Sleep restriction to 5 h/night (TIB) for 1 week in nonobese, healthy men significantly reduced insulin sensitivity as assessed by two techniques, the euglycemic-hyperinsulinemic clamp and the IVGTT, yet did not affect the acute insulin response to intravenous glucose administration. Sleep restriction led to elevations of afternoon and evening levels of free cortisol, but these increases were not linearly related to changes in insulin sensitivity. The effects of sleep restriction on measures of glucose metabolism and on salivary cortisol were not altered by administration of modafinil, though modafinil did improve subjective and objective measures of sleepiness. These changes in insulin sensitivity support the hypothesis that insufficient sleep duration leads to insulin resistance.
Our finding that sleep restriction leads to a decrease in insulin sensitivity is consistent with earlier studies showing impaired glucose metabolism with altered sleep duration. The earliest direct assessment of the relationship between sleep and glucose metabolism demonstrated that complete sleep deprivation for 3–4 days led to an elevation of glucose levels on an oral glucose tolerance test (39
). Spiegel et al. (22
) from the Van Cauter laboratory performed frequently sampled IVGTT (FSIVGTT) in healthy subjects during a sleep debt condition (4 h per night) and the sleep-replete condition (12 h/night). They found that the sleep debt condition led to impaired glucose metabolism characterized by 30–40% reductions in glucose tolerance, glucose effectiveness, and acute insulin response to glucose but a nonsignificant reduction in insulin sensitivity. We also demonstrated impairment in glucose metabolism with sleep restriction (to 5 h/night compared with a baseline sleep repletion of 10 h/night), but the impairment was attributable to a decrease in insulin sensitivity rather than to impairments in insulin secretion or glucose effectiveness. However, we did not observe a compensatory increase in insulin secretion despite the reduction in insulin sensitivity, so it is possible that more than one mechanism is contributing to impaired glucose metabolism with sleep restriction in our study. Our results are consistent with recent results in 11 overweight, middle-aged adults that sleep restriction to 5.5 h/night with an ad libitum diet reduces insulin sensitivity but does not change insulin secretion on an IVGTT (40
). The current study extends from these findings with two techniques for assessing insulin sensitivity, the insulin-modified FSIVGTT and the gold standard euglycemic-hyperinsulinemic clamp, with concordant results. In further support of the hypothesis that alterations in sleep may affect insulin sensitivity, Van Cauter et al. (24
) recently reported that the nearly total suppression of slow-wave sleep by acoustic disruption for 3 nights (without changing total sleep duration) reduces insulin sensitivity as well as acute insulin response.
Substantive differences in the current protocol compared with the results of Spiegel et al. may account for our different results. While both studies examined the effects of sleep restriction in healthy subjects, the baseline sleep-replete condition actually came after the sleep debt condition in the Spiegel protocol, so the sleep-replete condition may reflect more of a recovery process than the actual baseline for each individual. We believe that our sleep-replete baseline more accurately defines (in experimental and ecological terms) the changes in both sleep and metabolism from sleep-replete to sleep-restricted conditions. In addition, the current protocol carefully controlled food intake and activity, whereas the Spiegel protocol allowed subjects to leave the laboratory each day during sleep-restricted conditions. Also, the dose of sleep restriction could influence the results because Spiegel et al. restricted sleep to 4 h/night, whereas we used 5 h/night (to apply to a greater proportion of the adult population). Finally, the specific procedures to assess glucose metabolism differed between the two studies. The Spiegel study (24
) used the tolbutamide-assisted FSIVGTT, and this procedure may not have had sufficient sensitivity to detect a significant increase in insulin resistance with sleep restriction.
Previous studies have shown that sleep restriction increases self-reported hunger and appetite for carbohydrate food (41
). Therefore, to control for potential variations in diet, subjects in the current study consumed a consistent diet throughout the protocol. In addition, subjects maintained a sedentary (but not bed rest) level of activity. Thus, the current study did not allow behavioral changes in diet composition (43
), caloric intake, or activity/exercise levels that may have contributed to the association of reduced habitual sleep duration and metabolic dysregulation in previous studies. We did not observe any changes in resting metabolic rate using indirect calorimetry, which is consistent with a prior report of a nonsignificant change in total energy expenditure with sleep restriction (42
A further strength of the current study is that all subjects began the study in a similar sleep-replete state prior to the imposition of sleep restriction. Under our experimental conditions, there was a deterioration of subjective and objective measures of sleepiness with sleep restriction, consistent with the known effects of sleep restriction. Modafinil administration partially mitigated this effect. However, modafinil treatment had no discernable affect on glucose metabolism. Activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system are two key counterregulatory pathways for increasing glucose levels during hypoglycemia. Both these pathways also have been proposed as possible mediators of the impairments in glucose tolerance associated with sleep restriction (22
). In the current study, sleep restriction led to a significant increase in salivary cortisol and urinary norepinephrine and epinephrine. Catecholamine increases with sleep restriction were amplified by modafinil treatment, consistent with prior reports of increased catecholamine levels with modafinil administration (49
). However, we found no association, under our experimental conditions, between changes in SI
and changes in hypothalamic-pituitary-adrenal axis function and sympathetic nervous system function, suggesting that these systems do not mediate the changes in SI
with moderate sleep restriction.
In the present study, the relatively modest restriction of the sleep period to 5 h per night led to a small increase in slow-wave sleep amount by the third night, reflecting an increase in homeostatic sleep drive. A study that deliberately reduced slow-wave sleep through acoustic disruption without changing total sleep time led to a reduction in SI
). In the current study, we observed reductions in SI
due to reductions in total sleep time—not to reductions in slow-wave sleep. Our experimental design is much more closely related to the type of sleep restriction that occurs in healthy individuals who voluntarily restrict sleep.
The limitations of this study include the small sample size that is limited to healthy nonobese men and the lack of a control group that continued the sleep-replete condition of 10 h/night TIB from baseline through to the end of the study. Future studies are needed to determine the effects of sleep restriction on insulin sensitivity in other populations, including women, obese patients, and individuals with insulin resistance or diabetes. It is unlikely that the protocol alone (in the absence of sleep restriction) would lead to decreased insulin sensitivity because, in other published studies, repeating these intensive glucose metabolism test has not led to worsening of metabolic function. Other authors, in validating different types of metabolic challenge tests, have demonstrated the reproducibility of the test results, especially for SI
). Furthermore, the careful control of diet and exercise allowed us to focus on effects of sleep restriction. However, sleep restriction increases appetite and increases the desire for high- carbohydrate/high-fat foods, so the control of food intake may have dampened the full effects of sleep restriction on glucose metabolism. In addition, we did not measure circadian phase changes directly. However, using a validated, data-based mathematical model, we estimate a <9 min variation in circadian phase under the experimental conditions and light levels employed in this study (32
). Thus, circadian phase changes are unlikely to be responsible for the differences we found in insulin sensitivity.
Insufficient sleep duration (quantity) has been associated with an increased risk of obesity (3
), type 2 diabetes (7
), hypertension (12
), cardiovascular disease (13
), metabolic syndrome (a combination of cardiovascular and metabolic dysfunction) (15
), and early mortality (14
). Our finding that reducing sleep increases insulin resistance provides one possible mechanism for these associations. In prospective studies, decreases in the disposition index, the product of insulin secretion and SI
, are a strong predictor of diabetes onset and worsening of metabolic function pre- and postdiagnosis (53
). Our finding that sleep restriction reduces the disposition index further supports the hypothesis that sleep restriction contributes to the development of metabolic dysregulation resulting in elevated risk for diabetes. Future studies are needed to determine whether chronic short sleep has detrimental effects on insulin resistance and glucose metabolism and whether short sleep is a risk factor for disease processes associated with insulin resistance.