lipid synthesis.⁵⁹ Impaired clearance of triglyceride-rich lipoproteins and inactivation of lipoprotein lipase and upregulation of lipoprotein lipase inhibition may contribute to hyperlipidaemia fasting levels of plasma triglycerides and very LDL cholesterol.^112,113 With animal models of intermittent hypoxia, there may be more control over variables such as diet, genotypes, oxygen profile, obesity and sleep fragmentation.¹¹⁴ The protocols may however vary in frequency, intermittent hypoxia cycle length and severity of the hypoxic stimulus.⁴⁷ Levels of intermittent hypoxia may be more severe than that seen in OSA. Furthermore, intermittent hypoxia causes hypoxaemia with hyperventilation and hypocapnia rather than hypercapnia that occurs with airway obstruction.¹¹⁴ These factors may potentially affect gene expression and may limit generalizability of these findings.

Treatment – CPAP

CPAP treatment abolishes repetitive upper airway obstruction during sleep to reduce daytime sleepiness and improves health status and quality of life.^115,116 CPAP intervention studies have allowed the study of the potential effects of OSA treatment and whether specific effects in patients can be modified and provided important insights on the relation between SDB and altered metabolism. OSA therapy may be a potential avenue for addressing cardiometabolic risk given the role of OSA in glycaemic and metabolic dysregulation.

Diabetes

Studies have explored that the influence of CPAP therapy on glucose homeostasis has thus far yielded mixed findings.^117
–119 Harsch et al. reported that there was improved insulin sensitivity in patients without diabetes at 2 days and at 3 months of CPAP treatment,¹²⁰ but these subjects were non-obese, limiting the generalizability of this finding. Although Dawson et al. found no significant change in glycated haemoglobin (HbA1c) levels after an average of 41 days of CPAP treatment, it was noted that nocturnal glucose levels were decreased with CPAP therapy and therefore a potential effect on glycaemia.¹²¹ In an observational study by Babu et al., there were lower fasting and postprandial glucose levels following 3 months of CPAP, with improved glycaemic control in patients with HbA1c > 7%.¹²² Nevertheless, these studies were limited by an absence of a placebo treatment group.

Several randomized controlled trials have been performed (Table 2). It was demonstrated that nasal CPAP treatment of OSA for 1 week improved insulin sensitivity in males without diabetes, and this improvement appeared to be maintained after 12 weeks of treatment in those with moderate obesity.¹²³ Another study by Weinstock et al. found that CPAP did not aid a reversion to normal glucose tolerance in subjects with impaired glucose tolerance. However, there was suggestion of improved insulin sensitivity in those patients with severe OSA (AHI > 30).¹²⁴ However, West et al. reported that CPAP treatment compared with sham-CPAP treatment in men with OSA and type 2 diabetes improved Epworth Sleepiness Scale (ESS) scores, but did not improve glycaemic control or insulin resistance.¹²⁵ Individual heterogeneity in terms of glycaemic responses to CPAP suggests most of these studies were probably underpowered to show significant effects on glycaemic control and that the encouraging results seen in uncontrolled observational studies are in general not confirmed in randomized controlled trials. It is possible that for individuals with impaired glucose tolerance, other approaches such as intensive lifestyle intervention may be more effective in preventing progression to type 2 diabetes.^126
–128 Nevertheless, a recent observational study of OSA patients with type 2 diabetes assessed clinical outcomes and cost-effectiveness of CPAP treatment compared with non-treatment. It was found that CPAP use was associated with significantly lower blood pressure, improved glycaemic control and was more cost-effective compared with patients who were not treated with CPAP.¹²⁹ However, this study had limitations because patients were not randomized to the treatments received, by the use of observational data and reliance on clinical outcome findings that were based on clinical entries in patient records. Therefore, no cause-and-effect inferences regarding CPAP treatment and these outcomes can be made.

Table 2.

Therapeutic versus sham-CPAP studies in glucose control and insulin resistance.

Study	Population	Parameters	CPAP regimen	Findings	Reference
West et al.	42 Men with type 2 diabetes and newly diagnosed OSA (>10 oxygen desaturation of >4% per hour) randomized	Glycaemic control and insulin resistance (insulin resistance was assessed by both HOMA and euglycaemic hyperinsulinaemic clamp); lipid profile, adiponectin and hs-CRP	Randomized to therapeutic (n = 20) or placebo CPAP (n = 22) for 3 months	CPAP did not affect glycaemic control or insulin resistance.	¹²⁵
Comondore et al.	Subjects with AHI > 15 (13 patients completed protocol)	Cardiovascular measures (urinary microalbumin, catecholamines, blood pressure, homeostasis model for insulin resistance score and endothelial function)	Randomized to either CPAP or no therapy for 4 weeks followed by washout for 4 weeks and then a crossover to the other intervention	Although insulin resistance (HOMA) decreased with CPAP, the difference was not significant. Likewise, the other cardiovascular measures did not show significant improvements.	¹³⁰
Lam et al.	61 Men randomized with moderate-to-severe OSA (AHI > 15)	Effects of nasal CPAP treatment of OSA on insulin sensitivity in male subjects without diabetes mellitus	Randomized to therapeutic nasal CPAP (n = 31) or sham-CPAP (n = 30) (n = 29 completed 12 weeks therapeutic CPAP, n = 30 completed 1 week of sham-CPAP)	Therapeutic nasal CPAP treatment for 1 week improved insulin sensitivity in obese men (BMI > 25) without diabetes, and the improvement was maintained after 12 weeks of treatment.	¹²³
Weinstock et al.	50 Subjects with OSA (AHI > 15) and impaired glucose tolerance	Normalization of the mean 2-h OGTT; a secondary outcome was improvement in the Insulin Sensitivity Index	Randomized to 8 weeks of CPAP or sham-CPAP; patients crossed over to other therapy after a 1-month washout	CPAP did not normalize impaired glucose regulation. Insulin sensitivity improved in subjects with severe OSA (AHI ≥ 30).	¹²⁴
Hoyos et al.	65 Men randomized with AHI > 20 and ODI >15 (46 completed protocol)	Visceral abdominal and liver fat, insulin sensitivity	Real or sham-CPAP for 12 weeks; at the end of the 12-week blinded period all participants had real CPAP for an additional 12 weeks	No group differences at 12 weeks; at 24 weeks, insulin sensitivity was improved but not visceral abdominal or liver fat.	¹³¹

OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure; HOMA: Homeostasis Model Assessment; hs-CRP: high-sensitivity C-reactive protein; AHI: apnoea–hypopnoea index; BMI: body mass index; OGTT: oral glucose tolerance test; ODI: oxygen desaturation index.

Metabolic syndrome

In order to understand CPAP treatment effects on cardiometabolic profiles, studies have examined the effect of CPAP on the metabolic syndrome components as end points. Randomized controlled trials have evaluated the metabolic syndrome by comparing therapeutic and sham-CPAP (Table 3). A meta-analysis of randomized trials found that there were favourable effects of CPAP treatment in terms of improving blood pressure responses.¹³⁴ In terms of the effects on lipid profiles, there have been mixed results from different studies although the current evidence suggests that CPAP treatment may decrease total and LDL cholesterol.¹³⁵ Previous work by Coughlin et al., a randomized crossover trial with sham-CPAP as control did not show any differences in lipids.¹³² In other controlled trials, Comondore et al. randomized subjects to 4 weeks of CPAP or no therapy, with crossover after washout for 4 weeks; although no significant difference in lipid levels were found, there appeared to be reduced triglyceride levels.¹³⁰ Robinson et al. randomized patients to either 1 month therapeutic or sub-therapeutic CPAP and found a trend towards a decrease in total cholesterol after CPAP.¹³⁶ One randomized crossover trial with 2 months of therapeutic and sham-CPAP showed that treatment with CPAP improved postprandial triglyceride and total cholesterol levels.¹³⁷

Table 3.

Therapeutic versus sham-CPAP studies in metabolic syndrome.

Study	Population	Parameters	CPAP regimen	Findings	Reference
Coughlin et al.	Randomized controlled trial. 35 OSA subjects randomized (34 completed protocol)	Metabolic syndrome (using NCEP-ATP III); blood pressure, glucose, lipids and insulin resistance	Each group received 6 weeks of therapeutic or sham-CPAP, then treatment crossover for further 6 weeks	Significant decreases in systolic and diastolic blood pressure. No change in glucose, lipids, insulin resistance or the proportion of patients with metabolic syndrome.	¹³²
Hoyos et al.	Analysis of results from a randomized controlled trial. 65 Men with OSA randomized (46 completed protocol)	Effect on metabolic syndrome (using international consensus guidelines and NCEP-ATP III criteria) (analysis of results from Hoyos et al.¹³¹)	Real or sham-CPAP for 12 weeks	12 weeks of CPAP therapy had did not affect numbers of patients with metabolic syndrome	¹³³

OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure; NCEP-ATP III: National Cholesterol Education Program–Adult Treatment Panel III.

An interventional controlled study in men without diabetes did not find a significant change in weight, body fat, insulin resistance or lipid profiles with 6 weeks of CPAP treatment as opposed to sham-CPAP therapy.¹³² Nevertheless, there were improvements in blood pressure control following CPAP intervention.¹³² A controlled study by Hoyos et al. evaluated 12 weeks of therapeutic versus sham-CPAP on visceral adiposity and insulin sensitivity in males without diabetes and found that there was no significant effect of CPAP on either parameter.¹³¹ In a further analysis, it was noted that the 12 weeks of CPAP therapy did not have a significant effect on the number of subjects with metabolic syndrome.¹³³ In another placebo-controlled study by Kritikou et al. compared 2 months of therapeutic and sham-CPAP in non-obese subjects and found no significant difference in metabolic markers including IL-6, TNF, leptin, adiponectin and highly sensitive C-reactive protein. CPAP treatment was not sufficient to alter these factors in this study, although it was noted that the short duration of therapy may have limited metabolic alterations.¹³⁸ Taken together, the results of studies suggest that CPAP in isolation may not be sufficient for OSA patients with the metabolic syndrome, although there is reasonably consistent evidence for a beneficial effect on blood pressure. It has been proposed that there may be a role for a multifaceted approach for these individuals in order to manage their cardiometabolic risk.¹²⁶ Thus it is envisaged that measures to promote proper sleep hygiene and weight loss may be important.

Treatment – weight loss

It is clear that the promotion of weight loss activities and lifestyle changes has the potential to improve glucose regulation. There is also evidence that supports the role of weight loss in the treatment of OSA.¹⁴⁸ These studies are presented in Table 4. In the Wisconsin Sleep Cohort study, subjects were prospectively observed for change in AHI and the development of SDB with weight change; weight control was associated with decreased AHI and a reduced likelihood of OSA.¹³ These findings are supported by evidence from randomized controlled trials. In the Sleep AHEAD study, obese subjects with type 2 diabetes and OSA were either randomized to a programme of intensive lifestyle intervention comprising behavioural weight loss and physical activity or to diabetes support and education. It was found that the intensive lifestyle intervention reduced weight and AHI over 4 years more than diabetes support and education alone.¹³⁹ Other randomized trials investigating various lifestyle modifications such as very low-calorie diets (VLCDs) combined with active lifestyle counselling,¹⁴⁰ intensive exercise training,¹⁴² cognitive–behavioural weight loss, and VLCD¹⁴³ showed improved OSA severity with these interventions. These effects of lifestyle measures in OSA may potentially be sustained over time.^139,141 In a randomized parallel group trial that compared the effects of CPAP, weight loss or both treatments for 24 weeks in adults with obesity, combination therapy with weight loss and CPAP had a beneficial effect in reducing insulin resistance, serum triglyceride levels and blood pressure.¹⁴⁵

Table 4.

Selected studies relating to weight loss in OSA.

Lifestyle interventions
Study	Population	Study protocol	Key findings	Reference
Peppard et al.	690 Randomly selected employed Wisconsin residents	Prospective study of change in AHI and odds of developing moderate-to-severe SDB with respect to change in weight	Relation between weight gain and increased SDB severity. Weight loss was associated with reduced SDB severity and likelihood of developing SDB.	¹³
Kuna et al.	264 Obese adults with type 2 diabetes and OSA	Randomized to either intensive lifestyle intervention with a behavioural weight loss programme (controlled diet, physical activity) or diabetes support and education (three group sessions annually) over 4 years	Intensive lifestyle intervention produced greater reductions in weight and AHI over 4 years than diabetes support and education. Effects on AHI persisted at 4 years, despite an almost 50% weight regain.	¹³⁹
Tuomilehto et al.	72 patients (BMI 28–40) with mild OSA completed the protocol	Randomized to either VLCD programme with supervised lifestyle modification or routine lifestyle counselling for 1 year	VLCD combined with active lifestyle counselling effectively reduced body weight and a significant reduction in AHI compared with the control group.	¹⁴⁰
Tuomilehto et al.	Follow-up study to Tuomilehto et al.¹⁴⁰ 57 Patients completed the follow-up over 4 years	Assessment of long-term efficacy of lifestyle intervention during 4-year follow-up in OSA subjects who participated in the initial 1 year randomised intervention trial (see Tuomilehto¹⁴⁰)	Intervention achieved reduction in the incidence of progression of the OSA compared with the control group. The improvement in OSA that was sustained even 4 years after the active intervention.	¹⁴¹
Kline et al.	43 Sedentary and overweight/obese adults with OSA AHI ≥ 15	Randomized to intensive exercise training or low intensity stretching regimen	Compared with stretching, exercise resulted in a significant reduction in AHI and ODI despite non-significant changes in body weight.	¹⁴²
Kajaste et al.	31 Obese male symptomatic OSA patients (ODI > 10)	All subjects had active weight reduction based on the CBT approach (24 months) and a VLCD (6 weeks) and were randomly selected to have either nasal CPAP or without CPAP for the initial 6 months	Weight loss and improvement of OSA was achieved by the CBT weight loss programme. CPAP in the initial phase of the weight reduction program did not result in significantly greater weight loss.	¹⁴³
Thomasouli et al.	Systematic review and meta-analysis of 12 randomized controlled trials with lifestyle interventions in adults with OSA. Diet and diet plus CPAP therapy were compared in three studies (n = 261), and intensive lifestyle programmes and routine care were compared in six studies (n = 483)	To evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity and OSA parameters	Intensive lifestyle management can significantly reduce obesity and OSA severity Lifestyle modification combined with CPAP may confer additional benefits in OSA	¹⁴⁴
Chirinos et al.	181 obese patients, moderate-to-severe OSA and CRP >1 mg/L. 136 completed the study. Intention to treat analysis for 146 subjects	Randomized parallel group 24-week trial that compared the effects of CPAP, weight loss or both in adults with obesity (weight loss interventions included weekly counselling, unsupervised exercise and CBT)	Weight loss with CPAP therapy had an incremental effect in reducing insulin resistance and serum triglyceride levels, compared with CPAP alone. Additionally, combined treatment may result in a larger reduction in blood pressure than either treatment alone.	¹⁴⁵
Metabolic bariatric surgery
Dixon et al.	60 Obese patients (BMI 35–55), recently diagnosed OSA AHI ≥ 20	Randomized to a conventional weight loss programme (regular consultations with dietician and physician, with use of VLCDs) or to laparoscopic adjustable gastric banding.	Bariatric surgery produced greater weight loss but did not result in a statistically greater reduction in AHI than conventional weight loss therapy.	¹⁴⁶
Buchwald et al.	Systematic review and meta-analysis of 136 fully extracted studies (total 22,094 patients)	Systematic review and meta-analysis to determine the impact of bariatric surgery on weight loss, diabetes, hyperlipidaemia, hypertension and OSA.	Bariatric surgery produced effective weight loss in morbidly obese individuals with beneficial effects in the majority in terms of diabetes, hyperlipidaemia, hypertension and OSA.	¹⁴⁷

AHI: apnoea–hypopnoea index; SDB: sleep-disordered breathing; BMI: body mass index; VLCD: very low-calorie diet; OSA: obstructive sleep apnoea; ODI: oxygen desaturation index; CBT: cognitive–behavioural therapy; CPAP: continuous positive airway pressure; CRP: C-reactive protein.

Concerning the effects of surgical weight loss, in a meta-analysis of bariatric surgery outcomes, Buchwald et al. reported improvements in glycaemic control, dyslipidaemia, hypertension, blood pressure and OSA following bariatric surgery, but the included studies were often of poor quality with a high proportion of patients lost to follow-up.¹⁴⁷ However, a randomized controlled trial investigated whether weight loss by bariatric surgery (laparoscopic gastric banding) was more effective than conventional weight loss therapy (medical consultations and low calorie diets) in the management of OSA. Despite more significant weight loss, it was found that surgical weight loss did not lead to significantly greater improvements in OSA, and, therefore, most patients would still require CPAP treatment post-bariatric surgery.¹⁴⁶ Hence bariatric surgery alone may not be sufficient to obviate the need for CPAP therapy. In a review that sought to compare surgical and non-surgical weight loss studies in relation to BMI and AHI, no definitive statement could be made regarding the relative benefits of surgical therapy in OSA mainly because of inherent differences between trials and the need for more comparative studies between surgical and non-surgical methods of treating OSA.¹⁴⁹ Nevertheless, in relation to metabolic effects, improved glycaemic control is seen in type 2 diabetes with surgical weight loss approaches.^150,151 It is possible that the different pathophysiological mechanisms operating in OSA may not be completely reversed by surgical weight loss alone, despite our knowledge of the potential for amelioration of cardiometabolic risks with weight loss in obesity and type 2 diabetes by lifestyle modifications. Conceivably, it would be expected that the extent of patient responses to different approaches may differ according to individual circumstance. Thus, a combination of weight loss interventions and CPAP may be complementary in influencing health outcomes for OSA patients.¹⁴⁴

Conclusion

In summary, there are multiple interacting mechanisms intricately linked with intermittent hypoxia and sleep fragmentation in OSA, which may contribute to the associations between OSA, type 2 diabetes and metabolic dysregulation. These include changes in sympathetic nervous system activity, hormonal changes, inflammation and oxidative stress. The rising rates of obesity and diabetes and the increasing awareness of the potential role of SDB, in particular OSA, to increase cardiometabolic risk means that further investigation of the mechanisms by which OSA drives metabolic risk and potential methods for early screening or assessment are important. Knowledge of these interactions may potentially yield molecular and therapeutic targets, for example, by identification of mechanistic links, which may also improve management of SDB in patients who are at risk, thereby improving health outcomes.

Footnotes

Acknowledgements

We thank the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals, UK.

Conflict of interest

The authors declared no conflicts of interest.

Funding

This research has received grants from the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals.

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Sleep-disordered breathing,type 2 diabetes and the metabolic syndrome

Abstract

Keywords

Introduction

Search strategy

Compromised metabolism

Insulin resistance and type 2 diabetes

Autonomic function

HPA axis

Oxidative stress and activation of inflammatory pathways

Changes in adipokine profiles

Sleep duration/fragmented sleep

Diabetes complications

Metabolic syndrome

Obesity

Hypertension

Dyslipidaemia

Treatment – CPAP

Diabetes

Metabolic syndrome

Treatment – weight loss

Conclusion

Footnotes

Acknowledgements

Conflict of interest

Funding

References