Sleep Apnea and Daytime Sleepiness and Fatigue: Relation to Visceral Obesity, Insulin Resistance, and Hypercytokinemia

Abstract

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-␣ and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age-and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-␣ and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age-and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (Ͻ0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.

Non-alcoholic fatty liver disease - the heart of the matter

“…OSAS is accompanied by proinflammatory cytokine production, platelet aggregation, endothelial dysfunction and metabolic dysregulation which can increase the risk of cardiovascular disease [53] . OSA has been shown to be a risk factor for insulin resistance [54][55][56][57][58][59][60] and carotid intima media thickening [61] , and in addition there are reports of ischemic hepatitis accompanying severe OSAS [62,63] . A study of 163 non-drinking OSAS patients found that the more severe the OSAS, sufferers had more insulin resistance and more steatosis and fibrosis [64] .…”

Intermittent hypoxia activates temporally coordinated transcriptional programs in visceral adipose tissue

“…measures independent of weight change [3][4][5]. Chronic exposure to IH has become a well-established animal model for human OSA, capturing its cyclical hypoxic pattern and replicating many of its systemic consequences including increased oxidative stress [6] and insulin resistance [7].…”

Identification of significant obstructive sleep apnoea in the obese patient: development of the novel DX-OSA score

“…Males have a two-to threefold increased risk of OSA as compared to women [2], which may be related to differences in the distribution of adipose tissue in men [21,[43][44][45], who have a predominantly central fat deposition pattern around the neck, trunk, and abdominal viscera [46,47].…”