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Clinical Trial
. 2012 Apr 11;4(129):129ra43.
doi: 10.1126/scitranslmed.3003200.

Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined With Circadian Disruption

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Free PMC article
Clinical Trial

Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined With Circadian Disruption

Orfeu M Buxton et al. Sci Transl Med. .
Free PMC article

Abstract

Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.

Figures

Figure 1
Figure 1. Study schedule
Dark bars represent the scheduled sleep episodes. Subjects completed a 39-day protocol with a baseline ‘sleep replete’ condition with 3 weeks of 10 h/day of time in bed (TIB) at home, then 6 days with ≥10 h TIB per day. Sleep opportunities were then spread across the circadian cycle on a 28-h “forced desynchrony” (FD) protocol, with 6.5 h TIB (equivalent to 5.6 h per 24h) and 21.5 h of monitored wakefulness for 3 weeks. A subsequent period of 10 days of circadian re-entrainment with sleep recovery (10 h TIB/24 h) with the sleep period adjusted to the same circadian phase as the baseline sleep condition by modification of the duration of the wake period after the last FD day. Standardized breakfast meal responses (B); daily fasted blood samples for assessment of glucose, insulin, cortisol (F); core body temperature minimum (white X). Time from midpoint of sleep to start of breakfast (grey horizontal arrow) was maintained by choosing a day in the last week of sleep restriction plus circadian disruption such that the standardized meal occurred during this exposure at the same circadian phase as baseline within 4 h (0.7 ± 1.8 h), resulting in an average exposure duration of 19.2 ± 2.8 24-h days (range 15-22 days).
Figure 2
Figure 2. Glucose and insulin response to a meal in young and older participants at baseline, following an average of 19 days of prolonged sleep restriction combined with circadian disruption, and following 9 days of stable re-entrainment and recovery sleep
In young (panels A-D) and older subjects (panels E-H), mean profiles (± 95% C.I) are depicted for glucose (panels A, B, E, F) and insulin (panels C, D, G, H) responses to an identical, standardized breakfast (striped horizontal bar at time=0) under conditions of baseline sleep replete (≥10 h TIB/24 h [dashed black line]), history of prolonged sleep restriction combined with circadian disruption (5.6 h TIB/24 h [solid red line; left panels]), and following 9 days of stable circadian re-entrainment and recovery sleep (10 h TIB/24 h [solid grey line; right panels]). In each condition, breakfast was served at the same circadian temperature phase ± 4 h (0.7 h ± 1.8 h).
Figure 3
Figure 3. Metabolic effects of prolonged exposure to sleep restriction combined with circadian disruption in young and older participants
Young and older participants were assessed during the conditions of baseline sleep replete (10 hTIB/24 h [B, black bars]), following an average of 19 days of sleep restriction combined with circadian disruption (5.6 h TIB/24 h [SRCD, red bars]), and after 9 days of stable circadian re-entrainment and recovery sleep (10 h TIB/24 h [R, grey bars]). In each condition, a fasted sample was collected prior to an identical breakfast and assayed for glucose (panel A), insulin (panel B), and leptin (panel G). For an hour after the identical breakfast, samples were taken every 10 minutes, and another at 90 minutes post meal and assayed for glucose and insulin. Peak (panels C-D) and area under the curve (AUC) values (panels E-F), were calculated over the first 90 postprandial minutes. Resting metabolic rate (panel H) was determined prior to the meal. Insulin and leptin were log-transformed prior to statistical testing. Values are means ± SE. Bonferroni-adjusted P-values were based on mixed-effects models with age, condition, and age*condition (and gender for RMR) as the fixed effects and participants as the random effects, and are depicted as follows; p≤0.05 *; p≤0.01 **; p≤0.001 ***; p≤0.0001 ****. Bonferroni adjustments were applied to each age group separately.
Figure 4
Figure 4. Circadian rhythms of fasted glucose, insulin, and cortisol during the first week (dotted red lines) and third week (solid red lines) of exposure to prolonged sleep restriction combined with circadian disruption
Mean fasted levels (±95% CI) of glucose (A), log insulin (B), cortisol (C) from samples collected within an hour of awakening at all circadian phases and post-void body weight (D). For reference, the mean level (±95% CI) of the fasted value at baseline for each measure is depicted at the approximate circadian phase of the baseline assessment (black circle). Circadian phase of the sample collection was determined using core body temperature recordings (see Methods). There was a significant circadian variation, but no significant effects of age for all measures. Week 1 differed from week 3 for insulin levels and weight. Significant p values are depicted as follows; p≤0.05 *; p≤0.01 **; p≤0.001 ***; p≤0.0001 ****.
Figure 5
Figure 5
Free ghrelin and leptin response to a meal in young and older participants at baseline, following an average of 19 days of prolonged sleep restriction combined with circadian disruption, and following 9 days of stable re-entrainment and recovery sleep. In young (panels A, C, E, G) and older subjects (panels B, D, F, H), mean profiles (± 95% C.I) are depicted for free ghrelin (panels A-D) and leptin per percent body fat (panels E-H) and aligned relative to an identical, standardized breakfast (time=0) under conditions of baseline sleep replete (≥10 h TIB/24 h [dashed black line]), history of prolonged sleep restriction combined with circadian disruption (5.6 h TIB/24 h [solid red line]), and following 9 days of stable circadian re-entrainment and recovery sleep (10 h TIB/24 h [solid grey line]). In each condition, breakfast was served at the same circadian temperature phase ± 4 h (0.7 h ± 1.8 h). Sleep periods are depicted by horizontal bars, meals by vertical bars.

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