Our findings provide a potential mechanistic link between animal laboratory work and human epidemiological findings in terms of how prolonged sleep restriction and prolonged circadian disruption impair glucose regulation and reduce metabolism. The robust changes we observed with exposure to chronic and concurrent circadian disruption and sleep restriction have potential relevance to the millions of people who experience these challenges on a daily basis and who are more likely to develop the metabolic syndrome and diabetes. Findings of particular clinical relevance for exposure to chronic sleep restriction with circadian disruption include a 32% decrease in insulin secretion in response to a standardized meal, a very large effect that led to inadequate glucose regulation: glucose levels were higher for a longer time and rose to pre-diabetic levels in some participants. Finally, the 8% drop in RMR with sleep restriction and circadian disruption, assuming no changes in activity or food intake, would translate into ~12.5 pounds increase in weight over a single year (120 kcal/day × 365 days / 3500 kcal of fat mass), which has clear clinical relevance as chronic sleep restriction with circadian disruption is endemic in our society.
The seminal work of Spiegel et al in 1999 described adverse metabolic effects in humans when sleep was restricted to 4 h/night for 1 week, leading the authors to hypothesize “…that chronic sleep loss could increase the severity of age-related pathologies, such as diabetes
). In general, the primary mechanisms in the development of impaired glucose metabolism are changes in insulin secretion, the ability of the pancreatic beta-cells to respond to a glucose stimulus, and insulin sensitivity, the ability of peripheral tissues to respond to an insulin signal, such as occurs after a meal, by increasing glucose uptake. A host of secondary mechanisms can further modulate insulin sensitivity and insulin secretion. In a recent study of one week of sleep restriction to 5 h/night, young adult men had reductions in insulin sensitivity (measured using both euglycemic hyperinsulinemic clamps and intravenous glucose tolerance tests), with no change in the acute insulin response, and without a change in RMR (3
). These findings are consistent with those observed in middle-aged adults exposed to sleep restriction of 5.5 h/night for two weeks, who exhibited significant decreases in insulin sensitivity (30
). Thus, we are beginning to understand the extent to which sleep deficiency impairs glucose metabolism, but need more information about the extent, mechanisms, and dynamics of these changes. The magnitude (hours of sleep per night) and duration of sleep restriction (days to weeks) are likely to be important factors in determining the speed and extent of any diabetogenic changes, i.e., elevations of circulating glucose levels caused by reduced insulin sensitivity of peripheral tissues and/or insufficient insulin secretion by the pancreas. Our current findings are consistent with recent epidemiological work demonstrating that lifestyle factors, including habitually short sleep duration, increase the risk of weight gain over the life course (31
), and provide mechanistic insights into how this may occur via alterations of glucose metabolism and energy expenditure.
Another recent study demonstrated that acute circadian misalignment (sleeping during the biological day and eating during the biological night), as occurs with jet lag and shift work, results in similar adverse effects on glucose metabolism: increased postprandial glucose despite increased circulating insulin levels, suggesting reduced insulin sensitivity coupled with an inability of the pancreas to sufficiently increase insulin secretion (21
). Circadian misalignment usually also involves some degree of sleep restriction (sleep efficiency declined by 17% when misaligned in that study), representing a combined physiological challenge. Here we demonstrate the effects of a much more prolonged and more severe combined challenge in both young and older subjects, exposure to sleep restriction of 5.6 h sleep per 24 h with concurrent circadian disruption for an average of 19 days (range 15-22 days). Sleep restriction alone in younger men and middle-aged adults leads to no change in RMR (3
). However, we observed a notable decrease in RMR with prolonged sleep restriction and circadian disruption, along with significantly elevated glucose in response to a meal, but quite unexpectedly, a decreased insulin response suggesting pancreatic dysfunction that was unrelated to the small loss of body weight. Previous sleep restriction studies have shown reduced insulin sensitivity with no change in the insulin response to a tolerance test (3
) or meal response (1
). Acute circadian misalignment results in an inadequate post-prandial insulin response (21
). Our new findings demonstrate that with chronic exposure to sleep restriction and circadian disruption the pancreas exhibits more severe dysfunction as evidenced by the fact that insulin levels actually decreased despite elevated plasma glucose levels. Insulin clearance might also change. This physiological mechanism could explain the association of habitual sleep deficiency and elevated risk for obesity and diabetes (5
), and on weight gain and diabetes in a longitudinal study of male nightworkers (33
). Notably, in our study these effects in these healthy individuals were reversible with 9 days of stable circadian re-entrainment and recovery sleep.
The metabolic assessments during baseline and after exposure to chronic sleep restriction and circadian disruption were made at the same transiently realigned phase of the central circadian pacemaker. Controlling for the central circadian pacemaker phase of the metabolic assessment ensured that the effects observed were due to the combination of the prior histories of prolonged sleep restriction and of circadian disruption, rather than acute misalignment. Such effects have been proposed as important factors in the development of metabolic dysregulation via desynchronization of the central circadian pacemaker with respect to sleep-wake, fasting-feeding, and dark-light cycles (35
Peripheral clocks are entrained by timing of food intake in rodents (36
). Although no data are available from human studies, it is possible that the effects we observed reflect a reduced temporal coordination between central circadian pacemaker and peripheral tissues (37
) such as the pancreas that may be responding to changes in meal timing independently of central circadian clocks (38
). Misalignment of peripheral oscillators (e.g., in the pancreas and liver) with respect to the phase alignment of the central circadian pacemaker may thus also play a role in metabolic dysregulation. If the central circadian pacemaker and peripheral pacemakers were out of phase then the normally coordinated response to a meal may be dysfunctional, and lead to abnormal physiological responses to food intake. Peripheral oscillators relevant to metabolism coordinate both metabolic and circadian pathways (39
) required for normal hepatic lipid metabolism and homeostasis (40
). These findings and others (35
), taken together with our current results, suggest that synchronized central and peripheral circadian processes are necessary for the optimal regulation of energy homeostasis in mammals.
Previous studies of sleep restriction in healthy young men have shown a decrease in plasma leptin and an increase in total ghrelin coupled with increased hunger and appetite (41
), possibly reflecting relative underfeeding in those studies. A study of young women exposed to a single night of partial sleep restriction revealed an elevation of fasted morning leptin levels (43
). Epidemiological studies of short sleep duration have observed an association of shorter self-reported habitual sleep duration with lower leptin levels and higher total ghrelin levels (44
). In contrast, another laboratory study in middle-aged men and women exposed to either 8.5 or 5.5 h/night of time in bed for 2 weeks but with ad libitum
food observed no differences in leptin or ghrelin levels between the sleep duration conditions. Instead, caloric consumption in the form of snacking increased, such that the subjects consumed over 200 kcal more food per day in the sleep-restricted condition (32
). This increased food intake may have thereby normalized the leptin- and ghrelin-related hunger signal associated with sleep restriction. Although, we observed no change in fasted morning leptin levels in either young or older subjects exposed to prolonged sleep restriction with concurrent circadian disruption, and with controlled caloric intake, we did observe that, at the end of this period and through recovery, leptin was lower and ghrelin was higher, albeit a very small effect size (). The combination of sleep restriction plus circadian disruption may be a qualitatively different challenge than either sleep restriction or circadian disruption alone, or the prolonged duration of our stimulus (averaging 19 days) may have contributed to our findings. Further studies are needed to better quantify the relationships between adipocyte physiology and the extent of sleep restriction (hours in bed per night) and duration of sleep restriction or circadian disruption (days to weeks to months).
Glucose and cortisol profiles were higher during the first week of the combined disruptions (relative to baseline) and these raised levels persisted at all circadian phases throughout the third week of exposure. In contrast, fasting insulin levels were the same for the first week of the exposure as occurred at baseline, yet lower throughout the third week of exposure and not accompanied by further alterations in glucose. These different responses between variables suggest that multiple adaptive or maladaptive processes are at play, and that the extended duration of the combined challenge in our study revealed this dynamic system. The changes in the levels of fasted insulin from the first to the third weeks of exposure in the current study are presumably a result of repetitive and maladaptive insulin responses to meals during the prolonged exposure period.
We observed some age-related differences (e.g. adiposity, RMR, fasted leptin, body weight) but generally the effects of the exposure were age-independent: both young and older participants responded to prolonged sleep restriction combined with circadian disruption with higher glucose levels and lower insulin responses to a standard meal eaten at a consistent circadian phase. This lack of age effect was contrary to our expectations. We note that we studied healthy non-obese participants to ensure that comorbidities did not influence results. Thus, our older participants were very likely to be more healthy that the general older population at large, in whom responses may be different.
We investigated the effects of up to three weeks of exposure to the combined challenge of a relatively moderate degree of sleep restriction (5.6 h in bed per 24 h) and circadian disruption. This degree of sleep restriction is similar to that observed in permanent night workers who meet criteria for shift work disorder (15
). We assumed that the results of this 3-week challenge would reveal any adaptive or maladaptive physiological effects that would emerge beyond the immediate acute metabolic effects observed in previous sleep restriction studies or circadian misalignment studies in humans (1
). Metabolic assessments were made from standardized meal responses at the end of each condition (baseline, sleep restriction with concurrent circadian disruption, and recovery). Although we did see differences between the first and third week of the challenge, to determine the actual mechanisms that yield the time course of the associated metabolic deficits, future studies will need to be performed with more frequent assessments for weeks to months of exposure, and with perturbation analyses using such challenges as meal responses, intravenous glucose tolerance tests, and or glucose clamp studies. We did not assess changes by, or control for, the phase of the menstrual cycle in female participants, but there were no notable differences by sex or between age groups, possibly suggesting no difference between responses in these younger premenopausal and older postmenopausal women. The weight loss observed during the sleep restriction and circadian disruption period may have reflected a relatively underfed state that could have induced physiological changes. However, the average observed weight loss was quite minor (1.2% of body weight throughout the exposure). Moreover, in correlation analyses, the degree of weight loss in individual participants was not significantly related to the metabolic changes observed, and the weight loss persisted during the recovery phase when metabolic responses had returned to baseline. Thus, the reduction in insulin levels with sleep restriction and circadian disruption in the current study likely occurred via mechanisms unrelated to body mass or any underfeeding. Future studies might avert weight change by measuring metabolic rate rather than estimating metabolic rate prior to calculating dietary requirements, responding to small weight changes with caloric intake changes, and assessing body composition at multiple timepoints across a challenge and recovery (we only assessed body composition at baseline).