Sleep, Aging and Metabolic Syndrome – S. Ramnathan Iyer and Revati R. Iyer
Good sleep in both quantity and quality is essential for maintaining good health. The growth of 24X7 society has pushed sleep to a secondary level of importance. Fast-paced life style is now a global phenomenon. Villages are being transformed into towns; and towns into cities. Modern life style has given birth to sleep deprivation, which is possibly a hidden epidemic. Sleep deprivation affects the functioning of several body systems. There are errors in secretion of hormones, which can ultimately culminate into serious metabolic disorders. In fact, sleep is a metabolic regulator. Sleep deprivation induces or aggravates snoring by increasing muscular hypotonia and delaying contraction of the dilator muscles of the pharynx.1 Sleep deprivation also induces stress and stress can lead to obesity. Snoring and excessive daytime sleepiness are prominent symptoms of obstructive sleep apnea (OSA), which is a widely prevalent sleep disorder. Repetitive pharyngeal collapses in sleep with resultant cyclical hypoxemia are characteristics of OSA. These have deleterious effects in various organ systems. OSA is a risk factor for hypertension, diabetes, ischemic heart disease, strokes and other disorders. In society, habitual snoring is often considered as a sign of sound sleep. There is lack of awareness of sleep disorders in general population. Studies have shown that snoring predicts the onset of diabetes.2,3 OSAis closely linked to diabetes.4 Daytime sleepiness may be masked by the consumption of tea, juices, coffee, water, snacks, tobacco chewing, smoking, etc. The subject might resort to binge eating resulting in increase in body weight. Smoking is a risk factor for diabetes. Cessation of smoking increases appetite resulting in further increase in body weight. Sleep loss is associated with impaired glucose tolerance and diabetes. Glucose tolerance is markedly better in the morning than in the evening.5 Spigel et al.6 have demonstrated that slee p debt results in impaired glucose tolerance and diabetes. Obesity often unmasks diabetes in a genetically prone individual. Sleep deprivation in such individuals can trigger the development of diabetes. The association of obesity and sleep apnea is well known. Sleep apnea promotes obesity and obesity promotes sleep apnea (vicious cycle). Diabetic mothers are known to deliver oversized babies. The predominant pattern of body fat distribution in sleep apnea is central and it is the intrabdominal fat (visceral fat and not generalized obesity) that predisposes to sleep apnea.8,9
As age advances there is increase in fat content and loss of lean muscle mass. This fat (visceral adipose tissue) is metabolically active and has been associated with insulin resistance, dyslipidemia, type 2 DM, hypertension and cardiovascular problems.10 The prevalence of SDB increases with age ranging from 5–15% in middle-aged adults to approximately 24% in community dwelling older adults.11,12 Udwadia et al.7 reported habitual snoring in 26% of the study population (middle-aged urban Indian men) and the estimated prevalence of SDB (apnea hypopnea index of 5 or more) was 19.5% and that of obstructive sleep apnea-hypopnea syndrome ( SDB with daytime hypersomnolence) was 7.5%. OSA is common in older subjects. It is also interesting to note that the prevalence of diabetes also increases with age.13 OSAis independently associated with an increased prevalence of metabolic syndrome.14 The age distribution of metabolic syndrome is similar to age distribution of symptomatic sleep apnea.15 Therefore a close as sociation exists between aging, OSA, and metabolic syndrome. The addition of OSA to Syndrome X has been labeled as “Syndrome Z”.16 Sleep disordered breathing in pregnancy can have adverse effects on the mother and foetus (Pregnancy induced hypertension and small for gestational birth).17 28% of babies born in India are of low birth weight. Such babies are prone to have elevated glucocorticoid levels in later life. Excessive daytime sleepiness (EDS), a prominent symptom of OSA, is also observed in subjects of polycystic ovarian syndrome. Tumor necrosis factor and interleukin-1® and interleukin-6 are involved in physiological sleep regulation. Vgontzas et al.18 have reported that TNF-a is significantly elevated in sleep apneics and narcoleptic subjects while IL-6 concentrations are markedly elevated in sleep apneic subjects as compared to normal controls. Both these cytokines are positively correlated with the presence of EDS. Proinflammatory cytokines contribute to the pathogenesis of OSA/sleepiness. In cli nical practice, it is observed that some subjects of OSA suffer from EDS in spite of adequate usage of continuous positive airway pressure (CPAP). Also drowsiness in diabetic subjects may be due to hypercytokinemia. Vgontzas et al.19 have observed a significant marked decrease of sleepiness by etanercept, a molecule that neutralizes TNF-a. Obesity and insulin resistance by releasing growth factors may lead to soft tissue edema of the neck. Also, elevated plasma TNF-a levels have been associated not only with obesity and insulin resistance, but also with hypertriglyceridemia, glucose intolerance and negatively correlated with HDL cholesterol.20,21 Leptin deficiency and leptin resistance may lead to respiratory depression in obesity especially during sleep.22
There appears to be a link between communicable and noncommunicable diseases.4 There is possibly a relation between snoring, chronic inflammation and insulin insensitivity. Chronic inflammation is known to act as a trigger for chronic insulin insensitivity.23 Disorders with insulin insensitivity (e.g. obesity, type – 2 DM and atherosderosis) also show increased cytokine production and markers of inflammation. Evidence at present favors chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation. Once OSA sets in, the nocturnal events result in sympathetic stimulation, and catecholamine secretion resulting in metabolic errors. Habitual snorers have inflamed soft palate and are also prone to repeated respiratory infections. We propose the hypothesis that chronically inflamed upper airway acts as a trigger for chronic insulin insensitivity. Also, studies have shown that snoring predicts the onset of diabetes.2,3 OSA is observed in lean and normal body weight subje cts indicating that OSA might contribute to the development of diabetes in these subjects. In India, a large number of diabetic subjects are either low body weight or of normal body weight. It would be interesting to do studies to establish the link between these two disorders. Ip and associates observed that the association between OSA and insulin resistance was present even in nonobese subjects.24
Endocrine functions obey certain circadian rhythmicity and changes in sleep wake cycle have profound influence on them. Endocrinal disorders may themselves lead to sleep disorders. OSA is common in acromegaly. In one study25, diabetes was associated with more frequent complaints of difficulty in initiating sleep (21.1%), difficulty in maintaining sleep (21.9%), and excessive daytime sleepiness (12.2%). Nocturia also disturbs sleep. As age advances, the total amount of time spent in delta sleep seems to be reduced and subsequently the amount spent in stages 1 and 2 increase. The older subject takes longer to fall asleep and experiences an increased period of wakefulness after sleep initiation (wake after sleep onset).26 It is therefore imperative to record sleep history particularly with reference to snoring in all diabetic and elderly subjects. It has been recently been reported that OSA is associated with several eye disorders viz, floppy eyelid syndrome, anterior ischemic optic neuropathy, optic neur opathy, glaucoma, papilloedema secondary to raised intacranial pressure.27 We proposed in 20034 that the retina is the highest oxygen consuming part of the body and cyclical hypoxemia can have deleterious effects on the retina. We now propose that the possible stimulus for progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy is cyclical hypoxemia in subjects of diabetes with OSA. Diabetes is more prevalent in SDB and this relationship is independent of other risk factors.28 Treatment of OSA in diabetic subject can be rewarding since studies have shown that CPAP increases insulin sensitivity.29 Therefore it is advisable to screen all diabetic subjects for OSA.
A close relationship exists between sleep, circadian rhythm, aging, obesity, hormones, hypertension and cardiovascular morbidity and mortality. The metabolic syndrome express highway desperately needs a U-turn. Preventing the pharyngeal collapse by mechanisms like usage of CPAPwill probably close the gate, which leads to the development of many disorders.
S. Ramnathan Iyer, MD
Sleep Medicine, Ambika Clinic, Thane
Revati R. Iyer, MD – Sleep Medicine,
Dr. L. H. Hiranandani Hospital, Mumbai.
1. Leither, J. C., Knuth, S. L., Barlett, D. (1985) The effect of sleep deprivation on activity of genioglossus muscle. Am. Rev. Respir Dis. 132: 1242–1245.
2. Elmsary, A., Janson, C., Lindberg, E., Gisalson, T., Tageldin, M. A., Boman, G. (2002) The role of habitual snoring and obesity in the development of diabetes; 10 year follow up study in a male population. J. Intern. Med. 248: 13–20.
3. AI – Delaimy, W. K., Manson, J. E., Willet, W. C., Stampfer, M. J., Ju, F. B. (2002) Snoring as a risk factor for type II diabetes mellitus; a prospective study. Am. J. Epidemiol 155: 387–393.
4. Iyer S. R. (2003) Type 2 Diabetes Express Highway, Where Is The “ U “ Turn ? J. Assoc. Physicians India 51: 495–500.
5. Van Cauter, E., Polonsky, K. S., Schee, A. J. (1997) Role of Circadian rhythmicity and sleep in human glucose regulation. Endocr. Rev. 18: 716–738.
6. Spiegel, K., Leproult, R., Van Cauter, E. (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354: 1435–1439.
7. Udwadia, Z. F., Doshi, A. V., Lonkar, S. G. and Singh CI. (2004) Prevalence of sleep disordered breathing and sleep apnea in middle aged urban Indian men. Am. J. Resp. Crit. Care. Med. 169:167–173.
8. Vgontzas, A. N., Tan, T. L., Bixler E. O., Sleep apnea and sleep disruption in obese patients. Arch. Intern. Med. 1994; 154: 1705–1711.
9. Vgontzas, A. N., Papanicolau, D. A., Bixler, E. O., et al. (2000) Sleep apnea and daytime sleepiness and fatigue relation to visceral obesity, insulin resistance and hypercytokinemia. J. Clin. Endocrinol. Metab. 85: 1151–1158.
10. Bjorntop, P. (1991) Metabolic implications of body fat distribution. Diabetes care 14: 1132–1143.
11. Ancoli Israel, S., Kripke, D. F., Klanber, M. R., et al. (1991) Sleep disordered breathing in community dwelling elderly Sleep 14: 486–495.
12. Young, T., Palta, M., Dempsey, J., et al. (1993) The occurence of sleep disordered breathing among middle aged adults New Engl. J. Med. 328: 1230–1235.
13. Iyer, S. R., Iyer Revati, R., Upasani, S. V. and Baitule, N. M. (2001) Diabetes mellitus in Dombivli – an Urban population study. J. Assoc. Physicians India 49: 713–716.
14. Coughlin, S. R., Mawdsely, L., Mugarza, J. A., Calverly, P. M. A., Wilding John, P. H. (2004) Obstructive Sleep Apnea is independently associated with an increased prevalence of metabolic syndrome. European Heart Journal 25: 735–741.
15. Park, Y-W., Zhu, S., Palaniappan, L., Heshka, S., Carnethon, M. R., Heymsfield, S. B. (2003) The metabolic syndrome prevalence and associated risk factor findings in the US population from the third maternal health and nutrition examination survey 1988–1994. Arch, Int. Med. 63: 427–436.
16. Wilcox, I., Mc Namara, S. G., Collins, F. L., Grunstein, R. R., Sullivan, C. E. Syndrome Z the interaction of sleep apnea; Vascular risk factors and heart disease Thorax 53(suppl 3); S25–S28.
17. Pien, G. W. and Schwab, R. J. (2004) Sleep disorders during pregnancy. Sleep 27 (7) 1405–1417.
18. Vgontzas, A. N., Papanicolaou, D. A., Bixter, O., Kales, A., Tyson, K., Chrousos, G. P. (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness. Role of sleep disturbance and obesity J. Clin. Endocrinol. Metab. 82: 1313–1316.
19. Vgontzas, A. N., Zourmakis, E., Lin, H–M., Vela-Bueno, A., Chrousos, P. (2004) Marked decrease of sleepiness in patients with sleep apnea by etanercept. J. Clin. Endrocrinol. Metab. 89: 4409–4413.
20. Jovinge, S., Hamsten, A., Tomvall, P., et al. (1998) Evidence for a role of tumor necrosis factor alpha in disturbances of triglycerides and glucose metabolism predisposing to coronary heart disease. Metabolism 47: 113–118.
21. Corica, F., Allegra, A., Corsonello, A., et al. (1999) Relationship between plasma leptin and the tumor necrosis factor alpha system in obese subjects. Int. J. Obes. Metab. Disord. 23: 355–360.
22. O’Donnell, C. P., Tankerslet, C. G., Polotsky, V. P., Schwartz, A. R., Smith, P. L. (2000) Leptin, obesity, and respiratory function. Respir Physiol. 119: 173–180.
23. Grimble, R. F. (2002) Inflammatory status and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 5: 551–559.
24. IP, M.S.M., Lam, B., Ng, M.M.T., Lam, W.K., Tsant, K.W.T., Lam, K.S.L. Obstructive Sleep apnea is independently associated with insulin resistance. Am. J. Respir. Crit. Care Med. 2002;165: 670–676.
25. Gisalason, T., Almqvist, M. (1987) Somatic diseases and sleep complaints Acta Med. Scand 221: 475–481.
26. Avidan, A. Y. (2002) Sleep changes and disorders in the elderly patient. Current neurology and Neuroscience reports 2: 178–185.
27. McNab, A. A. (2005) The eye and Sleep. Clin Experiment Ophthalnol 33: 117–125.
28. Reichmuth, K. J., Austin, D., Skaturd, J. B., Young, T. (2005) Association of sleep apnea and Type II diabetes Am. J. Respir. Crit. Care Med. 172: 1590–1595.
29. Harsh, I. A., Schahin, S. P., Radespier – Trogen, M. et al. (2004) Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am. J. Resp. Crit. Care Med. 169(2): 139–140.
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