There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/ feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h ''day.'' Subjects ate 4 isocaloric meals each 28-h ''day.'' For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling Ϸ1,000 assays/ subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept Ϸ12 h out of phase from their habitual times, systematically decreased leptin (؊17%, P < 0.001), increased glucose (؉6%, P < 0.001) despite increased insulin (؉22%, P ‫؍‬ 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (؉3%, P ‫؍‬ 0.001), and reduced sleep efficiency (؊20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work. autonomic nervous system ͉ diabetes ͉ glucose metabolism ͉ leptin ͉ obesity A pproximately 8.6 million Americans perform shift work (1), which is associated with increased risk of obesity, diabetes, and cardiovascular disease (2-6). The endogenous circadian timing system, including the suprachiasmatic nucleus (SCN) in the hypothalamus and peripheral oscillators in vital organs, optimally regulates much of our physiology and behavior across the 24-h day when it is properly aligned with the sleep/wake cycle. However, shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/ feeding cycles (7,8). Shift workers often experience symptoms akin to jet lag, with gastrointestinal complaints, fatigue, and sleepiness during the scheduled wake periods, and poor sleep during the daytime sleep attempts (9). Moreover, chronic circadian misalignment has been proposed to be the underlying cause for the adverse metabolic and cardiovascular health effects of shift work (10, 11). The SCN regulates circadian rhythms in leptin, plasma glucose, glucose tolerance, corticosteroids, and ...

Epidemiological studies link short sleep and circadian disruption with risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur with shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks in controlled laboratory conditions including: sleep extension (baseline), 3-week sleep restriction (5.6 h sleep/24 h) combined with circadian disruption (recurring 28-h ‘days’), and 9-day recovery sleep with circadian re-entrainment. Prolonged sleep restriction with concurrent circadian disruption significantly decreased resting metabolic rate, and increased postprandial plasma via inadequate pancreatic beta cell responsivity; these normalized with 9 days of recovery sleep and stable circadian reentrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase risk of obesity and diabetes.

Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/ feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show-by using two 8-d laboratory protocols-in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower earlyphase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.circadian disruption | shift work | night work | glucose metabolism | diabetes I n healthy humans, there is a strong time-of-day variation in glucose tolerance, with a peak in the morning and a trough in the evening and night (1-6). Understanding the underlying mechanisms of the day/night variation in glucose tolerance is important for diurnally active individuals as well as shift workers, who are at increased risk for developing type 2 diabetes (7-9). The endogenous circadian system and circadian misalignment (i.e., misalignment between the endogenous circadian system and 24-h environmental/behavioral cycles) have been shown to affect glucose metabolism (4,(10)(11)(12)(13)(14). However, the relative and separate importance of the endogenous circadian system and circadian misalignment-after accounting for behavioral cycle effects (including the sleep/wake, fasting/feeding, and physical inactivity/activity cycles, etc.)-on 24-h variation in glucose tolerance is not well understood.Most species have evolved an endogenous circadian timing system that optimally times physiological variations and behaviors relative to the 24-h environmental cycle (15-17). The mammalian circadian system is comp...

Among a group of North American police officers, sleep disorders were common and were significantly associated with increased risk of self-reported adverse health, performance, and safety outcomes.

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease 1, 2, but the molecular basis is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (e.g. short or long QT syndromes, heart failure) 3-5 or pattern (e.g. Brugada syndrome) 6 of myocardial repolarization. Here we provide the first molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion channel expression and QT interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a novel clock-dependent oscillator, Krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito). 7 Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. In sum, these findings identify circadian transcription of ion channels as a novel mechanism for cardiac arrhythmogenesis.

The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.

All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.

Human motor control systems orchestrate complex scale-invariant patterns of activity over a wide range of time scales (minutes to hours). The neural mechanisms underlying scale-invariance are unknown in humans. In rats, the master circadian pacemaker [suprachiasmatic nucleus (SCN)] is crucially involved in scaleinvariant activity fluctuations over multiple time scales from minutes to 24 h. Aging and Alzheimer's disease (AD) are associated with progressive dysfunction of the SCN. Thus, if the SCN is responsible for the scale-invariant activity fluctuations in humans, we predict disturbances of scale-invariant activity fluctuations in elderly humans and even more pronounced disturbances in elderly humans with AD. To test these hypotheses, we studied spontaneous daytime activity patterns in 13 young adults (mean ؎ SD: 25.5 ؎ 6.1 y); 13 elderly people with early-stage AD (68.5 ؎ 6.1 y) matched with 13 elderly controls (68.6 ؎ 6.1 y); and 14 very old people with late-stage AD (83.9 ؎ 6.7 y) matched with 12 very old controls (80.8 ؎ 8.6 y). In young adults, activity exhibited robust scale-invariant correlations across all tested time scales (minutes to 8 h). The scale-invariant correlations at 1.5-8 h declined with age (P ‫؍‬ 0.01) and were significantly reduced in the elderly (P ‫؍‬ 0.04) and very old controls (P ‫؍‬ 0.02). Remarkably, an age-independent AD effect further reduced the scale-invariant correlations at 1.5-8 h (P ‫؍‬ 0.04), leading to the greatest reduction of the scale-invariant correlations in very old people with late-stage AD-resembling closely the loss of correlations at large time scales in SCN-lesioned animals. Thus, aging and AD significantly attenuate the scale invariance of activity fluctuations over multiple time scales. This attenuation may reflect functional changes of the SCN.actigraphy ͉ fractal ͉ motor control ͉ sleep-wake rhythm ͉ suprachiasmatic nucleus H uman motor activity displays complex temporal fluctuations characterized by scale-invariant/fractal patterns, i.e., the temporal structure and properties of fluctuations remain similar over a wide range of time scales (1, 2). The scale-invariant patterns are independent from scheduled and environmental influences and identical in humans and rats, suggesting a common intrinsic activity control mechanism in the 2 species (2). Although the underlying neural mechanisms are unknown in humans, lesion studies in rats have shown that the circadian pacemaker [suprachiasmatic nucleus (SCN)] is crucially involved in scale-invariance of activity fluctuations at multiple time scales (minutes to 24 h) with strongest influences at large time scales (greater than Ϸ4 h) (2). This multiscale influence of the SCN on activity in rats supports the hypothesis of a neuronal network for scale-invariant activity regulation, and suggests that the SCN is a major node in this network (2). Moreover, these data suggest that an index of scale-invariant activity regulation could potentially be used as a noninvasive marker of SCN function.Neuroanatomical changes in th...