Circadian Misalignment Augments Markers of Insulin Resistance and Inflammation, Independently of Sleep Loss

Rachel Leproult; Ulf Holmbäck; Eve Van Cauter


Diabetes. 2014;63(6):1860-1869. 

In This Article

Abstract and Introduction


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.


Worldwide in industrialized countries, nearly 20% of working adults are shift workers.[1–3] Prospective epidemiologic studies indicate that shift work is associated with an increased risk of type 2 diabetes and cardiovascular disease.[4–9] Shift work is generally associated with chronic sleep loss, which adversely affects glucose tolerance and cardiovascular function.[10–13] Most shift workers also have irregular sleep schedules, resulting in circadian misalignment, a condition in which the behavioral sleep–wake schedule and the feeding schedule are not aligned with endogenous circadian rhythms. Because the timing of sleep and food intake synchronizes a number of neural, endocrine, and metabolic rhythms, whereas others remain locked to the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian misalignment involves a lack of synchrony among endogenous 24-h rhythms. Two recent laboratory studies in which healthy participants were exposed to circadian misalignment associated with reductions in total sleep time provided causative evidence for a deleterious effect on diabetes risk and cardiovascular function.[14,15] Whether circadian misalignment has adverse cardiometabolic effects that are distinct from those imparted by sleep loss is a fundamental and as yet unanswered question with important implications for the health of millions of shift workers.

We therefore designed an experimental study in which the major determinants of diabetes risk (insulin sensitivity [SI] and β-cell function) as well as a predictor of cardiovascular risk (plasma levels of high-sensitivity C-reactive protein [hsCRP], an inflammatory marker[16–19] were compared in healthy adults under conditions of circadian alignment versus misalignment, keeping the amount of daily sleep identical.