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...

Objective Diet-induced thermogenesis (DIT) is lower in evening and at night than in the morning. This may help explain why meal-timing affects body weight regulation and why shift work is a risk factor for obesity. The separate effects of the endogenous circadian system—independent of behavioral cycles—and of circadian misalignment on DIT are unknown. Methods Thirteen healthy adults undertook a randomized, crossover study with two 8-day laboratory visits: three baseline days followed either by repeated simulated night shifts including 12-h inverted behavioral cycles (circadian misalignment) or by recurring simulated day shifts (circadian alignment). DIT was determined for up to 114 min (hereafter referred to as “early DIT”) following identical meals given at 8AM and 8PM in both protocols. Results During baseline days, early DIT was 44% lower in the evening than morning. This was primarily explained by a circadian influence rather than any behavioral cycle effect; early DIT was 50% lower in the biological evening than biological morning, independent of behavioral cycle influences. Circadian misalignment had no overall effect on early DIT. Conclusions The circadian system plays a dominating role in the morning/evening difference in early DIT and may contribute to the effects of meal-timing on body weight regulation.

Epidemiological studies show that adverse cardiovascular events peak in the morning (i.e., between 6 AM and noon) and that shift work is associated with cardiovascular disease, obesity, and diabetes. The endogenous circadian timing system modulates certain cardiovascular risk markers to be highest (e.g., cortisol, nonlinear dynamic heart rate control, and platelet activation) or to respond most unfavorably to stressors such as exercise (e.g., epinephrine, norepinephrine, and vagal cardiac modulation) at an internal body time corresponding to the time of day when adverse cardiovascular events most likely occur. This indicates that the circadian timing system and its interaction with external cardiovascular stressors (e.g., physical activity) could contribute to the morning peak in adverse cardiovascular events. Moreover, circadian misalignment and simulated night work have adverse effects on cardiovascular and metabolic function. This suggests that misalignment between the behavioral cycle and the circadian timing system in shift workers contributes to that population’s increased risk for cardiometabolic disease.