COMMENTARY

Slow-wave sleep, diabetes, and the sympathetic nervous system

Derk-Jan Dijk* Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XP, United Kingdom

leep oscillates between two dif- of SWS that has accumulated. The latter less provides supportive evidence for the ferent states: non-rapid eye conclusion was derived from SWS depri- notion that SWS is restorative also for movement (NREM) sleep and vation experiments in which stimuli, usu- the body and that negative effects asso- rapid-eye movement (REM) ally acoustic stimuli [although early on ciated with disruption of this state may Ssleep. Slow-wave sleep (SWS) is a sub- in the history of SWS deprivation, mild extend to the body. state of NREM sleep, and its identifica- electric shocks were used (5)], are deliv- Many other physiological variables are tion is based primarily on the presence ered in response to the ongoing EEG. affected by the behavioral-state sleep, of slow waves, i.e., low-frequency, high- The drive to enter SWS is strong and is the NREM–REM cycle, and SWS. amplitude oscillations in the EEG. Upon the transition from wakefulness to Quantification of SWS is accomplished sleep, heart rate slows down. During by visual inspection of EEG records or Short habitual sleep sleep, the balance of sympathetic and computerized methods such as spectral parasympathetic tone oscillates in syn- analysis based on the fast Fourier trans- has been associated chrony with the NREM–REM cycle. form (FFT). Slow-wave activity (SWA; Analysis of autonomic control of the also referred to as delta power) is a with increased risk variability of heart rate demonstrates quantitative measure of the contribution that, within each NREM episode, as of both the amplitude and prevalence of for diabetes. SWA gradually increases, sympathetic slow waves in the EEG. The EEG oscil- tone gradually diminishes and vagal tone lations reflect the field potentials associ- gradually increases (9). At the transition ated with synchronized burst-pause particularly so in young individuals. Fre- to REM sleep, this state of low sympa- firing patterns in cortical neurons (1). In quent and loud stimuli (up to 110 dB) thetic activity gives way to sympathetic view of these brain-based defining char- are required to prevent SWS from oc- activation. The sleep-stage-dependent acteristics of SWS, it is not surprising curring. When these procedures are ap- modulation of the autonomic nervous that most theories on the functional sig- plied diligently, as in the experiment system can be observed not only nificance of SWS have focused on the by Tasali et al. (2), SWS can be sup- indirectly on the basis of heart rate brain. In a recent issue of PNAS, Tasali pressed without reducing total sleep variability, but also directly by et al. (2) draw attention to another as- time, even though brief awakenings and microneurography (10). pect of SWS: the effects of SWS disrup- microarousals will be induced. Upon The autonomic nervous system affects tion on glucose tolerance and insulin cessation of this suppression, a rebound not only the heart but also other visceral resistance. What do these new data tells of SWS is observed, either within the systems, including the insulin-producing us about SWS and its functional signifi- sleep episode or during subsequent, un- B cells of the pancreas, the leptin- cance? Is it for the body as well as the disturbed sleep episodes (6). Thus, SWS producing adipocytes, the vascular sys- brain? deprivation leads to an increase in the tem, etc. The autonomic nervous system ‘‘pressure’’ for SWS. These data provide is thus a powerful pathway through Regulation of SWS strong evidence for the accurate homeo- which sleep can affect the entire organ- The notion that SWS is an important static regulation of SWS. In accordance ism and its physiology. substate of sleep has its foundations in with the notion that SWS is for the the early observations that it is regu- brain, negative effects of SWS depriva- Sleep Disorders, Sleep Deprivation, and lated accurately in response to variation tion on waking function have emerged the Autonomic Nervous System in the duration of wakefulness. SWS (7). However, many authors have attrib- Alterations of the autonomic nervous increases in response to wake extension uted these effects of SWS deprivation system can also mediate the negative and is reduced after daytime naps, and on the associated effects on sleep conti- effects of sleep disruption on physiologi- these changes are observed in all EEG nuity rather than to the absence of slow- cal systems. Sleep apnea constitutes one derivations, although they are most wave oscillations or SWS per se. of the prime examples. In this condition, pronounced in frontal derivations (3). repeated cessation of airflow leads to Variations in the nature of the waking Correlates of SWS oxygen desaturation and frequent arous- experience, which may be associated A second line of evidence for the im- als from both REM sleep and NREM with activation of specific neuronal pop- portance for SWS stems from non-EEG sleep. These arousals are associated not ulations, exhibit a significant, but minor correlates of SWS, including endocrine and localized, influence on SWS (4). and autonomic variables. This view of SWS and SWA are predominant at the SWS emphasizes its characteristics as Author contributions: D.-J.D. wrote the paper. Conflict of interest statement: D.-J.D. has received research beginning of sleep and decline in the a behavioral and physiological state, i.e., support from and served as a consultant to several phar- course of sleep. This decline of SWS a constellation of multiple variables in maceutical companies, some of which have developed, or during sleep is not determined by circa- the brain and body. The major phase of are developing, hypnotics that enhance SWS. dian phase; it is observed at all circa- daily growth-hormone secretion is asso- See companion article on page 1044 in issue 3 of volume dian phases. It is also not simply ciated with SWS (8). Even though it is 105. determined by the time elapsed since now recognized that this association is *E-mail: [email protected]. sleep onset, but rather by the amount not as tight as once thought, it neverthe- © 2008 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0711635105 PNAS ͉ January 29, 2008 ͉ vol. 105 ͉ no. 4 ͉ 1107–1108 Downloaded by guest on September 24, 2021 only with a reduction in SWS and sleep frequent arousals induced by the acous- Research Implications continuity but also with sympathetic ac- tic stimulation provided the link be- Most of us will not be exposed to hun- tivation (11). The sympathetic activation tween SWS suppression and changes in dreds of loud tones while we sleep. is not only present during sleep but also insulin sensitivity. Surprisingly, the However, many of us will experience carries over in wakefulness when breath- authors report that no significant corre- circumstances in which SWS will be re- ing is normal. This activation of the lations between measures of sleep conti- duced. For example, apprehension about sympathetic nervous system is thought nuity and changes in insulin sensitivity the next day’s activities is correlated to be responsible, at least in part, for were observed. Instead, the authors ob- with a suppression of SWS and an in- the increased prevalence of diabetes in served correlations between the time crease in the number of arousals (14). people with sleep apnea. spent in SWS and changes therein and Repeated partial sleep deprivation leads The data by Tasali et al. (2) provide changes in insulin sensitivity. If we ac- to an increase in the pressure for SWS a new approach to investigate the sys- cept that changes in sympathetic tone (15), similar to SWS deprivation, as well temic consequences of SWS disruption mediate the alteration in insulin sensitiv- as changes in glucose tolerance (16). on physiology and its consequences for ity, then these correlations imply that Furthermore, short habitual sleep has glucose control in particular. Surpris- the extent to which large parts of the been associated with increased risk for ingly, the data show that, after as few as cortex oscillate in synchrony, leading to diabetes in a number of epidemiological three nights of disruption of SWS, the the state of SWS as we observe it in the studies (e.g., ref. 17), and short sleepers clearance of glucose after a glucose in- EEG, must have an impact on sympa- carry a sleep debt (18). The age-related fusion was markedly reduced and that thetic tone. Variations in SWS are reduction in SWS is the most marked this reduction was not compensated for thought to be related to changes in local change in sleep physiology that can be by an increase in insulin secretion by the cortical connectivity and variation in observed, and aging is associated with beta cells of the pancreas. Assessment neuromodulatory systems such as the increased incidence of diabetes. Men of sympathetic activation through analy- noradrenergic, serotonergic, histaminer- have less SWS than women at all ages ses of heart-rate variability during gic, and cholinergic systems (13). Cur- (19). Genes and the polymorphisms wakefulness implicated a shift toward rent understanding of the functional therein that are predictive of interindi- sympathetic dominance as the mecha- neuroanatomy of sleep and SWS allows vidual variation in SWS in humans have nism underlying this change in glucose for a two-way interaction between sleep now been identified (20, 21). The study tolerance. This all fits well with both our and activity of these neuromodulatory by Tasali et al. (2) provides a rationale understanding of the role of sympathetic systems, and these systems may in turn for the investigation of the role of SWS activation in insulin sensitivity as well as have an impact on the autonomic ner- as well as the sympathetic nervous sys- the association between SWS and reduc- vous system. Thus in this scenario, the tem as a final common pathway in the tions in sympathetic tone. However, on full development of SWS leads to a re- risk for diabetes and other ailments of the basis of sleep apnea studies (11) and duction in the activity of activating sys- the body in all of these populations. previous SWS deprivation studies (12), tems and the sympathetic branch of the Restful and deep sleep serves the body it may have been anticipated that the autonomous nervous system. as well as the brain.

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