Obesity has reached epidemic proportions in the United States. It is estimated that more than half of the adult population in this country is overweight or obese. The striking increase in the prevalence of obesity over the last two decades has affected men and women across all ages and in various racial and ethnic groups. Coincident with the increase in obesity has been a dramatic increase in the incidence of cardiovascular disease, cerebrovascular disease, hypertension, and type 2 diabetes mellitus. The Center for Disease Control and Prevention has noted that the prevalence of diabetes among Americans has risen from 1.5 million to 15.8 million cases per year, from 1980 to 2005.
This represents an enormous disease burden and one that is likely to rise further in the years ahead. As mentioned previously, the reported prevalence of OSAH in the US has varied, depending on the definitions and the population studied. Most experts in the field accept that it remains an underdiagnosed and often untreated malady. As the “epidemic of obesity” worsens, these numbers are likely to increase in the coming years as well. Phenotypically, the patients with diabetes commonly are hypertensive, overweight or obese, have poor metabolic control, suffer from cardiac disease, and list fatigue and lethargy as common complaints.
The typical patient with OSAH has a remarkably similar clinical profile, apart from the hyperglycemia seen in diabetes. The relationship between diabetes and OSAH is controversial because a true causal association has still not been proven. The question of whether diabetes may be a cause or a consequence of sleep disordered breathing, or whether these are just comorbid conditions, still needs to be definitively answered. Obesity as a cause of both insulin resistance and diabetes mellitus is often a confounding factor. Similarly, whether treatment of obstructive sleep apnea with CPAP results in clinical improvement of insulin resistance remains an area of some dispute.
Pathophysiology
Sleep disordered breathing has widespread systemic effects, many of which are underappreciated by those outside of the sleep specialist community. Activation of a multitude of adaptive physiological responses, including endocrine alterations, occurs when cellular gas exchange and acid–base balance are perturbed during apneas, hypopneas, and RERAs. Conversely, manifestation of sleep apnea is critically linked to inputs to the control of breathing. A body of research has established that the control of breathing incorporates both voluntary and involuntary (emotional, metabolic, neural, and endocrine) mechanisms. Sleep disordered breathing may interact with the endocrine system in several ways (Fig. 37.1). OSAH with recurrent episodes of apnea and hypopnea causes sleep fragmentation and disturbance of the sleep cycle and stages.
Frequent arousals from sleep induce stress responses resulting in increased levels of stress hormones. Hypoxia results in alterations in the hypothalamo-pituitary axis and disordered secretion from several endocrine glands. Animal studies using rats and dogs have shown that the levels of ACTH, renin, aldosterone, vasopressin, and corticosteroids increase with acute hypercapnia and hypoxia. Over time, multiple studies have shown an independent association between sleep apnea and insulin resistance. Vgontzas et al. showed that the circulating levels of insulin, the adipostatic hormone leptin, and the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are increased in patients with sleep apnea, independent of obesity. Both leptin and the two cytokines are released into the interstitial fluid of the adipose tissue and are known to cause marked insulin resistance. A recent study postulated that a possible mechanism for the development of diabetes in patients with sleep disordered breathing is that OSAH contributes to weight gain and obesity, especially central obesity. It is established that central obesity leads to insulin resistance via increased lipolysis and fatty acid availability. Sleep curtailment, as occurs in OSAH, has been shown to increase appetite and ghrelin levels, and to decrease leptin levels, all possibly leading to weight gain. Studies in animals and humans have shown perturbation in glucose homeostasis as a direct consequence of hypoxia. A study by Strohl et al. found that insulin levels increase with the level of apneic activity in patients with a BMI greater than 29.
The authors postulated that once a “critical mass” was reached, low oxygen values could trigger release of hormones (catecholamines and cortisol) that would result in gluconeogenesis and/or interfere with insulin action. A small study of 18 patients with sleep disordered breathing found that the frequency of oxygen desaturations with sleep apnea was associated with abnormalities in glucose tolerance tests and indices of insulin resistance. In a larger study by Ip et al., the minimum oxygen saturation in patients with sleep disordered breathing was found to be an independent predictor of fasting insulin levels and insulin resistance. Punjabi et al. looked at the association of insulin sensitivity and glucose tolerance with hypoxemia secondary to sleep disordered breathing. The investigators included the average drop in oxygen saturation associated with respiratory events as a continuous variable in a multivariable logistic regression model. They found that for every 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% confidence interval, 1.11–3.56) after adjusting for percent body fat, BMI, and AHI. As with glucose intolerance, insulin resistance also was related to the severity of hypoxemia associated with apneas and hypopneas.
The study reported an independent relationship between the minimum oxygen saturation at night and the indices Phenotypically, the patients with diabetes commonly are hypertensive, overweight or obese, have poor metabolic control, suffer from cardiac disease, and list fatigue and lethargy as common complaints. The typical patient with OSAH has a remarkably similar clinical profile, apart from the hyperglycemia seen in diabetes. The relationship between diabetes and OSAH is controversial because a true causal association has still not been proven. The question of whether diabetes may be a cause or a consequence of sleep disordered breathing, or whether these are just comorbid conditions, still needs to be definitively answered. Obesity as a cause of both insulin resistance and diabetes mellitus is often a confounding factor. Similarly, whether treatment of obstructive sleep apnea with CPAP results in clinical improvement of insulin resistance remains an area of some dispute.
Pathophysiology
Sleep disordered breathing has widespread systemic effects, many of which are underappreciated by those outside of the sleep specialist community. Activation of a multitude of adaptive physiological responses, including endocrine alterations, occurs when cellular gas exchange and acid–base balance are perturbed during apneas, hypopneas, and RERAs. Conversely, manifestation of sleep apnea is critically linked to inputs to the control of breathing. A body of research has established that the control of breathing incorporates both voluntary and involuntary (emotional, metabolic, neural, and endocrine) mechanisms. Sleep disordered breathing may interact with the endocrine system in several ways (Fig. 37.1). OSAH with recurrent episodes of apnea and hypopnea causes sleep fragmentation and disturbance of the sleep cycle and stages. Frequent arousals from sleep induce stress responses resulting in increased levels of stress hormones.
Hypoxia results in alterations in the hypothalamo-pituitary axis and disordered secretion from several endocrine glands. Animal studies using rats and dogs have shown that the levels of ACTH, renin, aldosterone, vasopressin, and corticosteroids increase with acute hypercapnia and hypoxia.Over time, multiple studies have shown an independent association between sleep apnea and insulin resistance. Vgontzas et al. showed that the circulating levels of insulin, the adipostatic hormone leptin, and the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are increased in patients with sleep apnea, independent of obesity. Both leptin and the two cytokines are released into the interstitial fluid of the adipose tissue and are known to cause marked insulin resistance. A recent study postulated that a possible mechanism for the development of diabetes in patients with sleep disordered breathing is that OSAH contributes to weight gain and obesity, especially central obesity. It is established that central obesity leads to insulin resistance via increased lipolysis and fatty acid availability. Sleep curtailment, as occurs in OSAH, has been shown to increase appetite and ghrelin levels, and to decrease leptin levels, all possibly leading to weight gain. Studies in animals and humans have shown perturbation in glucose homeostasis as a direct consequence of hypoxia. A study by Strohl et al. found that insulin levels increase with the level of apneic activity in patients with a BMI greater than 29.
The authors postulated that once a “critical mass” was reached, low oxygen values could trigger release of hormones (catecholamines and cortisol) that would result in gluconeogenesis and/or interfere with insulin action. A small study of 18 patients with sleep disordered breathing found that the frequency of oxygen desaturations with sleep apnea was associated with abnormalities in glucose tolerance tests and indices of insulin resistance. In a larger study by Ip et al., the minimum oxygen saturation in patients with sleep disordered breathing was found to be an independent predictor of fasting insulin levels and insulin resistance. Punjabi et al. looked at the association of insulin sensitivity and glucose tolerance with hypoxemia secondary to sleep disordered breathing. The investigators included the average drop in oxygen saturation associated with respiratory events as a continuous variable in a multivariable logistic regression model. They found that for every 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% confidence interval, 1.11–3.56) after adjusting for percent body fat, BMI, and AHI.
As with glucose intolerance, insulin resistance also was related to the severity of hypoxemia associated with apneas and hypopneas. The study reported an independent relationship between the minimum oxygen saturation at night and the indices for insulin sensitivity after adjusting for percent body fat. The investigators noted that for a two-point increase in the minimum oxygen saturation during sleep, there was an improvement in the insulin sensitivity suggesting a less insulin-resistant state with less hypoxemia during sleep. Sleep apnea patients have low growth hormone levels. Growth hormone secretion is decreased in OSAH not only due to obesity but also due to fragmented sleep causing a reduction in the amount of slow wave sleep. Repetitive hypoxemia may, in addition, affect growth hormone secretion. Growth hormone deficiency in adults is associated with impaired psychological well-being, insulin resistance, endothelial dysfunction, increased visceral fat, increased cardiovascular mortality, and accelerated aging. Spiegel et al. examined the effect of chronic sleep debt on metabolic and endocrine functions. In 11 healthy young men aged between 18 and 27 years, who were restricted to 4 h in bed for 6 nights, there was clear impairment of carbohydrate tolerance. The rate of glucose clearance after injection of an intravenous bolus of glucose (300 mg/kg body weight) was nearly 40% slower compared to when the subjects spent 12 h in bed. Glucose effectiveness (a measure of the ability of glucose to mediate its own disposal independent of insulin) was 30% lower, which is about the same amount of difference observed between normoglycemic white men and patients with non-insulin-dependent diabetes. The acute insulin response to glucose, which has been identified as an early marker for diabetes, was 30% lower, a magnitude similar to that seen in gestational diabetes.
To complete the circle, Strohl et al. hypothesized that hyperinsulinemia causes central fat deposition. Increasing central obesity would result in decreased functional residual capacity (FRC), decreased vital capacity, impaired diaphragm muscle action and, through a coupling of FRC to upper airway size, reduced pharyngeal size. These factors would propagate apneic activity and increase the susceptibility for sleep apnea. In summary, while there are several putative mechanisms by which OSAH is thought to cause impaired glucose metabolism and insulin sensitivity, a clear and definite answer is still lacking (Fig. 37.1). In conclusion, sleep disordered breathing is now recognized as being much more prevalent than was originally suspected. The preponderance of cross-sectional studies points toward an independent association between sleep disordered breathing and diabetes mellitus or a “prediabetic” state of insulin resistance. This relationship has not been conclusively shown to be due to a direct causal effect. The data from studies examining the improvement of diabetes with CPAP treatment span the spectrum from no effect, to improvement in insulin sensitivity but not glycemic control, to significant improvement in glycemic control. Although there is a growing body of literature on this subject, it is clear that the understanding of the complex interactions between diabetes and sleep disordered breathing is still in its infancy. The field remains wide open for further research, especially for the longitudinal analyses and the effects of CPAP treatment.
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