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Randomized Controlled Trial
. 2016 Mar;101(3):1066-74.
doi: 10.1210/jc.2015-3924. Epub 2016 Jan 15.

Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Workers

Christopher J Morris  1 , Taylor E Purvis  1 , Joseph Mistretta  1 , Frank A J L Scheer  1
Affiliations
Randomized Controlled Trial

Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Workers

Christopher J Morris et al. J Clin Endocrinol Metab. 2016 Mar.

Abstract

Context: Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and 24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown.

Objective: The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects.

Design: A randomized, crossover study with two 3-day laboratory visits.

Setting: Center for Clinical Investigation at Brigham and Women's Hospital.

Patients: Healthy chronic shift workers.

Intervention: The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment).

Main outcome measures: Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols.

Results: Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early and late phase insulin; both P ≤ .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38).

Conclusions: Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.

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Figures

Figure 1.
Figure 1.
Circadian alignment protocol (top panel) and circadian misalignment protocol (bottom panel). On day 1 in both protocols, participants received an ad libitum lunch at approximately 12:00 pm. The letters B and D indicate the test meals at breakfast (first meal of the scheduled wake episode) and dinner (last meal of the scheduled wake episode), respectively. Letters following B or D 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 Figure 3, we did the following: 1) averaged breakfast time (BA and BM) and dinner time (DA and DM) test meal values separately across both protocols (behavioral cycle effect); 2) averaged 8:00 am (BA and DM) and 8:00 pm (DA and BM) test meal values separately across both protocols (circadian phase effect); and 3) averaged alignment (BA and DA) and misalignment (BM and DM) test meal values within each protocol (circadian misalignment effect). Light levels (in the horizontal angle of gaze); approximately 90 lux to simulate typical room light intensity, 30-minute periods of approximately 450 lux to simulate the morning commute preceding the simulated day shift and following the simulated night shift, approximately 4 lux to permit assessment of dim-light melatonin levels, 0 lux during scheduled sleep opportunities. Light levels were also 90 lux during test meal assessments.
Figure 2.
Figure 2.
Dim light melatonin levels in the circadian alignment and misalignment protocols. Central circadian phase, as estimated by dim light melatonin profile, was similar for the circadian alignment and circadian misalignment protocol (top panel), resulting in an approximately 12-hour difference in circadian alignment relative to the behavioral cycle (bottom panel). Bottom panel, data are plotted according to scheduled wake time; in the circadian alignment protocol, data are plotted relative to a scheduled 7:00 am wake time on day 1, whereas in the circadian misalignment protocol, data are plotted relative to a scheduled 7:00 pm wake time on day 1 (start of wake period 2). Black bar represents sleep opportunity. In the circadian alignment protocol, no melatonin samples were obtained from 7:53 am to 2:53 pm, whereas in the circadian misalignment protocol, melatonin samples were obtained hourly for 24 hours. Samples for melatonin measurement were collected under dim light conditions (∼<4 lux in the horizontal angle of gaze). Data are presented as mean ± SEM.
Figure 3.
Figure 3.
Effects of the behavioral cycle (left panels), circadian phase (middle panels), and circadian misalignment (right panels) on postprandial glucose and insulin profiles. Data are derived from identical test meals given at 8:00 am and 8:00 pm in both the circadian alignment and misalignment protocols. Data are derived as described in the legend of Figure 1. Green bars represent 20-minute test meals. Probability values: behavioral cycle effect, breakfast vs dinner; circadian-phase effect, biological morning vs biological evening; misalignment effect, circadian alignment vs circadian misalignment. Data are presented as mean ± SEM.
Figure 4.
Figure 4.
Effects of circadian misalignment on 24-hour glucose and insulin levels. Black bar represents sleep opportunity; narrow green bar represents a test meal; narrow blue bar represents a lunch meal. Probability values from 24-hour area under the curve analyses are shown. Data are presented as mean ± SEM.
Figure 5.
Figure 5.
Effects of circadian misalignment on 24-hour cortisol levels. Upper panel, data are plotted according to clock time. Bottom panel, data are plotted relative to scheduled wake time. TSW, time since wake; black bar represents sleep opportunity; narrow green bar represents a test meal; narrow blue bar represents a lunch meal. Data are represented as mean ± SEM.
Figure 6.
Figure 6.
Effects of circadian misalignment on sleep duration and latency. Data are represented as mean ± SEM.
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