Vol. 15 •Issue 8 • Page 43
Sleep Apnea and Diabetes
Which is the chicken, and which is the egg?
Even in the early experience with sleep in a purely clinical sleep disorders center, an interesting clustering of obstructive sleep apnea, obesity, cardiovascular disease, cerebrovascular disease, congestive heart failure, and diabetes often was seen. In the mid-’80s, researchers studied these relationships, but no firm data existed.
At the time, myths about sleep abounded: OSA was a male-only problem; OSA was caused exclusively by obesity; OSA was interesting but not really a “medical” problem; and OSA easily could be solved if the obese patient just had the discipline to lose 50 to 100 pounds.
Things have changed. The interrelationship between OSA, diabetes, obesity, and vascular disease now is being studied seriously.
Scientists first described OSA in the context of the Pickwickian Syndrome in 1965.1 Since then, OSA has been recognized as a common problem, conservatively estimated to occur in more than 5 percent of the population worldwide.
The hallmark of OSA is the sleep-related obstruction of the upper airway. There are significant drops in oxygen saturation, changes in cardiac rhythm, arousals from sleep, and increases in sympathetic tone due to the apnea.
The frequent association of diabetes and OSA has been studied for more than 20 years.3 But 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. Investigators showed that obesity, hypertension, hyperlipidemia, and glucose intolerance occurred more often in men with OSA than in a non-apneic population.4 In this study, the diagnosis of OSA was made with both clinical and polysomnographic criteria.
These risk factors can manifest themselves in a hard endpoint: mortality. Initially, the risk of OSA seemed to be associated with mortality indirectly by increasing the incidence of hypertension.5,6
With stroke, however, OSA is likely an independent risk factor. Diabetes also was linked with OSA, and the two were among the factors that predicted increased stroke mortality.6 While outside the scope of this discussion, clearly there’s an important connection between OSA, vascular risk factors, stroke, and heart disease.7
Diabetes as a cause of OSA
The exact relationship between diabetes and OSA is unclear. In a relatively small study, researchers examined diabetics, both insulin- and non-insulin dependent (NIDDM).8
Five of 12 lean, insulin-dependent diabetics had sleep-disordered breathing. Only one of seven obese NIDDM patients had SDB. The investigators also noted that the SDB was associated with autonomic neuropathy as measured by autonomic testing of the vagus nerve.
In a larger study, 179 NIDDM patients were tested with an ambulatory monitor; 31 subjects with a body mass index > 35 had SDB.9 Seventy percent had severe OSA and relatively severe oxygen desaturation.
In an even heavier selected group (BMI 42.7 ± 4.7), all had severe OSA (average apnea-hypopnea index, 42.7; average oxygen desaturation, 74 percent). All these patients used continuous positive airway pressure and exhibited improved insulin resistance, as measured with a hyperinsulinemic euglycemic clamp method.
The researchers concluded that OSA was common in the NIDDM population, and treatment of the OSA with CPAP might help the insulin resistance.
Other than the possibility of an autonomic neuropathy, as mechanism for 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, may be a risk factor for insulin resistance, NIDDM, and obesity.10 Submitting otherwise healthy male subjects to sleep restriction caused insulin resistance and impaired glucose tolerance.
Researchers also suggest that sleep loss or sleep fragmentation possibly causes insulin resistance, weight gain, and type 2 diabetes.10 They discussed an association with leptin and ghrelin levels as well.
OSA, 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 also are stimulants to feeding.
Certainly, other humeral factors are important, and these mechanisms are under active study. OSA causes 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-based study, obese, middle-aged men with OSA were compared to age- and BMI-matched controls.14 The patients with OSA had higher levels of leptin and inflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin six (IL-6).
The oxygen desaturation associated with the OSA is possibly the cause of the elevated leptin levels, rather than the apnea itself.15 Insulin resistance also was higher in the apneic patients. In addition, the severity of the OSA was linked to the amount of visceral fat but not total body fat.
The endothelial inflammatory mechanism by which OSA 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.16
OSA as a cause of diabetes
A recent study compared multiple metabolic parameters in mildly obese, otherwise healthy men with OSA.17 Using PSG, multiple sleep latency testing, and glucose tolerance testing, the researchers found an AHI ³ 5 was associated with increased risk of impaired or diabetic glucose tolerance testing.
The impairment in the glucose tolerance testing was, in turn, related to severity of oxygen desaturation. For a 4-percent decrease in oxygen saturation, there was an increased risk of abnormal glucose tolerance (odds ratio = 1.99, 95 percent confidence interval, 1.11 to 3.56). Thus, even relatively mild SDB and oxygen desaturation were significant causes for abnormalities of glucose tolerance.
The confounding variable of obesity was controlled for in another study, and the researchers showed that the insulin resistance caused by OSA, as measured by fasting serum insulin levels, was seen in both the obese and non-obese subjects.18 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 underwent PSG testing.19 Of those with AHI > 15, 14.7 percent had a diagnosis of diabetes compared to 2.7 percent of subjects with AHI < 5. AHI > 15 was associated with an increased risk of developing diabetes within the next four years if it wasn’t present at entrance into the study, but a causal link between OSA and diabetes couldn’t be made.
A metabolic syndrome, which included hypertension, insulin resistance, impaired glucose tolerance, and hyperlipidemia, was studied in patients with OSA, compared to control subjects without OSA.20
OSA was associated with hypertension, elevated insulin levels, elevated triglyceride 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
Researchers studied hemoglobin A1c levels in patients with OSA before and after treatment with CPAP.21
They found a decrease in hemoglobin A1c in patients who used the CPAP for more than four hours per day, and the degree to which the Hg-A1c dropped was related to the number of days that the patient used the machine.
Similarly, insulin resistance improved within two days once CPAP began, 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.22
A proposed mechanism
The above review is in no way complete, but it gives an idea of where research is heading. For those of us attempting to care for patients with sleep disorders, a mechanistic framework is helpful.
One line of thinking 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
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 catecholamines secreted by the sympathetic nervous system also cause glucose intolerance.
When the pituitary releases adreno-corticotropic hormone 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.
In addition, adrenal medullary catecholamines add to the adrenergic effects upon glucose intolerance and insulin resistance. Detailed discussion of OSA and metabolic dysfunction can be found in the “Principles and Practices of Sleep Medicine.”23
Tip of the iceberg
There’s now an expanding body of evidence that OSA and the oxygen desaturation that accompanies it are associated directly with diabetes, insulin resistance, and metabolic syndrome. Treatment of OSA 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, also may have a causative role in the development of OSA.
The metabolic changes and the endothelial effects from the pro-inflammatory cytokines resulting from OSA offer some explanation for the increased mortality, increased risk of vascular disease, and the mortality associated with OSA.
No longer should we think of sleep apnea as simply a phenomenon of “air in-air out.” Perhaps, it’s more appropriate to consider sleep apnea as the initial “tip” of an increasingly complex pathophysiological iceberg.
For a list of references, please look under the “From Print” toolbar on the left side of our home page at www.advanceweb.com/respmanager.
Robert W. Fayle, MD, is the medical director of the Sleep Disorders Center at Park Plaza in Houston. He’s board certified in neurology and sleep disorders medicine.
