Adverse metabolic and cardiovascular consequences of circadian misalignment

Abstract

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 approximately 1,000 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 approximately 12 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.

Fig. 1.

Forced desynchrony protocol. Subjects completed 2 baseline days and nights, followed by the FD portion of the study consisting of 7 recurring 28-h “days” in dim light (example subject had habitual bedtime of 24:00). Thick horizontal bars, sleep episodes (interspersed by 2 brief awakenings to perform pulmonary function measurements); gray bars, meal times; B, breakfast; L, lunch; D, dinner; S, snack; thin open horizontal bars, waking episodes of days 1 and 2 at room light intensity (≈90 lux); thin black horizontal bars, waking episodes on days 3–11 in dim light (≈1.8 lux).

Fig. 2.

Independent influence of circadian cycle and behavioral cycle on metabolic, autonomic, and endocrine function. Left panels: influence of behavioral cycle, independent from circadian cycle. Right panels: influence of endogenous circadian cycle, independent from behavioral cycle. Error bars, SEM; gray areas, scheduled sleep episodes; short vertical gray bars, meal times as in Fig. 1; vertical dotted line, fitted core body temperature minimum; P-values, statistical significance for effect of behavioral cycle (Left panels) and circadian cycles (Right panels). Glucose and epinephrine scales are on the left and insulin and norepinephrine scales are on the right for both Left and Right panels.

Fig. 3.

Circadian misalignment suppressed leptin levels proportionally, with maximum suppression during maximum misalignment (by 12 h on fourth 28-h “day,” indicated in red rectangle) as compared to circadian alignment (indicated in green rectangle). Circles, mean; error bars, SEM; gray area, mean ± SEM on first 28-h day replotted for comparison (circadian alignment); horizontal black bars, scheduled sleep episodes; vertical lines, scheduled awakenings; blue numbers above x-axis, approximate hours of circadian misalignment of the scheduled wake time on each 28-h day.

Fig. 4.

Consequences of circadian misalignment on metabolic, autonomic, and endocrine function. Data are plotted according to time-since-wake, during normal circadian alignment (open green symbols; scheduled awakening at habitual wake time) and during circadian misalignment (filled red symbols; scheduled awakening 12 h out of phase from habitual wake time). P-values, statistical significance for effect of misalignment [based on 24-h cycle for variable mainly driven by circadian cycle (cortisol) and 28-h cycle for variables mainly driven by behavioral cycle (others)]; gray area, scheduled sleep episode; short vertical gray bars, meal times as in Fig. 1.

Fig. 5.

Circadian misalignment reduces glucose tolerance and insulin sensitivity. During circadian misalignment, 2-h postprandial glucose (Top panel) and insulin (Bottom panel) levels were significantly increased as compared to normal alignment. Dotted lines, 140 mg/dL and 200 mg/dL 2-h postprandial glucose, above which levels are considered prediabetic and diabetic, respectively; P-values, statistical significance for effect of misalignment.