Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss

Abstract

Shift workers, who are exposed to irregular sleep schedules resulting in sleep deprivation and misalignment of circadian rhythms, have an increased risk of diabetes relative to day workers. In healthy adults, sleep restriction without circadian misalignment promotes insulin resistance. To determine whether the misalignment of circadian rhythms that typically occurs in shift work involves intrinsic adverse metabolic effects independently of sleep loss, a parallel group design was used to study 26 healthy adults. Both interventions involved 3 inpatient days with 10-h bedtimes, followed by 8 inpatient days of sleep restriction to 5 h with fixed nocturnal bedtimes (circadian alignment) or with bedtimes delayed by 8.5 h on 4 of the 8 days (circadian misalignment). Daily total sleep time (SD) during the intervention was nearly identical in the aligned and misaligned conditions (4 h 48 min [5 min] vs. 4 h 45 min [6 min]). In both groups, insulin sensitivity (SI) significantly decreased after sleep restriction, without a compensatory increase in insulin secretion, and inflammation increased. In male participants exposed to circadian misalignment, the reduction in SI and the increase in inflammation both doubled compared with those who maintained regular nocturnal bedtimes. Circadian misalignment that occurs in shift work may increase diabetes risk and inflammation, independently of sleep loss.

Trial registration: ClinicalTrials.gov NCT00989534.

Figure 1

Schematic representation of the study design. The protocol followed a parallel group design with two experimental interventions: sleep restriction with circadian alignment (left) and sleep restriction with circadian misalignment (right). The black bars represent the periods allocated to sleep. In both groups, 3 baseline days of 10-h bedtimes (from 2200 to 0800 h; B1, B2, B3) were followed by 8 days of sleep restriction to 5-h bedtimes (R4–R11). In the circadian alignment group, all short sleep periods were centered at 0300 h (bedtimes: 0030 to 0530 h). In the circadian misalignment group, four of the eight short sleep periods (R5, R6, R8, and R9) were delayed by 8.5 h, such that sleep occurred during the daytime (0900 to 1400 h). In both groups, breakfast (B) was served between 0730 and 0830 h, lunch (L) between 1300 and 1400 h, and dinner (D) between 1900 and 1930 h. On shifted days in the misalignment group, lunch was served at 1500 h, 1 h after wakeup time, and a sandwich (S) was presented at 0100 h. Snacks were available at all times. An IVGTT was performed at 0900 h on B2 and on R10. Two 24-h sessions of blood sampling at 15- to 30-min intervals were performed on B3 and R11 (dashed lines). Caloric intake during these sessions was limited to three identical carbohydrate-rich meals (HC). No snacks were allowed. Saliva sampling at 30-min intervals was performed from 1600 to 0030 h on R4 and R11 to assess melatonin levels (gray bars).

Figure 2

Total sleep times achieved on each day for both study groups. Represented values are mean (SEM).

Figure 3

Assessments of circadian phase. Timing of DLMO before the first (●) and before the last (○) short sleep periods. The circadian phase could not be determined for one subject in the circadian misalignment group.

Figure 4

Individual changes in cardiometabolic variables. Values represent percentage change from baseline of SI, AIRg, DI, and hsCRP.

Figure 5

Temporal profiles of glucose (top) and insulin (bottom) levels during IVGTT. Mean (SD) glucose and insulin levels during IVGTT performed under baseline (i.e., rested) condition and after 7 days of sleep restriction to 5 h per day for the men in the circadian alignment (n = 10) and the circadian misalignment (n = 9) groups. Visual examination of these profiles suggests that the effect of sleep restriction on the decline of glucose concentrations is greater in the presence of circadian misalignment despite higher levels of insulin, consistent with a greater decrease in SI. Minimal model analysis of individual profiles confirmed this visual impression.

Figure 6

Changes in cardiometabolic variables in male participants. Mean (SD) changes in SI, AIRg, DI, and hsCRP from baseline to sleep restriction are shown in both intervention groups. *P < 0.05.