Even in the early experience with sleep in a purely clinical sleep disorders center, an interesting clustering of sleep apnea, obesity, cardiovascular disease, cerebrovascular disease, congestive heart failure and diabetes was often seen. At the time, in the mid-80’s, these relationships were already being studied, but there were, then, no firm data. Myths about sleep were common: 1. sleep apnea was thought to be a male-only problem, 2. sleep apnea was caused exclusively by obesity, 3. sleep apnea was interesting, but not really a “medical” problem, and 4. sleep apnea could easily be solved if the obese patient just had the discipline to lose 50-100 pounds of body weight. Things have changed. The inter-relationship between sleep apnea, diabetes, obesity, and vascular disease is now being studied seriously.
Sleep apnea was first described in the context of the Pickwickian Syndrome in 1965 (1). Since then, sleep apnea has been recognized as a common problem, conservatively estimated to occur in over 5% of the population worldwide (2). The hallmark of obstructive sleep apnea is the sleep-related obstruction of the upper airway. There are significant drops in the oxygen saturation, changes in cardiac rhythm, arousals from sleep and increases in sympathetic tone due to the apnea. The frequent association of diabetes and sleep apnea has been studied for over 20 years at this point (3). There are still questions as to the exact nature of the relationship and how each affects the other- is it the chicken or the egg?
Other important co-morbid conditions have been studied. Levinson, et al (4) showed that obesity, hypertension hyperlipidemia and glucose intolerance were more common in men with sleep apnea than in a non-apneic population. In their study the diagnosis of sleep apnea was made with both clinical and polysomnographic criteria. These risk factors can manifest themselves in a hard endpoint, mortality (5); initially the risk of sleep apnea seemed to be associated with mortality indirectly by increasing the incidence of hypertension (6). With stroke, however, sleep apnea may is likely an independent risk factor. Diabetes was also associated with the sleep apnea and the two were among the factors that predicted increased stroke mortality in a recent study by Basseti(6). While outside the scope of this discussion, clearly there is an important connection between sleep apnea, vascular risk factors, stroke and heart disease(7).
Diabetes as cause of sleep apnea
The exact relationship between diabetes and sleep apnea has been unclear. In a relatively small study, Mondini and Guilleminault (8), studied diabetics, both insulin (IDDM)- and non-insulin dependent (NIDDM). In five of 12 lean insulin-dependent diabetics, sleep disordered breathing was found. Only one of seven obese, non-insulin dependent patients had sleep disordered breathing They also noted that the sleep disordered breathing was associated with autonomic neuropathy as measured by autonomic testing of the Vagus Nerve. In a larger study, 179 NIDDM patients were studied using an ambulatory monitor to document sleep disordered breathing in 31 patients with BMI>35. 70% had severe sleep apnea and relatively severe oxygen desaturation. In an even heavier selected group (BMI 42.7 +/- 4.7), all had severe obstructive sleep apnea ( average AHI 42.7, average O2 desaturation 74%). All these patients were treated with continuous positive airway pressure (CPAP) and the insulin resistance, as measured with a hyperinsulinemic euglycemic clamp method, was improved with the CPAP. They concluded that obstructive sleep apnea (OSA) was common in the NIDDM population and that treatment of the OSA with CPAP might help the insulin resistance (9).
Other than the possibility of an autonomic neuropathy, which is a frequent complication of diabetes, as mechanism for the OSA in diabetics, other sleep issues complicate the picture. Simply missing sleep can be a problem. Sleep restriction whether voluntarily or as a result of other sleep disorders such as OSA, by itself may be a risk for insulin resistance, NIDDM and obesity (10). Submitting otherwise healthy male subjects to sleep restriction caused insulin resistance and impaired glucose tolerance. Spiegel , et al also suggest that sleep loss or sleep fragmentation possibly cause insulin resistance, weight gain and might be a cause for type2 diabetes. They also discussed an association with leptin and ghrelin levels.
Sleep apnea and Leptin and Ghrelin
The roles of Leptin and Ghrelin in the control of caloric control and feeding behavior have been the subject of increasing interest. A large body of work has arisen recently and has been reviewed (11,12). Leptin, secreted by fat cells in adipose tissue, suppresses feeding behavior by binding to neurons in the paraventricular and arcuate nuclei in the hypothalamus. Ghrelin stimulates the same areas to increase feeding. Insulin receptors in the Arcuate Nucleus are also stimulants to feeding. Certainly, other humeral factors are also important and these mechanisms are under active study. OSA was recently found to cause increased levels of serum leptin( suggesting an insensitivity to leptin, analogous to insulin resistance) and insulin/glucose ratio. When treated with CPAP, the leptin levels decreased (13). In a polysomnography (PSG)-based study (14) obese, middle-aged men with OSA were compared to age- and BMI-matched controls. The patients with OSA were found to higher levels of leptin as well as higher levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin six (IL-6). The O2 desaturation associated with the sleep apnea is possibly the cause of the elevated leptin levels, rather than the apnea itself (20). Insulin resistance was also higher in the apneic patients. The severity of the apnea was also linked to the amount of visceral fat, but not total body fat. The endothelial inflammatory mechanism by which sleep apnea is associated with cerebrovascular disease has been reviewed recently, and the increased levels of pro-inflammatory cytokines have been identified as a crucial link between stroke and sleep apnea (15).
Sleep apnea as a cause of diabetes
A recent study (16) compared multiple metabolic parameters in mildly obese, otherwise healthy men with OSA; as measured with PSG, multiple sleep latency testing(MSLT), and glucose tolerance testing; AHI >/= 5 was associated with increased risk of impaired, or even, diabetic glucose tolerance testing. The impairment in the glucose tolerance testing was, in turn, related to severity of O2 desaturation. For a 4% decrease in O2 saturation there was increased risk of abnormal glucose tolerance (OR=1.99, 95% CI, 1.11 to 3.56). Thus, even relatively mild sleep disordered breathing and relatively mild O2 desaturation were significant causes for abnormalities of glucose tolerance. The confounding variable of obesity was controlled for in the study by Ip and colleagues (17), and they showed that the insulin resistance, as measured by fasting serum insulin levels, caused by OSA was seen in both the obese and non-obese subjects. Their subjects were studied with PSG indicated for suspected OSA and had no clinical sign of diabetes.
In a large study of the Wisconsin Sleep Cohort, 1,387 subjects were studied with PSG. Of those with AHI>15, 14.7% had a diagnosis of diabetes compared 2.7 % of subjects with AHI<5. AHI> 15 was associated with an increased risk of developing diabetes within the next four years if it was not present at entrance into the study, but a causal link between OSA and diabetes could not be made(18). A metabolic syndrome, which included hypertension, insulin resistance, impaired glucose tolerance and hyperlipdemia , was studied in patients with OSA, compared to control subjects without OSA (19). OSA was found to be associated hypertension, elevated insulin levels, elevated triglceride levels, lower HDL levels, increased cholesterol: HDL ratio and a trend toward insulin resistance. The metabolic syndrome was 9.1 times more likely to be present in patients with OSA than in the controls.
Treatment with CPAP
The effect of treatment with CPAP has also been studied. Babu, et al (21), studied hemoglobin A1c levels in patients with OSA before and after treatment with CPAP, They found that there was a decrease in the hemoglobin A1c in patients who used the CPAP for greater than four hours per day and that the degree to which the Hg-A1c dropped was also related to the number of days that the machine was used. Similarly, insulin resistance was found to improve within two days once CPAP was started and the effect lasted for at least three months. The response at two days was more pronounced in patients with BMI <30 than in those who were more obese.
A proposed mechanism
The above review is in no way complete, but it does give one an idea of the direction of the current study. For those of us attempting to care for patients with sleep disorders, a mechanistic framework is helpful. Punjabi and Beamer (22) have synthesized this well. Their thought is that the sleep fragmentation and hypoxia caused by sleep apnea create a cascade of events: 1.activation of adipose cells to secrete leptin (OSA causes leptin insensitivity), TNF and IL-6; 2. Sympathetic Nervous System activation; and 3. Hypothalamo-pituitary-adrenal activation. The inflammatory cytokines produced by the adipose tissue causes glucose intolerance and endothelial dysfunction associated with cardio- and cerebrovascular disease. The catecholeamines secreted by the Sympathetic Nervous System also cause glucose intolerance. When the pituitary releases ACTH in response to the physiologic stress of OSA and other causes of sleep deprivation, the adrenal is stimulated to release cortisol which also causes insulin resistance and glucose intolerance. Adrenal medullary catecholamines also add to the adrenergic effects upon glucose intolerance and insulin resistance. Review of their chapter is recommended.
Summary
There is now an expanding body of evidence that sleep apnea and the oxygen desaturation that accompanies it are directly associated with diabetes, insulin resistance and the metabolic syndrome. Treatment of the sleep apnea with CPAP improves the insulin insensitivity rapidly, and the effect seems to be maintained for at least two months. Diabetes with its resultant autonomic neuropathy may also have a causative role in the development of sleep apnea. The metabolic changes and the endothelial effects from the pro-inflammatory cytokines which result from sleep apnea offer some explanation for the increased mortality, increased risk of vascular disease and the mortality associated with sleep apnea. No longer should we think of sleep apnea as simply a phenomenon of “air in-air out”. Perhaps, it is more appropriate to consider sleep apnea as the initial “tip” of an increasingly complex pathophysiological iceberg.
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Robert W. Fayle, M.D. is board certified in neurology and sleep disorders medicine. He is the medical director of The Sleep Disorders Center at Park Plaza in Houston, Texas.
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