PGMJ Online First, published on June 23, 2014 as 10.1136/postgradmedj-2013-132366 Review
Circadian clock desynchronisation and metabolic syndrome Mae Sheikh-Ali, Jaisri Maharaj Department of Medicine, University of Florida College of Medicine, Jacksonville, USA Correspondence to Dr Mae Sheikh-Ali, Division of Endocrinology, Department of Medicine, University of Florida, 653-1 West Eighth Street, Jacksonville, FL 32209, USA; [email protected]fl.edu Received 10 September 2013 Revised 2 June 2014 Accepted 3 June 2014
ABSTRACT There is emerging evidence in the literature to suggest that disruption of the normal circadian rhythm (sleep– wake cycle signalling) is a potential risk factor to explain the increased incidence of metabolic syndrome. Over the last century, obesity, diabetes and other components of metabolic syndrome have been on the rise. On the other hand, the amount of sleep has decreased from an average of 6–8 h per night. Furthermore, the quality of sleep has declined with more individuals voluntarily decreasing their amount of sleep to work or enjoy leisure activities. Over the last decade, researchers have examined the relationship between disruption in human circadian system and the emergence of symptoms related to metabolic syndrome. Indeed, epidemiological studies suggest a relation between sleep duration and diabetes and obesity. Moreover, experimental animal and human studies suggest such a relation. These studies propose optimum sleep duration of 7–8 h per night to avoid circadian rhythm disruption and suggest that sleep disturbance, whether iatrogenic or disease-related, should be considered as a risk factor for metabolic syndrome, and be addressed. This field is in its infancy and further understanding of specific pathophysiological pathways of circadian desynchronisation will help in developing novel preventive and therapeutic strategies.
INTRODUCTION
To cite: Sheikh-Ali M, Maharaj J. Postgrad Med J Published Online First: [please include Day Month Year] doi:10.1136/ postgradmedj-2013-132366
Metabolic syndrome describes a group of modifiable elements occurring in the same individual and is associated with a twofold increased risk of developing cardiovascular disease (CVD) and a fivefold increased risk of developing type 2 diabetes mellitus (DM).1 2 The current definition of metabolic syndrome, produced in 2009 in a joint interim statement agreed by six international groups, is the presence of any three of the following:3 ▸ elevated waist circumference ▸ elevated triglycerides ▸ elevated blood pressure (BP) ▸ reduced high-density lipoprotein cholesterol ▸ elevated fasting glucose The metabolic syndrome affects around 20%– 30% of the adult population in most countries, with the prevalence being even higher in some populations.4 In the 3rd National Health and Nutrition Examination Survey, metabolic syndrome was present in 22.8% and 22.6% of US men and women, respectively.5 Another study from 2008 to 2010 in 11 149 adults in Spain reported the prevalence of metabolic syndrome as 22.7%.6 A systematic review in Brazil revealed prevalence of metabolic syndrome in the general population to be 29.6% and as high as 65.3% in an indigenous population.7 Traditional risk factors for metabolic
Sheikh-Ali M, et al. Article Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366 Copyright author (or their employer) 2014. Produced
syndrome included older age, postmenopausal status, Mexican American ethnicity, higher body mass index, current smoking, low household income, high carbohydrate intake, no alcohol consumption and physical inactivity.5 Nowadays, there is emerging evidence to suggest that disruption of normal circadian rhythms is a novel risk factor that can explain the increased prevalence of metabolic syndrome. Circadian rhythms are generated in mammals in an attempt to adapt to the light–dark, sleep–wake cycling. Therefore, circadian rhythms are endogenous and need to be continuously synchronised with the environment. Synchrony between external environmental zeitgebers (time-keepers), such as day and night, and internal body circadian clocks that are responsible for different internal body signalling rhythm is essential for normal metabolism. Subsequently, loss of this synchrony results in circadian desynchronisation.8 Circadian desynchronisation may result from disruption in sleep–wake cycle and can lead to pathological situations.9 In the National Health Interview Survey, nearly 30% of US adults reported an average of ≤6 h of sleep per day in 2005–2007.10 Another study on selfreported sleep patterns in a British population cohort found that among 4923 women ages 49–90, although daily time in bed was between 8 and 9 h, average sleep duration was 8 h of sleep per night) were more than three times as likely to develop diabetes over the period of follow-up (RR 3.6 (1.79– 7.38)).57 This study concluded that sleep duration may represent a novel risk factor for diabetes and that there may be a U-shaped relationship between sleep duration and the development of diabetes.58 59 One possible explanation for these results is that unrecognised confounders such as obstructive sleep apnoea (OSA) could lead to both metabolic syndrome and an increased need for sleep.60
Sleep-disordered breathing and metabolic syndrome Recent data suggest a causal role for severe OSA in the development of metabolic syndrome.61 A study done by Parish et al, in which the presence of metabolic syndrome was correlated to the severity of OSA, concluded that the prevalence of metabolic syndrome and hypertension was significantly greater in the OSA patients. Furthermore, the worse the OSA, the higher the prevalence of metabolic syndrome.61 Moreover, animal models and translational studies indicate that OSA may induce or exacerbate the metabolic dysfunction.62–64 The possible mechanisms include the activation of nuclear factor κB by hypoxic stress and/or by increased adipokines and free fatty acids released by excess adipose tissue.65 In addition, in patients with severe OSA and metabolic syndrome, compliance with continuous positive airway pressure improves insulin sensitivity and reduces systemic inflammation, oxidative stress and the global CVD risk.66
Evidence from human experimental studies Experimental human studies that investigated the link between sleep disturbances and metabolic syndrome are in their beginnings. In a pioneering study, Spiegel et al found that sleep restricted to only 4 h per night for 1 week led to insulin resistance and weight gain in 11 healthy young men. In addition, glucose tolerance was lower in the sleep-deprived state compared with fully rested state. There were also significant hormonal changes. Thyrotropin concentration was lower while evening cortisol concentrations were raised and sympathetic nervous system activity was increased in the sleep-deprived state. An important conclusion of this study was that the effects of sleep deprivation were reversible with normal sleep hours when participants were allowed 12 h in bed per night for six nights.67 In another study by Qin et al,68 the 24-h patterns of plasma melatonin, leptin, glucose and insulin in volunteers who lived either a diurnal life or nocturnal life were observed. The volunteers for this study were healthy medical students in their early twenties. Volunteers of the diurnal group were asked to follow a life schedule consisting of three main meals at 07:00 h, 13:00 h and 19:00 h, and sleep from 22:30 to 06:30 h. Subjects of the nocturnal lifestyle group were deprived of breakfast and allowed lunch and dinner, and were asked to consume more than 50% of their daily food intake in the evening and at night. Their sleep period was scheduled from 01:30 to 08:30 h. After 3 weeks in the experimental life, the 24-h plasma concentrations of melatonin, leptin, glucose and insulin were collected every 3 h. As expected, both plasma melatonin and leptin showed 4
peaks at 03:00 h in the diurnal lifestyle group; however, the night peaks decreased in the nocturnal lifestyle group. Furthermore, the strong association between glucose and insulin in the diurnal lifestyle group after meals was not observed in the nocturnal lifestyle group. While glucose concentration remained high in the nocturnal lifestyle group between midnight and early morning, insulin secretion decreased significantly during this period. This study suggested that nocturnal life leads to blunted insulin response to glucose. Furthermore, there is mounting evidence to suggest that melatonin rhythmicity plays an important role in metabolic functions as an antiinflammatory and antioxidant agent. Taking these results together, the authors suggested that nocturnal life is likely to be one of the risk factors to the health of present-day people, via night eating and shifting and decreasing sleep time.
IMPLICATIONS FOR CLINICAL PRACTICE ▸ Sleep disturbance whether iatrogenic or disease related should be considered a risk factor for metabolic syndrome, and should be addressed and treated. ▸ Optimising sleep duration and avoiding disruption of circadian rhythm may prevent the development of metabolic syndrome. ▸ There is an optimum sleep duration and it may be of 7–8 h per night. ▸ Reducing carbohydrate intake at evening and switching evening activities to morning ones might be beneficial. ▸ Assessment of sleep habits should be included in the clinical evaluation of patients with metabolic syndrome. ▸ Sleep assessment should cover the sleep duration, timing of sleep, daytime somnolence, a history of witnessed apnoeas during sleep and shift work. ▸ It remains to be seen whether the use of melatonin supplements or currently available sleep facilitating drugs can prevent and or decrease the risk of developing metabolic syndrome.
CONCLUSIONS Nowadays, there is emerging evidence in the literature to suggest that circadian rhythm disruption is a risk factor for the development of metabolic syndrome. Circadian disruptions can result from sleep–wake cycling disturbance or night eating. In our contemporary society, individuals are voluntarily deceasing sleep duration for various reasons without knowing its future impact on their health. Indeed, general public awareness is needed especially among youngsters. Furthermore, since data have shown optimising sleep duration and avoiding circadian rhythm disruption may prevent the development of metabolic syndrome, attention needs to be made to address and treat sleep disturbances. Moreover, more studies are needed for nightshift workers: in particular, interventional studies to answer questions on how many nights back-to-back can an individual work
Main messages ▸ Evidence suggests that circadian rhythm disruption is a risk factor for metabolic syndrome. ▸ Optimising sleep and avoiding late night eating may prevent the development of metabolic syndrome. ▸ Assessment of sleep habits should be included in the clinical evaluation of patients with metabolic syndrome. Sheikh-Ali M, et al. Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366
Review REFERENCES Current research questions
1
▸ Does circadian rhythm desynchronisation contribute to the development of metabolic syndrome? ▸ Is there a relationship between sleep duration and the development of diabetes? ▸ Is there an optimum sleep duration? ▸ Should sleep habits be included in the clinical evaluation and treatment of metabolic syndrome?
2
3
4 5
Key references
6
▸ Staels B. When the Clock stops ticking, metabolic syndrome explodes. Nat Med 2006;12:54–5. ▸ Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308:1043–5. ▸ Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27 485 people. Occup Environ Med 2001;58:747–52. ▸ Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435–9. ▸ Grundy SM, Hansen B, Smith SC Jr, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/ American Diabetes Association conference on scientific issues related to management. Circulation 2004;109:551–6.
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Self assessment questions Please answer true (T) or false (F) to the below, 1. Epidemiological studies suggest that there is a U-shaped distribution between sleep duration and the development of diabetes. 2. The proposed optimum sleep duration is 6–7 h per night. 3. Sleep disturbance should be considered as a risk factor in clinical evaluation for metabolic syndrome. 4. A proper sleep assessment in the clinical setting should include sleep duration, timing of sleep, daytime somnolence, a history of witnessed apnoeas during sleep and shift work. 5. Avoidance of circadian rhythm disruption is important in the prevention of metabolic syndrome.
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without developing metabolic syndrome; how many rest days in-between is needed; and when is it not too late to reverse metabolic syndrome in nightshift workers. Further research will help to improve our understanding of the pathophysiology of circadian desynchronisation and the development of preventive and therapeutic strategies.
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Contributors All contributors met the criteria for authorship and are listed. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
Sheikh-Ali M, et al. Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366
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Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004;33:283–303. Ford ES. The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis 2004;173:309–14. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–45. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008;28:629–36. Park YW, Zhu S, Palaniappan L, et al. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003;163:427–36. Guallar-Castillón P, Pérez RF, López García E, et al. Magnitude and management of metabolic syndrome in Spain in 2008–2010: The ENRICA Study. Rev Esp Cardiol 2014;67:367–73. de Carvalho Vidigal F, Bressan J, Babio N, et al. Prevalence of metabolic syndrome in Brazilian adults: a systematic review. BMC Public Health 2013;13:1198. Marcheva B, Ramsey KM, Affinati A, et al. Clock genes and metabolic disease. J Appl Physiol 2009;107:1638–46. Golombek DA, Casiraghi LP, Agostino PV, et al. The times they’re a-changing: effects of circadian desynchronization on physiology and disease. J Physiol Paris 2013;107:310–22. Schoenborn CA, Adams PF. Health behaviors of adults: United States, 2005–2007. Vital Health Stat 10 2010;245:61–2. Leng Y, Wainwright NW, Cappuccio FP, et al. Self-reported sleep patterns in a British population cohort. Sleep Med 2014;15:295–302. Biggi N, Consonni D, Galluzzo V, et al. Metabolic syndrome in permanent night workers. Chronobiol Int 2008;25:443–54. La Sala M, Pietroiusti A, Magrini A, et al. Metabolic syndrome and work: identification of populations at risk [abstract]. G Ital Med Lav Ergon 2007; 29:(3 Suppl):445–7. Copertaro A, Bracci M, Barbaresi M, et al. Assessment of cardiovascular risk in shift healthcare workers. Eur J Cardiovasc Prev Rehabil 2008;15:224–9. Roden M. Blocking fatty acids’ mystery tour: a therapy for metabolic syndrome? Cell Metab 2007;6:89–91. Pi-Sunyer FX. Pathophysiology and long-term management of the metabolic syndrome. Obes Res 2004;12(Suppl):174–80. Camera A, Hopps E, Caimi G. Metabolic syndrome: from insulin resistance to adipose tissue dysfunction. Minerva Med 2008;99:307–21. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring) 2006; 14(Suppl 5):242–9. Ahima RS. Metabolic actions of adipocyte hormones: focus on adiponectin. Obesity (Silver Spring) 2006;14(Suppl 1):9–15. Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004;53(Suppl 1):143–51. Brooks NL, Moore KS, Clark RD, et al. Do low levels of circulating adiponectin represent a biomarker or just another risk factor for the metabolic syndrome? Diabetes Obes Metab 2007;9:246–58. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337–50. Huang W, Ramsey KM, Marcheva B, et al. Circadian rhythms, sleep, and metabolism. J Clin Invest 2011;121:2133–41. Dunlap JC. Molecular bases for circadian clocks. Cell 1999;96:271–90. Holzberg D, Albrecht U. The circadian clock: a manager of biochemical processes within the organism. J Neuroendocrinol 2003;15:339–43. Ptitsyn AA, Zvonic S, Gimble JM. Digital signal processing reveals circadian baseline oscillation in majority of mammalian genes. PLoS Comput Biol 2007;3:120. Hogenesch JB, Panda S, Kay S, et al. Circadian transcriptional output in the SCN and liver of the mouse. Novartis Found Symp 2003;253:171–80. Maury E, Hong HK, Bass J. Circadian disruption in the pathogenesis of metabolic syndrome. Diabetes Metab Published Online First: 14 Jan 2014. doi:10.1016/j. diabet.2013.12.005 Challet E. Circadian clocks, food intake, and metabolism. Prog Mol Biol Transl Sci 2013;119:105–35. Staels B. When the Clock stops ticking, metabolic syndrome explodes. Nat Med 2006;12:54–5. Higashi Y, Nakagawa K, Kimura M, et al. Circadian variation of blood pressure and endothelial function in patients with essential hypertension: a comparison of dippers and non-dippers. J Am Coll Cardiol 2002;40:2039–43. Curtis AM, Cheng Y, Kapoor S, et al. Circadian variation of blood pressure and the vascular response to asynchronous stress. Proc Natl Acad Sci USA 2007;104:3450–5.
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Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;81:528–36. Bray MS, Shaw CA, Moore MW, et al. Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol 2008;294:1036–47. Ohkura N, Oishi K, Fukushima N, et al. Circadian clock molecules CLOCK and CRYs modulate fibrinolytic activity by regulating the PAI-1 gene expression. J Thromb Haemost 2006;4:2478–85. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2000;342:1792–801. Viswambharan H, Carvas JM, Antic V, et al. Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 2007;115:2188–95. Ando H, Yanagihara H, Hayashi Y, et al. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 2005;146:5631–6. Shimba S, Ishii N, Ohta Y, et al. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA 2005;102:12071–6. Rudic RD, McNamara P, Curtis AM, et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2004;2:377. Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308:1043–5. Bray MS, Young ME. Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes Rev 2007;8:169–81. Hampton SM, Morgan LM, Lawrence N, et al. Postprandial hormone and metabolic responses in simulated shift work. J Endocrinol 1996;151:259–67. Morgan L, Arendt J, Owens D, et al. Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism. J Endocrinol 1998;157:443–51. Karlsson BH, Knutsson AK, Lindahl BO, et al. Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health 2003;76:424–30. Knutsson A. Health disorders of shift workers. Occup Med (Lond) 2003;53:103–8. Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med 2001;58:747–52. Biggi N, Consonni D, Galluzzo V, et al. Metabolic syndrome in permanent night workers. Chronobiol Int 2008;25:443–54. Knutsson A, Hallquist J, Reuterwall C, et al. Shiftwork and myocardial infarction: a case-control study. Occup Environ Med 1999;56:46–50. Bass J, Turek FW. Sleepless in America: a pathway to obesity and the metabolic syndrome? Arch Intern Med 2005;165:15–16. Santos AC, Ebrahim S, Barros H. Alcohol intake, smoking, sleeping hours, physical activity and the metabolic syndrome. Prev Med 2007;44:328–34. Vorona RD, Winn MP, Babineau TW, et al. Overweight and obese patients in a primary care population report less sleep than patients with a normal body mass index. Arch Intern Med 2005;165:25–30.
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Reilly JJ, Armstrong J, Dorosty AR, et al. Early life risk factors for obesity in childhood: cohort study. Bmj 2005;330:1357. Spiegel K, Tasali E, Penev P, et al. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004;141:846–50. Spiegel K, Leproult R, L’Hermite-Baleriaux M, et al. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004;89:5762–71. Kawakami N, Takatsuka N, Shimizu H. Sleep disturbance and onset of type 2 diabetes. Diabetes Care 2004;27:282–3. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care 2006;29:657–61. Ayas NT, White DP, Manson JE, et al. A prospective study of sleep duration and coronary heart disease in women. Arch Intern Med 2003;163:205–9. Burazeri G, Gofin J, Kark JD. Over 8 hours of sleep—marker of increased mortality in Mediterranean population: follow-up population study. Croat Med J 2003;44:193–8. Wolk R, Gami AS, Garcia-Touchard A, et al. Sleep and cardiovascular disease. Curr Probl Cardiol 2005;30:625–62. Parish JM, Adam T, Facchiano L. Relationship of metabolic syndrome and obstructive sleep apnea. J Clin Sleep Med 2007;3:467–72. Lam JC, Ip MS. An update on obstructive sleep apnea and the metabolic syndrome. Curr Opin Pulm Med 2007;13:484–9. Teramoto S, Yamamoto H, Yamaguchi Y, et al. Obstructive sleep apnea causes systemic inflammation and metabolic syndrome. Chest 2005;127:1074–5. Svatikova A, Wolk R, Gami AS, et al. Interactions between obstructive sleep apnea and the metabolic syndrome. Curr Diab Rep 2005;5:53–8. Alam I, Lewis K, Stephens JW, et al. Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states. Obes Rev 2007;8:119–27. Dorkova Z, Petrasova D, Molcanyiova A, et al. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134:686–92. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435–9. Qin LQ, Li J, Wang Y, et al. The effects of nocturnal life on endocrine circadian patterns in healthy adults. Life Sci 2003;73:2467–75.
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Answers 1. 2. 3. 4. 5.
True False True True True
Sheikh-Ali M, et al. Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366
Circadian clock desynchronisation and metabolic syndrome Mae Sheikh-Ali, Jaisri Maharaj Department of Medicine, University of Florida College of Medicine, Jacksonville, USA Correspondence to Dr Mae Sheikh-Ali, Division of Endocrinology, Department of Medicine, University of Florida, 653-1 West Eighth Street, Jacksonville, FL 32209, USA; [email protected]fl.edu Received 10 September 2013 Revised 2 June 2014 Accepted 3 June 2014
ABSTRACT There is emerging evidence in the literature to suggest that disruption of the normal circadian rhythm (sleep– wake cycle signalling) is a potential risk factor to explain the increased incidence of metabolic syndrome. Over the last century, obesity, diabetes and other components of metabolic syndrome have been on the rise. On the other hand, the amount of sleep has decreased from an average of 6–8 h per night. Furthermore, the quality of sleep has declined with more individuals voluntarily decreasing their amount of sleep to work or enjoy leisure activities. Over the last decade, researchers have examined the relationship between disruption in human circadian system and the emergence of symptoms related to metabolic syndrome. Indeed, epidemiological studies suggest a relation between sleep duration and diabetes and obesity. Moreover, experimental animal and human studies suggest such a relation. These studies propose optimum sleep duration of 7–8 h per night to avoid circadian rhythm disruption and suggest that sleep disturbance, whether iatrogenic or disease-related, should be considered as a risk factor for metabolic syndrome, and be addressed. This field is in its infancy and further understanding of specific pathophysiological pathways of circadian desynchronisation will help in developing novel preventive and therapeutic strategies.
INTRODUCTION
To cite: Sheikh-Ali M, Maharaj J. Postgrad Med J Published Online First: [please include Day Month Year] doi:10.1136/ postgradmedj-2013-132366
Metabolic syndrome describes a group of modifiable elements occurring in the same individual and is associated with a twofold increased risk of developing cardiovascular disease (CVD) and a fivefold increased risk of developing type 2 diabetes mellitus (DM).1 2 The current definition of metabolic syndrome, produced in 2009 in a joint interim statement agreed by six international groups, is the presence of any three of the following:3 ▸ elevated waist circumference ▸ elevated triglycerides ▸ elevated blood pressure (BP) ▸ reduced high-density lipoprotein cholesterol ▸ elevated fasting glucose The metabolic syndrome affects around 20%– 30% of the adult population in most countries, with the prevalence being even higher in some populations.4 In the 3rd National Health and Nutrition Examination Survey, metabolic syndrome was present in 22.8% and 22.6% of US men and women, respectively.5 Another study from 2008 to 2010 in 11 149 adults in Spain reported the prevalence of metabolic syndrome as 22.7%.6 A systematic review in Brazil revealed prevalence of metabolic syndrome in the general population to be 29.6% and as high as 65.3% in an indigenous population.7 Traditional risk factors for metabolic
Sheikh-Ali M, et al. Article Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366 Copyright author (or their employer) 2014. Produced
syndrome included older age, postmenopausal status, Mexican American ethnicity, higher body mass index, current smoking, low household income, high carbohydrate intake, no alcohol consumption and physical inactivity.5 Nowadays, there is emerging evidence to suggest that disruption of normal circadian rhythms is a novel risk factor that can explain the increased prevalence of metabolic syndrome. Circadian rhythms are generated in mammals in an attempt to adapt to the light–dark, sleep–wake cycling. Therefore, circadian rhythms are endogenous and need to be continuously synchronised with the environment. Synchrony between external environmental zeitgebers (time-keepers), such as day and night, and internal body circadian clocks that are responsible for different internal body signalling rhythm is essential for normal metabolism. Subsequently, loss of this synchrony results in circadian desynchronisation.8 Circadian desynchronisation may result from disruption in sleep–wake cycle and can lead to pathological situations.9 In the National Health Interview Survey, nearly 30% of US adults reported an average of ≤6 h of sleep per day in 2005–2007.10 Another study on selfreported sleep patterns in a British population cohort found that among 4923 women ages 49–90, although daily time in bed was between 8 and 9 h, average sleep duration was 8 h of sleep per night) were more than three times as likely to develop diabetes over the period of follow-up (RR 3.6 (1.79– 7.38)).57 This study concluded that sleep duration may represent a novel risk factor for diabetes and that there may be a U-shaped relationship between sleep duration and the development of diabetes.58 59 One possible explanation for these results is that unrecognised confounders such as obstructive sleep apnoea (OSA) could lead to both metabolic syndrome and an increased need for sleep.60
Sleep-disordered breathing and metabolic syndrome Recent data suggest a causal role for severe OSA in the development of metabolic syndrome.61 A study done by Parish et al, in which the presence of metabolic syndrome was correlated to the severity of OSA, concluded that the prevalence of metabolic syndrome and hypertension was significantly greater in the OSA patients. Furthermore, the worse the OSA, the higher the prevalence of metabolic syndrome.61 Moreover, animal models and translational studies indicate that OSA may induce or exacerbate the metabolic dysfunction.62–64 The possible mechanisms include the activation of nuclear factor κB by hypoxic stress and/or by increased adipokines and free fatty acids released by excess adipose tissue.65 In addition, in patients with severe OSA and metabolic syndrome, compliance with continuous positive airway pressure improves insulin sensitivity and reduces systemic inflammation, oxidative stress and the global CVD risk.66
Evidence from human experimental studies Experimental human studies that investigated the link between sleep disturbances and metabolic syndrome are in their beginnings. In a pioneering study, Spiegel et al found that sleep restricted to only 4 h per night for 1 week led to insulin resistance and weight gain in 11 healthy young men. In addition, glucose tolerance was lower in the sleep-deprived state compared with fully rested state. There were also significant hormonal changes. Thyrotropin concentration was lower while evening cortisol concentrations were raised and sympathetic nervous system activity was increased in the sleep-deprived state. An important conclusion of this study was that the effects of sleep deprivation were reversible with normal sleep hours when participants were allowed 12 h in bed per night for six nights.67 In another study by Qin et al,68 the 24-h patterns of plasma melatonin, leptin, glucose and insulin in volunteers who lived either a diurnal life or nocturnal life were observed. The volunteers for this study were healthy medical students in their early twenties. Volunteers of the diurnal group were asked to follow a life schedule consisting of three main meals at 07:00 h, 13:00 h and 19:00 h, and sleep from 22:30 to 06:30 h. Subjects of the nocturnal lifestyle group were deprived of breakfast and allowed lunch and dinner, and were asked to consume more than 50% of their daily food intake in the evening and at night. Their sleep period was scheduled from 01:30 to 08:30 h. After 3 weeks in the experimental life, the 24-h plasma concentrations of melatonin, leptin, glucose and insulin were collected every 3 h. As expected, both plasma melatonin and leptin showed 4
peaks at 03:00 h in the diurnal lifestyle group; however, the night peaks decreased in the nocturnal lifestyle group. Furthermore, the strong association between glucose and insulin in the diurnal lifestyle group after meals was not observed in the nocturnal lifestyle group. While glucose concentration remained high in the nocturnal lifestyle group between midnight and early morning, insulin secretion decreased significantly during this period. This study suggested that nocturnal life leads to blunted insulin response to glucose. Furthermore, there is mounting evidence to suggest that melatonin rhythmicity plays an important role in metabolic functions as an antiinflammatory and antioxidant agent. Taking these results together, the authors suggested that nocturnal life is likely to be one of the risk factors to the health of present-day people, via night eating and shifting and decreasing sleep time.
IMPLICATIONS FOR CLINICAL PRACTICE ▸ Sleep disturbance whether iatrogenic or disease related should be considered a risk factor for metabolic syndrome, and should be addressed and treated. ▸ Optimising sleep duration and avoiding disruption of circadian rhythm may prevent the development of metabolic syndrome. ▸ There is an optimum sleep duration and it may be of 7–8 h per night. ▸ Reducing carbohydrate intake at evening and switching evening activities to morning ones might be beneficial. ▸ Assessment of sleep habits should be included in the clinical evaluation of patients with metabolic syndrome. ▸ Sleep assessment should cover the sleep duration, timing of sleep, daytime somnolence, a history of witnessed apnoeas during sleep and shift work. ▸ It remains to be seen whether the use of melatonin supplements or currently available sleep facilitating drugs can prevent and or decrease the risk of developing metabolic syndrome.
CONCLUSIONS Nowadays, there is emerging evidence in the literature to suggest that circadian rhythm disruption is a risk factor for the development of metabolic syndrome. Circadian disruptions can result from sleep–wake cycling disturbance or night eating. In our contemporary society, individuals are voluntarily deceasing sleep duration for various reasons without knowing its future impact on their health. Indeed, general public awareness is needed especially among youngsters. Furthermore, since data have shown optimising sleep duration and avoiding circadian rhythm disruption may prevent the development of metabolic syndrome, attention needs to be made to address and treat sleep disturbances. Moreover, more studies are needed for nightshift workers: in particular, interventional studies to answer questions on how many nights back-to-back can an individual work
Main messages ▸ Evidence suggests that circadian rhythm disruption is a risk factor for metabolic syndrome. ▸ Optimising sleep and avoiding late night eating may prevent the development of metabolic syndrome. ▸ Assessment of sleep habits should be included in the clinical evaluation of patients with metabolic syndrome. Sheikh-Ali M, et al. Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366
Review REFERENCES Current research questions
1
▸ Does circadian rhythm desynchronisation contribute to the development of metabolic syndrome? ▸ Is there a relationship between sleep duration and the development of diabetes? ▸ Is there an optimum sleep duration? ▸ Should sleep habits be included in the clinical evaluation and treatment of metabolic syndrome?
2
3
4 5
Key references
6
▸ Staels B. When the Clock stops ticking, metabolic syndrome explodes. Nat Med 2006;12:54–5. ▸ Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308:1043–5. ▸ Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27 485 people. Occup Environ Med 2001;58:747–52. ▸ Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435–9. ▸ Grundy SM, Hansen B, Smith SC Jr, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/ American Diabetes Association conference on scientific issues related to management. Circulation 2004;109:551–6.
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Self assessment questions Please answer true (T) or false (F) to the below, 1. Epidemiological studies suggest that there is a U-shaped distribution between sleep duration and the development of diabetes. 2. The proposed optimum sleep duration is 6–7 h per night. 3. Sleep disturbance should be considered as a risk factor in clinical evaluation for metabolic syndrome. 4. A proper sleep assessment in the clinical setting should include sleep duration, timing of sleep, daytime somnolence, a history of witnessed apnoeas during sleep and shift work. 5. Avoidance of circadian rhythm disruption is important in the prevention of metabolic syndrome.
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without developing metabolic syndrome; how many rest days in-between is needed; and when is it not too late to reverse metabolic syndrome in nightshift workers. Further research will help to improve our understanding of the pathophysiology of circadian desynchronisation and the development of preventive and therapeutic strategies.
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Contributors All contributors met the criteria for authorship and are listed. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Answers 1. 2. 3. 4. 5.
True False True True True
Sheikh-Ali M, et al. Postgrad Med J 2014;0:1–6. doi:10.1136/postgradmedj-2013-132366
