Sleep-Disordered Breathing and the Current Epidemic of Obesity
Consequence or Contributing Factor?

Esra Tasali, M.D. and Eve Van Cauter, Ph.D.

Department of Medicine, University of Chicago, Chicago, Illinois

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Sleep-disordered breathing (SDB) is an increasingly common chronic condition that is characterized by repetitive episodes of partial or complete upper airway obstruction during sleep. Although the natural history of SDB remains to be fully elucidated, generalized sympathetic nervous activation has been clearly implicated and population-based studies have demonstrated an independent association between SDB and cardiovascular disease (1). In the present issue of the AJRCCM, two separate well-documented studies (2, 3), both involving large sample sizes and careful assessments of SDB by full polysomnography, add to a growing body of recent evidence supporting the existence of a link between SDB and insulin resistance independent of the degree of obesity. For example, Vgontzas and coworkers (4) recently reported that fasting glucose and insulin levels were significantly higher in patients with SDB when compared with weight-matched control subjects. Similarly, a large population-based study in normoglycemic hypertensive men indicated a significant correlation between the variables of SDB and indices of glucose metabolism after adjusting for measures of central obesity (5). If confirmed, the existence of a link between SDB and insulin resistance would imply that respiratory dysfunction during sleep represents an independent risk factor for the so-called metabolic syndrome, i.e., the association of insulin resistance, obesity, and hypertension that is highly prevalent in modern society.

Not all previous studies that have examined the association between SDB and abnormal glucose metabolism have had positive conclusions. In a cross-sectional study that tested middle-aged healthy volunteers for the presence or absence of SDB, Stoohs and colleagues (6) found that elevated insulin resistance in individuals with SDB was entirely dependent on body mass. These findings appeared to be in agreement with those of Davies and coworkers (7), who showed no significant hyperinsulinemia in sleep apneics and snorers when compared with control subjects individually matched for age, gender, body mass index, and smoking and drinking habits. It is noteworthy that both of these negative studies included a much smaller number of patients with SDB (n = 15 in both studies) than either the study by Punjabi and coworkers (n = 93) (pp. 677-682) or the study by Ip and colleagues (n = 185) (pp. 670- 676) in the present issue of the AJRCCM (2, 3). These previous studies may thus not have had the statistical power needed to detect an effect of SDB independent of degree of obesity. Evidence against an independent link between SDB and insulin resistance has also been derived from studies that have shown that treatment of SDB with continuous positive airway pressure (CPAP) failed to improve parameters of insulin-glucose regulation (8). Because the duration of CPAP treatment was short in all these studies, ranging from a single night to a maximum of 6 months, it is not surprising that insulin resistance associated with years of SDB and the attending alterations of metabolic and endocrine functions may not have been corrected by such a short-term intervention. In support of the hypothesis that correction of SDB by CPAP may have long-term beneficial metabolic effects are the findings that CPAP use decreases intra-abdominal visceral fat and normalizes leptin levels (9, 10). In obese diabetic patients with SDB, Brooks and coworkers (11) have reported a moderate improvement in insulin sensitivity after CPAP treatment.

Taken together, the findings of Punjabi and colleagues and Ip and coworkers provide compelling evidence in favor of an independent association between SDB and insulin resistance. Importantly, Ip and associates (3) observe that the association between obstructive sleep apnea and insulin resistance is present even in nonobese subjects. Furthermore, these authors indicate that increases in the number of apnea or hypopnea per hour are associated with increases in markers of insulin resistance. A key feature from the work by Punjabi and colleagues (2) is the demonstration of a significant relationship between the severity of intermittent hypoxemia associated with respiratory events and the magnitude of reductions in glucose tolerance after adjusting for percent body fat, body mass index, and apnea-hypopnea index. Indeed, the presence of recurrent hypoxemia and abnormal nocturnal sympathetic output, which are well demonstrated hemodynamic properties of obstructive sleep apnea, has been proposed as the mediating mechanism in the causal link between SDB and insulin resistance.

As pointed out by Punjabi and coworkers (2), sleep loss achieved by bedtime curtailment in normal healthy young adults results in marked alterations of glucose metabolism and endocrine function (12), suggesting that sleep loss per se, in the absence of breathing abnormalities, may promote insulin resistance. The state of "sleep debt" is in itself associated with increased sympathetic nervous activity and there is preliminary evidence that sleep restriction increases the severity of SDB. Conversely, sleep disruption by frequent arousal, as occurs in SDB, is likely to result in an ever-accumulating sleep debt in these patients. Thus, a feedforward cascade of negative effects may be generated by the interaction between SDB and the accompanying sleep debt to not only worsen the sleep disorder itself, but also contribute to the development of adverse metabolic consequences such as insulin resistance, further weight gain, and diabetes.

"Normal" sleep duration has decreased from approximately 9 hours in 1910 to an average of 7 hours today, and many individuals are in bed 5-6 hours per night on a chronic basis. Consistent with such short habitual bedtimes, time in bed in the patients who participated in the study by Punjabi and colleagues (2) was between 6.5 and 7 hours. Social pressures, and particularly the pressures of the working environment, impose such short bedtimes to an increasingly large number of individuals in western societies. It is likely that the prevalence and severity of SBD are increased by chronic sleep curtailment. The possibility that the current epidemic of obesity, diabetes, and SDB in the United States may be partly related to insufficient sleep has been recently recognized. The alarming increase in obesity, diabetes, and SDB represents a major public health problem, as a substantial proportion of these patients also have increased cardiovascular morbidity and mortality.

Finally, it should be noted that compliance with CPAP treatment in patients with SDB is dismally low. On average, one third of patients are noncompliant with CPAP use. The development of better-tolerated novel treatments, grounded in an improved understanding of the complex interaction between SDB, insulin resistance, and obesity, is thus urgently needed and may have considerable implications for lowering the risk of adverse cardiovascular outcome in this patient population.

	References

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