Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

Abstract

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 early-phase 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.

Keywords: circadian disruption; diabetes; glucose metabolism; night work; shift work.

Fig. 1.

Schematic diagram of the separate effects of the endogenous circadian system, the behavioral cycle, and circadian misalignment (interaction between the circadian cycle and behavioral cycle) on glucose tolerance. In addition, our analysis tested whether the effects of the endogenous circadian system, behavioral cycle, and circadian misalignment on glucose tolerance were dependent on circadian misalignment exposure duration (acute vs. repeated).

Fig. 2.

Circadian alignment protocol (Top) and circadian misalignment protocol (Bottom). On day 1 in both protocols, participants received an ad libitum lunch at ∼12:00 PM. Caloric intake was prorated for the 12-h behavioral cycle on day 4 of the circadian misalignment protocol (i.e., they received 50% of the caloric content compared with the 24-h days). Light level was also 90 lux during test meal assessments. The letters B and D indicate breakfast and dinner, respectively. Numbers following B or D indicate test days (first or third), and letters following these numbers indicate whether the test meals were consumed during the circadian alignment (A) or circadian misalignment (M) protocol. To graphically represent the independent effects of the behavioral cycle, circadian phase and circadian misalignment in the subsequent figures, we (i) averaged breakfast time (B^A and B^M) and dinner time (D^A and D^M) test meal values separately across both protocols for each test day (behavioral cycle effect); (ii) averaged 8:00 AM (B^A and D^M) and 8:00 PM (D^A and B^M) test meal values separately across both protocols for each test day (circadian phase effect); and (iii) averaged alignment (B^A and D^A) and misalignment (B^M and D^M) test meal values within each protocol for each test day (circadian misalignment effect).

Fig. 3.

Effects of the behavioral cycle (Left), circadian phase (Middle), and circadian misalignment (Right) on postprandial glucose and insulin profiles. Data are derived from eight identical test meals given at 8:00 AM or 8:00 PM in the circadian alignment and misalignment protocols. Data are derived as described in the legend of Fig. 2. Black bars represent 20-min test meals. Statistical comparisons between these conditions are presented in Fig. 4. Data are presented as mean ± SEM.

Fig. 4.

Effects of the behavioral cycle (Left), circadian phase (Middle), and circadian misalignment (Right) on postprandial glucose and early- and late-phase insulin AUCs. Data are derived as described in the legend of Fig. 2. Probability values: behavioral cycle, breakfast vs. dinner; circadian phase, biological morning vs. biological evening; alignment condition, circadian alignment vs. circadian misalignment; interaction with test day indicates if the abovementioned comparisons were dependent on circadian misalignment exposure duration (test day 1 vs. test day 3). Data are presented as mean ± SEM.

Fig. 5.

Effects of circadian misalignment on 24-h glucose and insulin levels. TD, test day; gray bar represents sleep opportunity; black bar represents a meal. Probability values from 24-h AUC analyses are shown. Data are presented as mean ± SEM.

Fig. 6.

Effects of circadian misalignment on 24-h FFA and triglyceride levels. TD, test day; gray bar represents sleep opportunity; black bar represents a meal. Probability values from 24-h AUC analyses are shown. Data are presented as mean ± SEM.