Abstract: Obstructive sleep apnea (OSA) and type 2 diabetes are both closely related to obesity and their prevalence is increasing due to the rising average body weight in Western countries. The findings of epidemiological studies have implicated that OSA increases the risk for cardiovascular disease, and metabolic disturbances, such as insulin resistance, may link OSA to vascular morbidity. A number of observational clinical studies have evaluated the relationship between OSA and insulin resistance, suggesting an independent association. However, the confounding effect of obesity complicates the establishment of a causal relationship between OSA and insulin resistance. Potential mechanisms that may underpin this relationship were evaluated in animal and human experimental studies and include intermittent hypoxia, arousals from sleep with concomitant sympathetic activation and sleep fragmentation. Currently only three randomized controlled trials investigating the effects of OSA on insulin resistance have been published. In these trials OSA patients were randomly assigned to treatment with continuous positive airway pressure (CPAP) or subtherapeutic CPAP and treatment effects on various measures of insulin resistance were examined. In two of these trials there was no effect of CPAP on glucose metabolism and in one trial a small beneficial effect of CPAP was observed. Further carefully conducted clinical studies and randomized controlled interventional CPAP trials are needed to determine the extent to which OSA is a risk factor for diabetes and its effect on glucose metabolism.
Obstructive sleep apnea (OSA) is a disorder characterized by repetitive episodes of partial or complete collapse of the upper airway during sleep leading to apnea and hypopnea. In severely affected patients more than 30 apneas occur per hour and are associated with oxygen desaturations, increased respiratory effort, and arousals from sleep (Kohler and Stradling, 2010). Symptomatic OSA is highly prevalent and occurs in about 4% of middle-aged men and in 2% of middle-aged women (Young et al., 1993). However, minimally symptomatic or asymptomatic OSA is estimated to occur in about one out of five adults (Young et al., 2002). As obesity is a major risk factor for OSA, the prevalence of OSA is expected to increase as the average body weight of the population rises. Sleep apnea may lead to a number of acute consequences, of which daytime sleepiness is the most noticeable for affected patients. Sleepiness causes impairment of quality of life and increases the risk of accidents, including when driving or operating machinery (Barbe et al., 1998; George et al., 2002). OSA is also proposed to be associated with a substantial cardiovascular morbidity (Marin et al., 2005) and has been proven to be an independent risk factor for hypertension (Haentjens et al., 2007; Kohler et al., 2008).
The treatment of choice for OSA is continuous positive airway pressure (CPAP) therapy (Jenkinson et al., 1999; Giles et al., 2006). The CPAP device generates a positive pressure in the upper airways via a breathing mask, preventing airway collapse, apneas, and sleep fragmentation, thus providing a more restful sleep without intermittent hypoxia and recurrent arousals from sleep.
Excess weight and visceral obesity are the predominant risk factors for insulin resistance and type 2 diabetes (Mokdad et al., 2001; Kopelman, 2000). In insulin resistance, body cells become increasingly resistant to the effects of insulin and this condition precedes the evolution of type 2 diabetes where the pancreas cannot produce sufficient insulin to maintain normoglycemia. Due to the higher prevalence of diabetes in patients with OSA as compared with the normal population (Meslier et al., 2003), it has been postulated that OSA may be a causal factor in the pathogenesis of diabetes.
Mechanisms underpinning the association between OSA and diabetes may include intermittent hypoxia and consecutive increased oxidative stress as well as arousals associated with sympathetic nervous system activation and sleep fragmentation (Punjabi et al., 2003).
In this review, we summarize the evidence on potential mechanisms underpinning the association between OSA and diabetes and discuss the results from epidemiological, clinical, and interventional studies.
Mechanisms Underpinning the Association Between OSA and Insulin Resistance
Intermittent hypoxia and oxidative stress
Obstructive apneas are often associated with oxygen desaturations resulting in intermittent hypoxia. As the effects of intermittent hypoxia are difficult to segregate from the effects of arousals, sympathetic activation, and sleep fragmentation, a limited number of studies used simulated intermittent hypoxia to clarify basic mechanisms in animal models by cycling delivery of oxygen, nitrogen, and air in closed chambers. In non-obese mice, intermittent hypoxia for 9 hours (60 cycles/hour with a FiO2 nadir of 5-6%) was shown to increase insulin resistance assessed by the hyperinsulinemic euglycemic clamp technique (Iiyori et al., 2007). This increase in insulin resistance also persisted when the autonomous nervous system was chemically blocked and thus the effect of intermittent hypoxia seemed to be independent from sympathetic nervous system activity. This might be due to intermittent hypoxia causing an increase in counter regulatory glucocorticoid levels. In obese mice, exposure to 12 weeks of intermittent hypoxia produced a sustained increase in insulin resistance (Polotsky et al., 2003). In the latter study, deficient leptin levels were identified as a factor linking intermittent hypoxia and insulin resistance as replacement or up-regulation of leptin protected the animals against the development of insulin resistance.
Another mechanism linking intermittent hypoxia with insulin resistance may be via increased oxidative stress, which itself has been implicated as a contributor to the onset of diabetes (Rains and Jain, 2011). The exact mechanisms by which oxidative stress may cause insulin resistance are unknown (Dandona et al., 2004; Maddux et al., 2001). In an animal model of long-term intermittent hypoxia (8 weeks) simulating oxygenation patterns of OSA in mice, several NADPH oxidase proteins were activated promoting oxidative injury and proinflammatory gene expression (Zhan et al., 2005). In another animal model study, simulated cycles of hypoxia and re-oxygenation accounted for a state of oxidative stress and significant increase of reactive oxygen species in mice (Xu et al., 2004).
There is also evidence that simulated intermittent hypoxia (6 hours per day for 4 days) in healthy humans leads to an increased level of oxidative stress by increased production of reactive oxygen species (Pialoux et al., 2009); however, data of simulated intermittent hypoxia in humans and its effect on glucose metabolism is scant. An experiment in 14 healthy volunteers revealed that exposure to hypoxia for 30 minutes (oxygen saturation 75%) caused glucose intolerance (Oltmanns et al., 2004). In the latter study, neurohormonal stress response was also evaluated and an increase in plasma epinephrine concentration was noted under hypoxic conditions. The effect of acute intermittent hypoxia on glucose metabolism was investigated in only one study; 13 healthy volunteers were exposed to 5 hours of intermittent hypoxia or normoxia during wakefulness (Louis and Punjabi, 2009). The authors reported a decrease in insulin sensitivity with intermittent hypoxia and a shift in sympathovagal balance towards an increase in sympathetic nervous system activity.
In summary, the present evidence from experimental studies in animals and humans indicate that intermittent hypoxia and concomitant oxidative stress may have a negative impact on glucose metabolism, predisposing to insulin resistance (Figure 1).
Arousals, sympathetic activation, and sleep fragmentation
Arousals are transient cortical activations during sleep that may occur as a result of interrupted ventilation in OSA. Fragmentation of sleep by arousals impairs the restorative slow-wave sleep and there is a close relationship between arousals and increased sympathetic nervous system activity. The individual effects of arousals on autonomous nervous system activity are difficult to disentangle. Mice exposed for 35 days to intermittent hypoxia showed increased levels of catecholamines and elevation in blood pressure (Dematteis et al., 2008). Randomized controlled studies investigating the effects of CPAP on catecholamine levels proved a causal relationship between OSA and increased sympathetic activation (Kohler et al., 2008). Increased sympathetic nervous system activity has been linked to insulin resistance in population based studies (Masuo et al., 1997).
In 11 healthy volunteers the impact of sleep time restriction and consecutive sympathetic activation on glucose metabolism was evaluated (Spiegel et al., 1999). A restricted sleep time of 4 hours per night lead to considerably increased sympathetic activity and a nearly 40% slower rate of glucose clearance when compared to 8 hours of sleep. Mechanisms by which sleep fragmentation may induce insulin resistance were recently studied in 11 healthy volunteers (Stamatakis and Punjabi, 2010). Fragmented sleep achieved by auditory and mechanical stimuli (approximately 30 events/hour) lead to a decrease in insulin sensitivity and to an increase in morning serum cortisol levels confirming increased nocturnal sympathetic activity. The authors of this study concluded that independent of sleep duration, fragmentation of sleep itself leads to altered glucose metabolism. In another experimental study including 9 healthy volunteers, slow wave sleep was suppressed by delivering acoustic tones of varying frequency (Tasali et al., 2008). This resulted in marked decreases in insulin sensitivity without adequate compensatory increases in insulin release.
In a recent controlled observational study, the effects of sleep duration and fragmentation on glucose metabolism were investigated with 6 days of wrist actigraphy to estimate sleep duration in 40 subjects with type 2 diabetes and 115 subjects without diabetes (Knutson et al., 2011). The results of this study suggested that sleep duration and fragmentation was not associated with abnormal glucose metabolism or insulin resistance in those without diabetes, but in those with diabetes, sleep fragmentation was associated with higher fasting glucose and insulin resistance.
The findings of these described studies suggest that increased sympathetic activity may be a mechanism linking OSA and impaired glucose metabolism.
The impact of sleepiness in relation to glucose metabolism in OSA was also evaluated in a limited number of studies. Barcelo et al. (2008) suggested that the presence of daytime sleepiness plays a crucial role in the pathogenesis of insulin resistance in OSA. The authors examined 22 OSA patients with daytime sleepiness and 22 without daytime sleepiness regarding their glucose metabolism. Excessive daytime sleepiness in OSA was associated with increased insulin resistance irrespective of obesity. More recently, 25 newly diagnosed otherwise healthy OSA patients with daytime sleepiness were compared to 25 age- and BMI (body mass index)-matched, non-sleepy OSA patients who served as controls (Nena et al., 2011). In this study, daytime sleepiness was associated with hyperglycemia, hyperinsulinemia, and increased insulin resistance.
In summary, the results of these studies suggest that insulin resistance and disturbed glucose metabolism may occur particularly in OSA patients suffering from increased daytime sleepiness.
Population Based Studies on Diabetes and OSA
In a study from the UK, 1,682 diabetics were included in a study investigating the prevalence of OSA in patients with type 2 diabetes. Based on a questionnaire and a subset of men studied with overnight oximetry, 23% of the diabetic men were estimated to have OSA (West et al., 2006).
Punjabi et al. (2004) demonstrated in a large study with 2,656 subjects that the severity of OSA assessed by the apnea-hypopnea index (AHI) was associated with fasting blood glucose levels. Further analysis of polysomnographic data also revealed that the degree of sleep-related hypoxemia was strongly associated with indices of glucose intolerance and insulin resistance. This association remained significant after adjustment for several important confounding covariates, including body mass index and waist circumference.
In 400 women, the association between OSA and insulin sensitivity was investigated by measurement of fasting blood glucose and glucose tolerance testing (Theorell-Haglow et al., 2008). AHI was found to be independently associated with decreased insulin sensitivity, after adjustment for age, waist-to-hip ratio, and self-reported physical activity.
The results of another large clinical study including 595 men with sleep-disordered breathing (494 patients with OSA and 101 non-apnoeic snorers) suggested an independent relationship between OSA severity and impaired glucose metabolism, after adjustment for body mass index and age (Meslier et al., 2003).
Glucose metabolism was assessed in 40 OSA patients, in 40 matched obese control subjects without OSA, and in 40 control subjects with normal weight (Sharma et al., 2007). In this study, patients with OSA were not found to have higher levels of fasting blood glucose or higher insulin resistance than obese control subjects without OSA. Thus, the authors concluded that obesity, but not sleep apnea, is responsible for the dysregulation of glucose metabolism.
Supporting this finding, Davies et al. (1994) evaluated 15 OSA patients and 18 snorers matched for age, sex, and BMI and found no difference in fasting insulin levels between the two groups.
In contrast, a rigorously matched case-control study from Japan compared 42 men with OSA with 52 men without OSA matched for age, BMI, and visceral fat (assessed by computed tomography) (Kono et al., 2007), and the authors found that fasting blood glucose was significantly higher in patients with OSA compared to control subjects. The different results from these studies may reflect their difficulties in finding a well-matched control group without OSA, with matching BMI and neck and waist circumference. Often these well matched controls are found to have OSA when sleep studies are performed. Insulin levels alone may also not be sensitive enough to show differences in insulin resistance.
Prospective Epidemiological Studies on Diabetes and OSA
The Wisconsin sleep study is the largest prospective study which investigated the prevalence and incidence of type 2 diabetes in subjects with OSA. At a 4-year follow-up (1,387 patients), there was a greater prevalence of diabetes with increasing levels of OSA, independent of age, sex, and body habitus (waist circumference). There was however no significant independent causal effect of OSA on the development of diabetes (Reichmuth et al., 2005). A more recent prospective cohort study evaluated 1,233 subjects referred for evaluation of sleep disordered breathing, of whom 544 were free from pre-existing diabetes and were re-assessed at a median follow-up time of 2.7 years (Botros et al., 2009). OSA was significantly associated with the incidence of diabetes after adjusting for age, gender, race, baseline fasting blood glucose, BMI, and change in BMI. In the same study, treatment of OSA by CPAP was associated with a reduced risk of developing diabetes but treatment was not randomly assigned. In a prospective study from Japan including more than 4,000 subjects, the number of oxygen desaturations per hour as a measure of OSA severity was independently associated with an increased risk of developing diabetes after correction for BMI (Muraki et al., 2010).
Effects of CPAP Treatment on Glucose Metabolism
It can be hypothesized that CPAP treatment of OSA would alleviate insulin resistance and improve glucose metabolism, through resolution of the intermittent hypoxia, sympathetic arousals, sleep fragmentation, and daytime sleepiness.
Several uncontrolled interventional studies investigated the effects of CPAP on glucose metabolism in diabetic and non-diabetic OSA patients. In the largest study that included 40 non-diabetic OSA patients, insulin sensitivity was assessed before and after 2 days and 3 months of CPAP therapy (Harsch et al., 2004a). The analysis showed that mean insulin resistance of the group was significantly improved at two days and these changes were sustained at three months. In those patients with a BMI of >30kg/m2 there was significant improvement of insulin sensitivity after 3 months but not after 2 days, whereas subjects with a BMI <30 kg/m2 insulin sensitivity already improved after two days with no further significant improvement at 3 months. There was no correlation between improvement in insulin resistance and CPAP compliance. The authors hypothesized that changes in sympathetic hormone activation following successful CPAP treatment may be responsible for the change in insulin resistance after two days, but changes in visceral fat distribution due to lifestyle changes may have contributed to the changes in insulin resistance seen at three months. Thus in obese OSA patients insulin sensitivity is mainly determined by obesity and the effect of OSA on insulin sensitivity may be less pronounced. The same group studied nine people with type 2 diabetes and OSA before commencing CPAP, following two nights of CPAP therapy and again after three months of CPAP (Harsch et al., 2004b). Insulin resistance was unchanged after two days of CPAP treatment, but was significantly improved after three months (p=0.02). The improvement in insulin resistance was greater in those patients with lower BMI than in more obese patients. BMI did not change.
Davies et al. (1994) investigated the effects of 3 months of CPAP therapy on insulin levels in 15 OSA patients and found no difference between insulin levels before and after treatment with CPAP. This was a small study and only measured insulin, with no measurement of insulin resistance. Trenell et al. (2007) investigated glucose metabolism in 29 obese OSA patients before and after 12 weeks of CPAP therapy. No improvement in measures of glucose control could be demonstrated, when comparing regular CPAP users to irregular users. The suggestion was made that any effect CPAP may exert on glucose metabolism is overcome by obesity. Similarly, no effect of 3 months of CPAP therapy on fasting glucose and insulin levels was found in a study including 16 obese OSA patients (Vgontzas et al., 2008).
These differing results may be accounted for by the fact that insulin resistance is subject to change by many variables, including weight loss, body fat distribution, and exercise, making a control group essential in order to interpret the effect of CPAP accurately. Acclimatization to the test being performed also occurs, meaning insulin resistance is higher the first time it is done compared to the second, regardless of the intervention (Wallace et al., 2004). A control group is also crucial to allow the significance of positive results to be interpreted.
Randomized controlled trials
Up to date only three randomized controlled trials on the effect of CPAP treatment on glucose metabolism in OSA have been published (Table 1). West et al. (2007) randomized 42 patients with type 2 diabetes and OSA (BMI = 36.7 kg/m2) to either 3 months of therapeutic or subtherapeutic (placebo) CPAP and evaluated the treatment effect on various measures of glucose metabolism and insulin sensitivity (euglycemic clamp and homeostatic model assessment, HOMA). The authors found no statistically significant improvement in insulin sensitivity and other measures of glycemic control after 3 months of therapeutic CPAP when compared to subtherapeutic CPAP. Another randomized controlled crossover trial which included 34 non-diabetic, mostly obese OSA patients (BMI = 36.1 kg/m2) evaluated the effects of 6 weeks of CPAP on fasting blood glucose and insulin resistance assessed by HOMA. Six weeks of therapeutic CPAP had no significant effect on fasting glucose and insulin resistance compared to subtherapeutic CPAP irrespective of their compliance to treatment (Coughlin et al., 2007). The authors of this study hypothesized that there might be a threshold level of obesity where excess body fat is the principal determinant of insulin sensitivity irrespective of the presence of OSA or its severity. A recently published trial from Hong Kong investigated the effects of 1 week of CPAP on insulin sensitivity assessed by short insulin tolerance test (SITT) and HOMA in non-diabetic OSA patients (BMI = 33.4 kg/m2) (Lam et al., 2010). Insulin sensitivity increased statistically significantly in the 31 patients receiving therapeutic CPAP compared to the 30 patients who received subtherapeutic CPAP. However, insulin resistance as assessed by HOMA did not differ between groups before and after treatment. After one week the study was continued uncontrolled (therapeutic CPAP only) and a significant improvement of insulin sensitivity was seen in those patients who were obese (BMI ≥ 25 kg/m2). Of note, two different techniques to estimate insulin sensitivity were used which probably represent different metabolic aspects of insulin resistance.
The published randomized controlled trials investigating the effects of CPAP on glucose metabolism in OSA patients have important differences regarding the selected patient populations (diabetic versus non-diabetic), the duration of the intervention period, and the techniques to assess insulin resistance. However, none of the trials reported an improvement of insulin resistance assessed by HOMA. It could be that CPAP use was not high enough to modify the changes in insulin resistance caused by OSA, or that in some patients, particularly those with established diabetes, insulin resistance was too severe for significant modification, but it certainly argues against a clinically important impact of CPAP treatment on glucose metabolism. However, more data from randomized controlled trials possibly including less or non-obese patients with OSA and with less severe insulin resistance are urgently needed to evaluate whether OSA plays a causative role in the pathogenesis of type 2 diabetes, and whether this should influence treatment decisions with CPAP.
Conclusions and Further Directions
OSA and type 2 diabetes are both conditions causally associated with obesity, with high levels of OSA in those with type 2 diabetes and high levels of type 2 diabetes in those with OSA. The causative effect of each condition on the other, independent of obesity, is harder to determine. To date, the evidence proving that OSA is an independent risk factor for diabetes is mostly lacking due to a limited number of carefully conducted randomized controlled trials. Randomized controlled trials investigating the effect of OSA on glucose metabolism in non-obese OSA patients with or without daytime sleepiness would possibly clarify the interrelations of the two diseases and provide further insight into basic pathophysiologic mechanisms.
Authors report no conflicts of interest.
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