Relationship of obesity and diabetes mellitus with obstructive sleep apnea syndrome

The article presents literature data from clinical studies in which obstructive sleep apnea syndrome (OSAS) is considered as a risk factor for the development of carbohydrate metabolism disorders, including type 2 diabetes mellitus. The relationship between the most significant factors influencing the progression of carbohydrate metabolism disorders in patients with obstructive sleep apnea is analyzed. An analysis of data on the relationship between obstructive sleep apnea and diabetic autonomic neuropathy and insulin resistance is provided. The possibility of using CPAP therapy to correct metabolic disorders in patients with diabetes mellitus is considered.

Type 2 diabetes mellitus (DM) is the most common chronic endocrine disease. According to Diabetes Atlas, in 2000, 151 million patients with type 2 diabetes were registered in the world. In different countries, the number of such patients ranges from 3 to 10% of the population, and according to WHO forecasts, by 2025 the number of patients with type 2 diabetes mellitus is expected to increase threefold.

The most dangerous consequences of the global epidemic of type 2 diabetes are its systemic vascular complications, which lead to disability and premature death of patients. Recently, it has been established that patients with type 2 diabetes are more likely to experience sleep apnea than the general population. The SHH study found that subjects with type 2 diabetes were more likely to have sleep apnea and more severe hypoxemia.

The prevalence of obstructive sleep apnea syndrome (OSAS) is 5-7% of the entire population over 30 years of age, with severe forms of the disease affecting about 1-2%. In people over 60 years of age, obstructive sleep apnea is observed in 30% of men and 20% of women. In people over 65 years of age, the incidence of the disease can reach 60%.

The following terms are used to characterize obstructive sleep apnea: apnea - complete cessation of breathing for at least 10 s, hypopnea - a decrease in respiratory flow by 50% or more with a decrease in blood oxygen saturation by at least 4%; desaturation - a drop in blood oxygen saturation (SaO2). The higher the degree of desaturation, the more severe the course of obstructive sleep apnea. Apnea is considered severe at SaO2 < 80%.

The American Academy of Sleep Medicine's proposed diagnostic criteria for obstructive sleep apnea are:

• A) severe daytime sleepiness (DS) that cannot be explained by other reasons;
• B) two or more of the following symptoms that cannot be explained by other causes:
  • choking or difficulty breathing during sleep;
  • recurring episodes of awakening;
  • "non-refreshing" sleep;
  • chronic fatigue;
  • decreased concentration.
• C) Five or more episodes of obstructive breathing disorder are detected during a polysomnographic study during one hour of sleep. These episodes may include any combination of apnea, hypopnea, or effective respiratory effort (ERE) episodes.

To make a diagnosis of obstructive sleep apnea/hypopnea syndrome, criterion A or B must be present in combination with criterion C.

The average number of apnea/hyponoe episodes per hour is designated by the apnea-hypopnea index (AHI). A value of this indicator less than 5 is considered acceptable in a healthy person, although this is not the norm in the full sense. According to the recommendations of a special commission of the American Academy of Sleep Medicine, apnea syndrome is divided into three degrees of severity depending on the AHI value. AHI < 5 is normal; 5 < AHI < 15 is mild, 15 < AHI < 30 is moderate, AHI > 30 is severe.

Obstructive sleep apnea is the result of the interaction of anatomical and functional factors. The anatomical factor is caused by the narrowing of the upper respiratory tract (URT), the functional factor is associated with the relaxation of the muscles that expand the URT during sleep, which is often accompanied by the collapse of the upper respiratory tract.

The mechanism of airway obstruction in apnea is realized as follows. When the patient falls asleep, the pharyngeal muscles gradually relax and the mobility of its walls increases. One of the next breaths leads to a complete collapse of the airways and cessation of pulmonary ventilation. At the same time, respiratory efforts are maintained and even increase in response to hypoxemia. Developing hypoxemia and hypercapnia stimulate activation reactions, i.e., a transition to less deep stages of sleep, since in more superficial stages of sleep, the degree of activity of the dilator muscles of the upper respiratory tract is sufficient to restore their lumen. However, as soon as breathing is restored, after some time, sleep deepens again, the tone of the dilator muscles decreases, and everything is repeated again. Acute hypoxia also leads to a stress reaction, accompanied by activation of the sympathoadrenal system and an increase in blood pressure. As a result, during sleep, such patients experience conditions for the development of chronic hypoxemia, the impact of which determines the diversity of the clinical picture.

The most common cause of narrowing of the airway at the level of the pharynx is obesity. Data from the American National Sleep Foundation survey showed that approximately 57% of obese people have a high risk of obstructive sleep apnea.

In severe sleep apnea, the synthesis of somatotropic hormone and testosterone is disrupted, the peaks of secretion of which are observed in the deep stages of sleep, which are practically absent in obstructive sleep apnea, which leads to insufficient production of these hormones. With a lack of growth hormone, fat utilization is disrupted and obesity develops. Moreover, any dietary and medicinal efforts aimed at losing weight are ineffective. Moreover, fat deposits at the level of the neck lead to further narrowing of the airways and the progression of obstructive sleep apnea, creating a vicious circle that is almost impossible to break without special treatment for apnea syndrome.

Sleep apnea is an independent risk factor for hypertension, myocardial infarction, and stroke. A study of men with hypertension found that the prevalence of obstructive sleep apnea in patients with type 2 diabetes mellitus was 36% compared with 14.5% in the control group.

The prevalence of OSA in individuals with type 2 diabetes ranges from 18% to 36%. In a report by SD West et al., the incidence of sleep apnea in patients with diabetes was estimated at 23% compared with 6% in the general population.

An analysis of data from a multicenter study showed an extremely high prevalence of undiagnosed obstructive sleep apnea in obese patients with type 2 diabetes mellitus. On the other hand, it was found that about 50% of patients with apnea syndrome have type 2 diabetes mellitus or carbohydrate metabolism disorders. In individuals with severe daytime sleepiness, the severity of obstructive sleep apnea correlated with the presence of type 2 diabetes mellitus. The prevalence of type 2 diabetes mellitus among patients with breathing disorders increases with increasing AHI, since in individuals with an AHI greater than 15 per hour, the incidence of diabetes mellitus was 15% compared with 3% in patients without apnea. The observed relationships suggested that sleep apnea is a new risk factor for type 2 diabetes mellitus and, conversely, that chronic hyperglycemia may contribute to the development of obstructive sleep apnea.

Factors that increase the risk of sleep apnea include male gender, obesity, age, and race. A study by S. Surani et al. showed a very high prevalence of diabetes in the Spanish population with obstructive sleep apnea compared to other Europeans.

Obesity is a common risk factor for obstructive sleep apnea and insulin resistance (IR), with visceral fat distribution being particularly important. Approximately two-thirds of all patients with apnea syndrome are obese, and its influence as a predictor of obstructive sleep apnea is 4 times greater than age and 2 times greater than male gender. This is evidenced by the results of a survey of patients with diabetes and obesity, 86% of whom were diagnosed with sleep apnea, corresponding to 30.5% of moderate severity and 22.6% of severe obstructive sleep apnea, and the severity of apnea correlated with an increase in body mass index (BMI).

In addition to the above factors, sleep fragmentation, increased sympathetic activity, and hypoxia play a significant role in the development of IR and metabolic disorders in obstructive sleep apnea.

Cross-sectional studies have found an association between increasing severity of apnea and glucose metabolism abnormalities, together with an increased risk of developing diabetes. The only prospective 4-year study found no association between initial severity and incident diabetes. Data from a recent large population-based study of over 1,000 patients suggest that sleep apnea is associated with incident diabetes, and that increasing severity of apnea is associated with an increased risk of developing diabetes.

In patients with normal body weight (BMI < 25 kg/m2), who thus did not have a major risk factor for developing diabetes mellitus, frequent snoring episodes were associated with decreased glucose tolerance and higher HbA1c levels.

In healthy men, AHI and the degree of nocturnal oxygen desaturation were found to be associated with impaired glucose tolerance and IR, independent of obesity. Finally, specific evidence was provided by the SHH study. In a population of 2656 subjects, AHI and mean oxygen saturation during sleep were associated with elevated fasting glucose levels and 2 h after an oral glucose tolerance test (OGTT). The severity of sleep apnea was correlated with the degree of IR, independent of BMI and waist circumference.

There is evidence that prolonged intermittent hypoxia and sleep fragmentation increase the activity of the sympathetic nervous system, which in turn leads to disturbances in glucose metabolism. A recent study by A. C. Peltier et al. found that 79.2% of patients with obstructive sleep apnea had impaired glucose tolerance and 25% were newly diagnosed with diabetes mellitus.

Based on the results of polysomnography and OGTT, it was found that diabetes mellitus occurred in 30.1% of patients with obstructive sleep apnea and in 13.9% of individuals without breathing disorders. With increasing severity of apnea, regardless of age and BMI, fasting and postprandial blood glucose levels increased, and insulin sensitivity decreased.

Pathophysiological mechanisms leading to changes in glucose metabolism in patients with obstructive sleep apnea syndrome

There are most likely several pathophysiological mechanisms leading to changes in glucose metabolism in patients with OSA.

Hypoxia and sleep fragmentation can lead to activation of the hypothalamic-pituitary axis (HPO) and increased cortisol levels, negatively affecting insulin sensitivity and secretion.

Intermittent hypoxia

Studies conducted at high altitudes have shown that prolonged hypoxia has a negative effect on glucose tolerance and insulin sensitivity. Acute prolonged hypoxia led to impaired glucose tolerance in healthy men. One study also noted that in healthy people, 20 minutes of intermittent hypoxia caused prolonged activation of the sympathetic nervous system.

Sleep fragmentation

Obstructive sleep apnea involves shortened total sleep time and sleep fragmentation. There is considerable evidence that short sleep and/or sleep fragmentation in the absence of breathing disorders negatively affect glucose metabolism. Several prospective epidemiological studies support the role of sleep fragmentation in the development of diabetes. The results were consistent with the increased risk of developing diabetes in individuals without diabetes at baseline who suffer from insomnia. Another study reported that short sleep and frequent snoring were associated with a higher prevalence of diabetes.

The studies conducted have established an independent relationship between apnea and several components of metabolic syndrome, especially IR and lipid metabolism disorders.

The relationship between obstructive sleep apnea and IR is poorly understood and the results are contradictory. IR, as assessed by the Home Oxygen Management Association Index (HOMA-IR), has been found to be independently associated with apnea severity. However, several studies have reported negative results. In 1994, Davies et al. showed no significant increase in insulin levels in a small number of patients with apnea syndrome compared with age-, BMI-, and smoking-history-matched controls. In addition, two case-control studies involving larger numbers of patients published in 2006 found no association between obstructive sleep apnea and IR.

Vgontzas et al. suggested that IR is a stronger risk factor for sleep apnea than BMI and plasma testosterone levels in premenopausal women. Later, in a population of healthy mildly obese men, it was found that the degree of apnea correlated with fasting and 2-h post-glucose insulin levels. A two-fold increase in IR was also reported in subjects with AHI > 65 after controlling for BMI and body fat percentage. It was noted that in subjects with obstructive sleep apnea, AHI and minimum oxygen saturation (SpO2) were independent determinants of IR (the degree of IR increased by 0.5% for each hourly increase in AHI).

Repeated episodes of apnea are accompanied by the release of catecholamines, the elevated levels of which during the day may increase the level of cortisol. Catecholamines predispose to the development of hyperinsulinemia by stimulating glycogenolysis, gluconeogenesis, and glucagon secretion, and elevated cortisol levels may lead to impaired glucose tolerance, IR, and hyperinsulinemia. High blood insulin concentrations in patients with IR may initiate specific tissue growth factors through interaction with the insulin-like factor receptor-effector system. Such findings indicate a mechanism for the relationship between obstructive sleep apnea and insulin sensitivity based on factors such as sleep interruption and hypoxemia.

Physical inactivity due to daytime sleepiness and sleep deprivation may also be important contributing factors. Daytime sleepiness has been shown to be associated with increased IR. Patients with apnea syndrome and severe daytime sleepiness had higher plasma glucose and insulin levels than subjects who did not report daytime sleepiness at the time of examination.

Obstructive sleep apnea is also characterized by a proinflammatory state and elevated cytokine levels, such as tumor necrosis factor-a (TNF-a), which can lead to IR. TNF-a is typically increased in individuals with obesity-induced IR. The researchers hypothesized that subjects with sleep apnea had higher concentrations of IL-6 and TNF-a than obese individuals without obstructive sleep apnea.

IR is also caused by increased lipolysis and the presence of fatty acids. SNS activation associated with apneic episodes increases the circulation of free fatty acids through stimulation of lipolysis, thus contributing to the development of IR.

Leptin, IL-6, and inflammatory mediators have also been implicated in the pathogenesis of IR and other components of metabolic syndrome. Leptin levels were shown to be elevated above normal in patients with sleep apnea, and adipokine levels were decreased.

The cyclic hypoxia-reoxygenation phenomena that occur in patients with obstructive sleep apnea are also a form of oxidative stress, leading to increased formation of reactive oxygen species during reoxygenation. This oxidative stress causes activation of adaptive pathways, including decreased NO bioavailability and increased lipid peroxidation. Increased oxidative processes have been shown to be an important mechanism in the development of IR and diabetes mellitus.

Thus, the results of numerous studies show that obstructive sleep apnea is associated with the development and progression of diabetes mellitus independently of other risk factors such as age, gender and BMI. An increase in the severity of obstructive sleep apnea is associated with an increased risk of developing diabetes mellitus, which can be explained by the presence of chronic hypoxia and frequent micro-awakenings. In other words, there are quite a lot of patients whose carbohydrate metabolism disorders can be considered as complications of apnea syndrome. As a treatable condition, obstructive sleep apnea is thus a modifiable risk factor for the development of type 2 diabetes mellitus.

Reverse causality may also be possible, as diabetic autonomic neuropathy (DAN) has been shown to impair control of diaphragmatic movement. Some researchers have suggested that IR and chronic hypoxemia may in turn lead to the development of obstructive sleep apnea.

Diabetic neuropathy

Over the past decade, clinical and experimental evidence has accumulated on the association between IR and obstructive sleep apnea in non-obese diabetics with AON. A laboratory-based study has shown that such patients are more likely to have obstructive and central apnea than diabetics without AON.

Patients with DAN have a high incidence of sudden death, especially during sleep. Several studies have been conducted to investigate the potential role of sleep-disordered breathing and to evaluate respiratory impairment in these patients. In patients with diabetes mellitus and autonomic neuropathy without anatomical changes and/or obesity, functional factors seem to be of critical importance. This is supported by the fact that cardiovascular events occurred more frequently in the REM phase of sleep, when the tonic and phasic activity of the muscles that dilate the upper respiratory tract is significantly reduced, even in subjects without apnea.

JH Ficker et al. assessed the presence of obstructive sleep apnea (AHI 6-10) in a group of patients with diabetes with and without DAN. They found that the prevalence of apnea syndrome reached 26% in diabetics with DAN, while patients without DAN did not suffer from obstructive sleep apnea. In another study, the incidence of sleep apnea among patients with DAN, regardless of the severity of their autonomic neuropathy, was 25-30%.

S. Neumann et al. demonstrated a close correlation between nocturnal desaturation and the presence of DAN. A study of clinical symptoms of obstructive sleep apnea in patients with DAN showed that this group of patients had more pronounced daytime sleepiness, assessed using the Epfort Sleepiness Scale.

Thus, the data from recent studies indicate that DAN itself may contribute to the development of apnea in patients with diabetes mellitus. In addition, these results indicate the need to evaluate the reflexes of the upper respiratory tract in patients with DAN and generally confirm its role in the pathogenesis of obstructive sleep apnea.

When assessing the impact of apnea syndrome and diabetes mellitus on endothelial function, it was found that both diseases equally impaired endothelium-dependent vasodilation of the brachial artery. However, in isolated obstructive sleep apnea, unlike diabetes mellitus, no damage to the microvascular bed was observed.

In addition to its effect on the vascular wall, obstructive sleep apnea has been shown to worsen diabetic retinopathy. A recent study in the UK found that more than half of patients with diabetes and sleep apnea were diagnosed with diabetic retinopathy, compared to 30% of diabetics without apnea. The findings were independent of age, BMI, diabetes duration, glycemic control, and blood pressure. Sleep apnea was a better predictor of diabetic retinopathy than glycated hemoglobin or blood pressure. CPAP therapy improved the fundus picture.

Thus, a vicious circle arises, when complications of diabetes mellitus contribute to the development of obstructive sleep apnea, and obstructive sleep breathing disorders, in turn, provoke IR and impaired glucose tolerance. In this regard, and also taking into account the proven negative impact of obstructive sleep apnea on beta-cell function and IR, the International Diabetes Federation published clinical guidelines in which physicians were advised to examine patients with diabetes for the presence of obstructive sleep apnea and vice versa. Correction of sleep apnea for such patients is an essential component of adequate diabetes therapy.

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Effect of CPAP therapy on glucose metabolism and insulin resistance

Continuous positive airway pressure (CPAP) is one of the most effective treatments for patients with moderate to severe obstructive sleep apnea. It has proven to be effective in eliminating obstructive breathing events during sleep and daytime sleepiness, improving sleep structure and quality of life. CPAP is commonly used to treat obstructive sleep apnea, providing constant pressure throughout inhalation and exhalation to maintain the tone of the airways during sleep. The device consists of a generator that provides a continuous flow of air to the patient through a mask and a system of tubes.

CPAP therapy is not only a treatment for obstructive sleep apnea, but may also have beneficial effects on IR and glucose metabolism in these patients. It has been suggested that CPAP may reduce intermittent hypoxia and sympathetic hyperactivity. This additional therapeutic benefit provided by CPAP is currently of considerable interest, but the issue is actively debated. The results of numerous studies on the effects of CPAP on glucose metabolism in both diabetic and nondiabetic patients have been contradictory.

There is evidence that metabolic disturbances can be partially corrected by CPAP therapy. One such study examined 40 patients without diabetes but with moderate to severe obstructive sleep apnea using the euglycemic-hyperinsulin clamp test, considered the gold standard for assessing insulin sensitivity. The authors showed that CPAP therapy significantly improved insulin sensitivity after 2 days of treatment, and the results were maintained over a 3-month follow-up period without any significant changes in body weight. Interestingly, the improvement was minimal in patients with a BMI > 30 kg/m2. This may be due to the fact that in individuals with obvious obesity, IR is largely determined by excess adipose tissue, and the presence of obstructive sleep apnea in this case may play only a minor role in impaired insulin sensitivity.

After 6 months of CPAP therapy, patients without diabetes mellitus showed a decrease in postprandial blood glucose levels compared with the group not receiving CPAP treatment. However, in a similar group of patients, no significant changes in IR and glucose metabolism were found.

Dawson et al. used a continuous glucose monitoring system during polysomnography recordings in 20 patients with diabetes mellitus with moderate to severe obstructive sleep apnea before treatment and then after 4-12 weeks of CPAP treatment. In obese patients, nocturnal hyperglycemia was reduced and interstitial glucose levels varied less during CPAP treatment. Mean glucose levels during sleep decreased after 41 days of CPAP therapy.

Another study assessed insulin sensitivity in obese patients with diabetes mellitus after 2 days and after 3 months of CPAP therapy. A significant improvement in insulin sensitivity was noted only after 3 months of CPAP therapy. However, no decrease in HbA1c levels was observed.

AR Babu et al. measured HbAlc and performed 72-hour blood glucose monitoring in patients with diabetes mellitus before and after 3 months of CPAP therapy. The authors found that blood glucose levels one hour after meals significantly decreased after 3 months of CPAP use. A significant reduction in HbAlc levels was also noted. In addition, the reduction in HbAlc levels significantly correlated with the number of days of CPAP use and adherence to treatment for more than 4 hours per day.

A population-based study demonstrated a reduction in fasting insulin and HOMA index after 3 weeks of CPAP therapy in men with OSA compared with a matched control group (AHI < 10) without CPAP therapy. A positive response to CPAP therapy was also demonstrated with improved insulin sensitivity, decreased fasting and postprandial glucose in groups of patients with and without diabetes. In 31 patients with moderate/severe obstructive sleep apnea who were prescribed CPAP therapy, insulin sensitivity was improved compared with 30 controls who received sham CPAP treatment. Further improvement was observed after 12 weeks of CPAP therapy in patients with a BMI greater than 25 kg/m2. However, another study did not detect changes in blood glucose levels and IR, assessed by the HOMA index, in patients without diabetes after 6 weeks of CPAP therapy. According to the authors, the study period was short enough to detect more significant changes. The recent results suggest that the relative response time to CPAP treatment may differ for cardiovascular and metabolic parameters. Analysis of another randomized trial also does not show improvement in HbA1c levels and IR in patients with diabetes mellitus and obstructive sleep apnea after 3 months of CPAP therapy.

L. Czupryniak et al. noted that in nondiabetic subjects, an increase in blood glucose was observed during one night of CPAP therapy, with a tendency for fasting insulin and IR to increase after CPAP. This effect was attributed to secondary effects related to the increase in growth hormone levels. Several studies reported a decrease in visceral fat after CPAP use, while another found no change.

There is evidence that in patients with daytime sleepiness, CPAP therapy helps reduce IR, while in individuals who do not report sleepiness, treatment of obstructive sleep apnea does not affect this indicator. Against the background of CPAP therapy, a decrease in cholesterol, insulin, and HOMA index levels and an increase in insulin-like growth factor were noted in individuals with DS, while in the absence of DS in patients, CPAP therapy did not affect the listed parameters.

Conflicting results in studies of the effects of CPAP therapy may be partly explained by differences in the study populations (diabetic, obese, non-diabetic and non-obese); primary outcomes; methods of assessing glucose metabolism (fasting glucose, HbA1c, hyperinsulinemic glycemic clamp, etc.); duration of CPAP therapy (ranging from 1 night to 2.9 years) and patient adherence to CPAP use. Duration of CPAP therapy up to 6 months, provided that the device was used for > 4 h per day, was considered adequate adherence to treatment. It is currently unknown whether a longer duration of therapy and better adherence to CPAP treatment are really necessary to correct metabolic disturbances.

Recent research increasingly supports the role of CPAP therapy in improving insulin sensitivity. A number of studies are currently underway that will hopefully shed light on this highly relevant and complex issue.

Thus, in patients with severe obstructive sleep apnea, obesity, and diabetes mellitus, CPAP therapy apparently improves insulin sensitivity and glucose metabolism, and may therefore influence the prognosis of diseases involving multiple organ dysfunction.

In contrast, in individuals with normal BMI and mild to moderate obstructive sleep apnea, the effect of CPAP therapy on carbohydrate metabolism currently lacks convincing evidence.

Prof. V. E. Oleynikov, N. V. Sergatskaya, Assoc. Prof. Yu. A. Tomashevskaya. The relationship between obesity and carbohydrate metabolism disorders with obstructive sleep apnea syndrome // International Medical Journal - No. 3 - 2012