The relationship between obesity and diabetes mellitus with obstructive sleep apnea syndrome in sleep

The literature data of clinical trials in which obstructive sleep apnea (OSAS) syndrome is considered as a risk factor for the development of carbohydrate metabolism disorders, including type 2 diabetes mellitus, are presented . The interrelation of the most significant factors affecting the progression of carbohydrate metabolism disorders in patients with obstructive sleep apnea is analyzed. The analysis of data on the relationship between obstructive sleep apnea and diabetic autonomic neuropathy and insulin resistance is given. The possibility of using CPAP therapy for correction of metabolic disorders in patients with diabetes mellitus is considered.

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

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 in patients with type 2 diabetes mellitus, respiratory arrest in sleep (apnea) is more common than in the main population. In the SHH study, it was revealed that subjects with type 2 diabetes mellitus were more likely to have respiratory distress in their sleep and more severe hypoxemia.

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

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

The diagnostic criteria for obstructive sleep apnea proposed by the American Academy of Sleep Medicine are as follows:

• A) pronounced daytime sleepiness (DS), which can not be explained by other causes;
• B) two or more of the following symptoms, which can not be explained by other causes:
  • choking or shortness of breath during sleep;
  • recurring episodes of awakening;
  • "Not refreshing" sleep;
  • chronic fatigue;
  • decreased concentration of attention.
• C) During a polysomnographic study, five or more episodes of obstructive breathing are detected within one hour of sleep. These episodes can include any combination of episodes of apnea, hypopnea, or effective respiratory effort (ERA).

For the diagnosis of the syndrome of obstructive sleep apnea / hypopnea, the presence of criterion A or B in combination with the criterion C is necessary.

The average number of episodes of apnea / hyponea within an hour is indicated by the apnea-hypopnea index (IAH). The 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 the Special Commission of the American Academy of Sleep Medicine, the apnea syndrome is divided into three degrees of severity, depending on the value of the YAG. IAG <5-norm; 5 30-severe degree.

Obstructive sleep apnea is the result of the interaction of anatomical and functional factors. Anatomical due to narrowing of the upper respiratory tract (VDP), the functional factor is associated with relaxation of the muscles that dilate the VAP during sleep, which is often accompanied by collapse of the upper respiratory tract.

The implementation of the mechanism of airway obstruction in apnea occurs as follows. When the patient falls asleep, there is a gradual relaxation of the muscles of the pharynx and an increase in the mobility of its walls. One of the next breaths leads to a complete collapse of the airways and the cessation of pulmonary ventilation. At the same time, the respiratory effort persists and even intensifies in response to hypoxemia. Developing hypoxemia and hypercapnia stimulate the activation reactions, i.e. The transition to the less deep stages of sleep, since in the more superficial stages of sleep the degree of activity of the muscles - the dilators of the upper respiratory tract is sufficient to restore their lumen. However, as soon as the breathing is restored, after a while the dream re-deepens, the muscle tone of the dilator muscles decreases, and everything repeats again. Acute hypoxia also leads to a stress reaction accompanied by activation of the sympathoadrenal system and a rise in blood pressure. As a result, during sleep, such patients create conditions for the formation of chronic hypoxemia, the impact of which determines the variety of the clinical picture.

The most common cause of narrowing of the airway lumen at the pharynx level 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 the case of severe sleep apnea, the synthesis of growth hormone and testosterone is disrupted, the peaks of secretion are noted in the deep stages of sleep, which are practically absent in obstructive sleep apnea, which leads to inadequate production of these hormones. With a deficiency of growth hormone, the utilization of fats is disrupted and obesity is developing. And any dietary and medicamentous efforts aimed at weight loss, are ineffective. Moreover, the fatty deposits at the neck level lead to further narrowing of the airways and the progression of obstructive sleep apnea, creating a vicious circle, which is virtually impossible without special treatment of the apnea syndrome.

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

The prevalence of OSA in patients with type 2 diabetes is between 18% and 36%. In a report by SD West et al. The incidence of sleep apnea in patients with diabetes is estimated at 23% compared with 6% in the general population.

Analysis of the data from the multicenter study showed an extremely high prevalence of unidentified obstructive sleep apnea in obese patients with type 2 diabetes mellitus. On the other hand, it has been established that about 50% of patients with apnea syndrome have type 2 diabetes mellitus or disorders of carbohydrate metabolism. In persons with severe daytime sleepiness, the severity of obstructive sleep apnea correlated with the presence of type 2 diabetes. The prevalence of type 2 diabetes mellitus among patients with respiratory disorders increases with the increase in IAG, as in people with IAG more than 15 per hour the incidence of diabetes was 15% compared with 3% in patients without apnea. The noted interrelations allowed to suggest that sleep apnea is a new risk factor for type 2 diabetes mellitus and, conversely, that chronic hyperglycemia can contribute to the development of obstructive sleep apnea.

Factors that increase the risk of sleep apnea include males, obesity, age and race. A study by S. Surani et al. Showed a very high prevalence of diabetes in the population of Spaniards suffering from obstructive sleep apnea, compared with the rest of Europe.

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

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

In cross-section studies, a correlation was found between the increase in the severity of apnea and the disturbances in glucose metabolism, together with an increased risk of developing diabetes mellitus. The only prospective four-year study did not reveal the relationship between its initial severity and the incidence of diabetes mellitus. A recent large-scale population study involving more than 1,000 patients suggests that sleep apnea is associated with a diabetes incidence, and that an increase in the severity of apnea is associated with an increased risk of developing diabetes.

In patients with normal body weight (BMI <25 kg / m2), which were thus not the main risk factor for developing diabetes, frequent episodes of snoring were associated with a decrease in glucose tolerance and a higher level of HbAlc.

It was found that in healthy men, IAG and the degree of nocturnal desaturation are associated with impaired glucose tolerance and IR, regardless of obesity. Finally, concrete evidence was obtained from the results of the SHH study. In a population of 2656 subjects, the IAG and the average oxygen saturation during sleep were associated with elevated fasting glucose levels and 2 hours after an oral glucose tolerance test (PTTG). The severity of sleep apnea correlated with the degree of ID regardless of the BMI and waist circumference.

There is evidence that prolonged intermittent hypoxia and fragmentation of sleep increase the activity of the sympathetic nervous system, which in turn leads to disturbances in glucose metabolism. In a recent study, AS Peltier et al. It was found that 79.2% of patients with obstructive sleep apnea had a violation of glucose tolerance and 25% had a first diagnosis of diabetes mellitus.

Based on the results of polysomnography and PTTG it was found that diabetes mellitus was found in 30.1% of patients with obstructive sleep apnea and in 13.9% of persons without respiratory failure. With the increase in the severity of apnea, regardless of age and BMI, fasting blood glucose levels increased after eating, and insulin sensitivity decreased.

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

The pathophysiological mechanisms leading to changes in glucose metabolism in OSA patients are likely to be few.

Hypoxia and fragmentation of sleep can lead to activation of the hypothalamic-pituitary axis (GGO) and increase in the level of cortisol, having a negative impact on insulin sensitivity and its secretion.

Intermittent hypoxia

Studies conducted in the highlands have shown that prolonged hypoxia negatively affects glucose tolerance and sensitivity to insulin. Acute prolonged hypoxia led to impaired glucose tolerance in healthy men. In one study, it was also noted that in healthy people, 20-minute intermittent hypoxia caused a prolonged activation of the sympathetic nervous system.

Fragmentation of sleep

In obstructive sleep apnea, there is a reduction in total sleep time and its fragmentation. There is much evidence that short sleep and / or fragmentation of sleep in the absence of respiratory disorders adversely affect glucose metabolism. Several prospective epidemiological studies confirm the role of sleep fragmentation in the development of diabetes mellitus. The results were consistent with data on the increased risk of diabetes in people who did not initially have it, but who suffer from insomnia. Another study reported that short sleep and frequent snoring were associated with a higher prevalence of diabetes mellitus.

In the studies conducted, an independent relationship between apnea and several components of the metabolic syndrome was established, especially with MI and lipid metabolism disorders.

The association of obstructive sleep apnea with sleep is not well understood, and the results of the studies are very contradictory. It was found that IR, estimated by the index of insulin resistance (HOMA-IR), is independently related to the severity of apnea. However, several studies reported negative results. In 1994, R. Davies et al. Did not show any significant increase in insulin levels in a small number of patients with the apnea syndrome compared to the control group of the same age, BMI and smoking experience. In addition, in the results of two case-control studies published in 2006, involving more patients, there was no association between obstructive sleep apnea and MI.

A. N. Vgontzas et al. Suggested that MI is a stronger risk factor for sleep apnea than BMI and plasma testosterone levels in pre-menopausal women. Later, in a population of healthy men with mild obesity, it was found that the degree of apnea correlated with fasting insulin levels and 2 hours after loading with glucose. There was also reported a double increase in MI in subjects with IAG> 65 after monitoring for BMI and percentage of body fat. It was noted that in subjects with obstructive sleep apnea, IAG and minimal oxygen saturation (SpO2) were independent determinants of MI (the degree of MI was increased by 0.5% for each hourly increase in IAG).

The recurring episodes of apnea are accompanied by the release of catecholamines, an elevated level of which, during the course of the day, may increase the cortisol content. Catecholamines predispose to the development of hyperinsulinemia, stimulating glycogenolysis, gluconeogenesis and glucagon secretion, and an elevated level of cortisol can lead to impaired glucose tolerance, MI and hyperinsulinemia. A high concentration of insulin in the blood in patients with MI is able to initiate specific tissue growth factors through interaction with the insulin-like factor of the receptor-effector system. Similar findings point to a mechanism of communication between obstructive sleep apnea and insulin sensitivity, based on factors such as sleep discontinuity and hypoxemia.

Physical inertness due to daytime sleepiness and sleep deprivation can also be important contributing factors. It is shown that daytime drowsiness is associated with increased IR. In patients with apnea syndrome and severe daytime sleepiness, plasma glucose and insulin levels were higher than those who did not have daytime sleepiness at the time of the examination.

Obstructive sleep apnea is also characterized by a proinflammatory state and elevated cytokine levels, for example, tumor necrosis factor-a (TNF-a), which can lead to MI. TNF-a usually increases in people with MI, caused by obesity. The researchers suggested that subjects with sleep apnea had higher concentrations of IL-6 and TNF-a than those who are obese, but without obstructive sleep apnea.

IR is also caused by increased lipolysis and the presence of fatty acids. Activation of the SNS associated with episodes of apnea increases the circulation of free fatty acids by stimulating lipolysis, thus contributing to the development of MI.

Leptin, IL-6 and inflammatory mediators are also involved in the pathogenesis of TS and other components of the metabolic syndrome. It was shown that leptin levels exceeded normal values in patients with sleep apnea, and adipokine content was reduced.

Cyclic phenomena of hypoxia - reoxygenation, which 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 the activation of adaptive pathways, including a decrease in the bioavailability of NO, an increase in lipid peroxidation. It was shown that the enhancement of oxidative processes is an important mechanism for the development of MI and diabetes mellitus.

Thus, the results of numerous studies show that obstructive sleep apnea is associated with the development and progression of diabetes mellitus regardless 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, which can be explained by the presence of chronic hypoxia and frequent micro-awakening. In other words, there are quite a few patients whose carbohydrate metabolism disorders can be considered as complications of the apnea syndrome. As a condition treatable, obstructive sleep apnea, thus, is a modifiable risk factor for the development of type 2 diabetes mellitus.

It is also possible to reverse the cause-effect relationship, since it is established that diabetic autonomic neuropathy (DAS) can weaken the control over the movement of the diaphragm. Some researchers have suggested that IR and chronic hypoxemia can, in turn, lead to the development of obstructive sleep apnea.

Diabetic Neuropathy

Over the past decade, clinical and experimental data on the relationship between MI and obstructive sleep apnea in non-obese diabetics with DAS have accumulated. A laboratory-based study showed that these patients had a higher probability of obstructive and central apnea than did diabetics without autonomic neuropathy.

Patients with DAS have a high incidence of sudden death, especially during sleep. To study the potential role of respiratory distress in sleep and assess respiratory disorders, several studies have been carried out in these patients. In patients with diabetes mellitus and autonomic neuropathy without anatomical changes and / or obesity, functional factors appear to be crucial. This is confirmed by the fact that cardiovascular events often occurred in the REM sleep phase, when the tonic and phase activity of the muscles that extend the VAD is significantly reduced even in subjects without apnea.

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

S. Neumann et al. Showed a close correlation between nocturnal desaturation and the presence of DAO. A study of the clinical symptoms of obstructive sleep apnea in patients with DAS showed that this group of patients had more pronounced daytime drowsiness, estimated by the Epforta Sleepiness Scale.

Thus, data from recent studies suggest that DAN alone can contribute to the emergence of apnea in patients with diabetes mellitus. In addition, these results indicate the need to evaluate the VDP reflexes in DDA patients and, on the whole, confirm its role in the pathogenesis of obstructive sleep apnea.

When assessing the effect of apnea and diabetes on endothelial function, it was established that both diseases equally affected endothelium-dependent vasodilation of the brachial artery. However, with isolated obstructive sleep apnea, unlike diabetes mellitus, there was no lesion of the microvascular bed.

It is proved that in addition to affecting the vascular wall, obstructive sleep apnea also aggravates the course of diabetic retinopathy. A recent study in the UK found that more than half of patients with diabetes and sleep apnea had diabetic retinopathy, while in diabetics without apnea, 30% were diagnosed. The data obtained were independent of age, BMI, duration of diabetes, glycemic control, and blood pressure. The presence of sleep apnea was a better predictor of diabetic retinopathy than the level of glycated hemoglobin or blood pressure. Against the backdrop of CPAP therapy, there was an improvement in the picture of the fundus.

Thus, a vicious circle arises when complications of diabetes mellitus contribute to the onset of obstructive sleep apnea, and obstructive breathing disorders during sleep, in turn, provoke IR and impaired glucose tolerance. In this connection, and taking into account the proven negative impact of obstructive sleep apnea on the function of beta cells and MI, the International Diabetes Federation published clinical recommendations in which doctors were asked to examine patients with diabetes for obstructive sleep apnea and vice versa. Correction of sleep apnea for such patients is an indispensable component of adequate therapy for diabetes mellitus.

[1], [2], [3], [4], [5], [6], [7]

The effect of CPAP therapy on glucose metabolism and insulin resistance

The method of treatment by creating a constant positive airway pressure (CPAP) is one of the most effective for patients suffering from moderate and severe obstructive sleep apnea. It has proven effective in eliminating obstructive respiratory events during sleep and daytime sleepiness, improving sleep patterns and quality of life. CPAP is commonly used to treat obstructive sleep apnea, providing constant pressure throughout the inhalation and expiration to maintain VDP tone 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 method of treating obstructive sleep apnea, but it can also have a beneficial effect on MI and glucose metabolism in these patients. It has been suggested that CPAP can reduce intermittent hypoxia and sympathetic hyperactivity. This additional therapeutic advantage provided by CPAP, is currently of considerable interest, but the issue is actively debated. The results of numerous studies on the effect of CPAP therapy on glucose metabolism both in diabetic patients and without diabetes were controversial.

There is evidence that metabolic disorders can be partially corrected by CPAP therapy. One such study examined 40 patients without diabetes, but with a moderate or severe degree of obstructive sleep apnea, using the euglycemic-hyperinsulin clamp test, considered the gold standard for assessing insulin sensitivity. The authors showed that CPAP-therapy significantly improves insulin sensitivity after 2 days of treatment, while the results were preserved during the 3-month observation period without any significant changes in body weight. Interestingly, the improvement was minimal in patients with a BMI> 30 kg / m2. Perhaps this is due to the fact that in persons with obvious obesity, MI is more determined by excess fatty tissue, and the presence of obstructive sleep apnea in this case can play only a minor role in the violation of insulin sensitivity.

After 6 months of CPAP therapy, a decrease in postprandial blood glucose was observed in non-diabetic patients compared to the group not treated with CPAP. However, in a similar group of patients, no significant changes in TS and glucose metabolism were detected.

A. A. Dawson et al. A continuous glucose monitoring system was used during the recording of polysomnography in 20 patients with diabetes mellitus, suffering from moderate to severe obstructive sleep apnea before treatment, and then after 4-12 weeks of treatment with CPAP. In obese patients, nighttime hyperglycemia was reduced, and the interstitial glucose level was less varied during CPAP treatment. The average glucose level during sleep decreased after 41 days of CPAP therapy.

In another study, insulin sensitivity was assessed in obese patients with diabetes mellitus after 2 days. And after 3 months. CPAP therapy. Significant improvement in insulin sensitivity was noted only after 3 months. CPAP therapy. However, there was no decrease in the level of HbAlc.

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

In a population study, there was a decrease in fasting insulin and MI (NOMA-index) after 3 weeks. CPAP therapy in men with OSAS, in comparison with the corresponding control group (IAG <10), but without CPAP therapy. A positive response to CPAP therapy was also shown with an improvement in insulin sensitivity, a decrease in fasting and postprandial glucose in groups with or without diabetes mellitus. In 31 patients with moderate / severe obstructive sleep apnea, who were prescribed CPAP therapy, there was an increase in insulin sensitivity, in contrast to 30 patients in the control group receiving fictitious CPAP treatment. An additional improvement was recorded after 12 weeks. CPAP therapy in patients with BMI more than 25 kg / m2. However, in another study, there were no changes in blood glucose and MI levels estimated by the NOMA index in patients without diabetes after 6 weeks. CPAP therapy. According to the authors, the period under study was short enough to identify more significant changes. Recent results suggest that the relative response time to CPAP treatment may differ in cardiovascular and metabolic parameters. The analysis of another randomized study also does not indicate an improvement in HbAlc and MI levels in diabetic patients with obstructive sleep apnea after 3 months. Therapy CPAP.

L. Czupryniak et al. Noted that in individuals who did not have diabetes mellitus, an increase in blood glucose was noted overnight CPAP therapy, with a tendency to increase fasting insulin and TS after CPAP. This effect was attributed to secondary phenomena associated with an increase in the level of growth hormone. Several studies reported a decrease in visceral fat after the use of CPAP, while the other did not find any changes.

There is evidence that in patients with daytime drowsiness CPAP therapy contributes to the reduction of MI, while in persons not showing drowsiness, treatment of obstructive sleep apnea does not affect this indicator. Against the backdrop of CPAP therapy, there was a decrease in cholesterol, insulin and HOMA index levels and an increase in insulin-like growth factor in people with DS, whereas in the absence of CP patients, CPAP therapy did not affect the listed parameters.

Contradictory results of studies on the effects of CPAP therapy may be due in part to differences in the populations studied - patients with diabetes mellitus, obesity, people who are not diabetic or obese; primary outcomes; methods for assessing glucose metabolism: fasting glucose, HbAlc, hyperinsulinemic glycemic clamp test, etc .; the period of CPAP therapy (ranging from 1 night to 2.9 years) and patient adherence to CPAP. The duration of CPAP therapy is up to 6 months. Provided that the device was used for> 4 hours a day was considered an adequate adherence to treatment. It is currently unknown whether a longer duration of therapy and better adherence to CPAP treatment is necessary to correct metabolic disorders.

The results of recent studies are increasingly indicative of the role of CPAP therapy in increasing insulin sensitivity. At present, a number of studies are underway, which, it is hoped, will shed light on this extremely urgent and multifaceted problem.

Thus, in patients with severe obstructive sleep apnea, obesity, diabetes mellitus, CPAP therapy apparently improves insulin sensitivity and glucose metabolism, so it can probably influence the prognosis of diseases accompanied by multi-organ damage.

In contrast, in persons with normal BMI, mild and moderate severity of the course of obstructive sleep apnea, the effect of CPAP therapy on carbohydrate metabolism currently does not have a convincing evidence base.

Prof. V. E. Oleinikov, N. V. Sergatskaya, Assoc. A. A. Tomashevskaya. Interrelation of obesity and violations of carbohydrate metabolism with the syndrome of obstructive sleep apnea // International Medical Journal - №3 - 2012