PITTSBURGH – Interventions to reduce or neutralize proinflammatory cytokines may be novel treatments in patients with sleep disorders and obesity, Dr. Alexandros Vgontas said at the International Congress of Neuroendocrinology.
Three inflammation-associated cytokines–tumor necrosis factor-α (TNF-α, interleukin-1 (IL-1), and IL-6–are elevated in obese and sleep-deprived patients, and may mediate excessive daytime sleepiness and fatigue. All three cytokines are part of the acute phase response and activate the hypothalamic-pituitary-adrenal axis.
“Proinflammatory cytokines may represent a pathophysiologic link to insulin resistance, obesity, and cardiovascular problems,” said Dr. Vgontas, director of the Center for Sleep Disorders Medicine and professor of psychiatry at Pennsylvania State College of Medicine in Hershey.
Over the last decade, research has focused on the role of proinflammatory cytokines in sleep loss and sleep disorders such as sleep apnea, narcolepsy, and insomnia. Studies have demonstrated that IL-6 and TNF-α plasma levels are elevated in patients with sleep apnea and narcolepsy, he said.
Dr. Vgontas and his colleagues also reported a positive correlation between IL-6 and TNF-α levels and body mass index. In a study in 73 obese patients and 45 healthy controls, both without sleep-disordered breathing, obese patients were significantly more likely to have excessive daytime sleepiness.
The finding was replicated by investigators at Pennsylvania State in a large, random community sample in which the strongest risk factors for excessive daytime sleepiness were depression, body mass index, age, sleep duration, diabetes, and finally sleep apnea (J. Clin. Endocrinol. Metab. 2005;90:4510–5).
Dr. Vgontas also studied women with polycystic ovary syndrome, a condition in which the primary pathogenetic mechanism is insulin resistance. In that study, he found that daytime sleepiness is present in 80% of women who have PCOS, and that there is a 30-fold increase in sleep apnea in this population, compared with healthy controls.
Based on these findings, he postulated that sleep apnea is primarily a manifestation of metabolic syndrome rather than a local abnormality of the respiratory track. TNF-α IL-1, and IL-6 are produced by adipose tissue, particularly visceral fat, where 30% of IL-6 is produced. CT scans have shown that sleep apnea patients have significantly more visceral fat in the abdominal area than do obese patients without sleep apnea, Dr. Vgontas said.
Several outside studies also support this systemic view of cytokines in sleep disorders and related health problems. One study showed that sleep apnea patients are more insulin resistant, older, and more obese, but also that insulin resistance is present even in nonobese apnea patients (Am. J. Respir. Crit. Care Med. 2002;165:670–6). Another study indicates that insulin resistance is present even in mild forms of sleep apnea (Am. J. Respir. Crit. Care Med. 2002;165:677–82).
Interventions in this area remain limited. The use of IL-1 or TNF-α receptor antagonists or IL-1b antibodies has been shown to reduce sleep in an animal model. A small pilot study in humans showed that the use of etanercept, a cytokine antagonist, decreased sleepiness in eight obese men with symptomatic apnea, Dr. Vgontas reported.
'Proinflammatory cytokines may represent a pathophysiologic link to insulin resistance.' DR. VGONTAS