Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: [Link]/locate/beem

Role of sleep duration in the regulation of glucose

metabolism and appetite
Lisa Morselli, Research project professional a, d, Rachel Leproult, Research
Associate (Assistant Professor) a, d, Marcella Balbo, Clinical associate of
medicine-Specialty endocrinology b, Karine Spiegel, Research scientist c, *
a
Department of Medicine, University of Chicago, 5841 South Maryland Ave., MC1027, Chicago, IL 60637, USA
b
Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Via Venezia 16, Alessandria, Italy
c
INSERM/UCBL – U628, Integrated Physiology of Brain Arousal Systems, Lyon, France

Keywords:
Sleep curtailment has become a common behavior in modern society.
Sleep deprivation This review summarizes the current laboratory evidence indicating
Glucose metabolism that sleep loss may contribute to the pathophysiology of diabetes
Appetite regulation mellitus and obesity. Experimentally induced sleep loss in healthy
Diabetes volunteers decreases insulin sensitivity without adequate compensa-
Obesity tion in beta-cell function, resulting in impaired glucose tolerance and
increased diabetes risk. Lack of sleep also down-regulates the satiety
hormone leptin, up-regulates the appetite-stimulating hormone
ghrelin, and increases hunger and food intake. Taken together with the
epidemiologic evidence for an association between short sleep and the
prevalence or incidence of diabetes mellitus and/or obesity, these
results support a role for reduced sleep duration in the current
epidemic of these metabolic disorders. Screening for habitual sleep
patterns in patients with “diabesity” is therefore of great importance.
Studies are warranted to investigate the putative therapeutic impact of
extending sleep in habitual short sleepers with metabolic disorders.
Ó 2010 Elsevier Ltd. All rights reserved.

Introduction

Evidence for a modulatory impact of sleep on many physiological functions, including metabolic
regulation and endocrine release, has been reported more than four decades ago. Nighttime hormonal

* Corresponding author. INSERM/UCBL – U628, Physiologie intégrée du système d’éveil, Université Claude Bernard Lyon 1, 8
Avenue Rockefeller, 69373 Lyon Cedex 08, France. Tel.: þ33 478 77 70 40; fax: þ33 478 77 71 50.
E-mail addresses: lmorsell@[Link] (L. Morselli), rleproul@[Link] (R. Leproult), mbalbo@ospedale.
[Link] (M. Balbo), [Link]@[Link] (K. Spiegel).
d
Both authors contributed equally to this work.

1521-690X/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/[Link].2010.07.005
688 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

release and glucose control are dependent on the occurrence of specific sleep stages.1–3 Human sleep is
composed of rapid-eye-movement (REM) sleep and stages 1, 2 and 3 of non-REM (NREM) sleep. During
the deeper stage of non-REM sleep, i.e. slow wave sleep (SWS) or stage NREM 3, brain glucose utili-
zation and sympathetic nervous activity are decreased and parasympathetic nervous activity is
increased, relative to both wake and REM sleep. SWS is also associated with robust elevations of growth
hormone (GH) levels, while pituitary–adrenal activity is inhibited.3 Hence SWS is likely to play a major
role in total body glucose regulation. More recently, orexin neurons in the lateral hypothalamus have
been identified as playing a central role in the maintenance of arousal as well as feeding behavior,4,5
suggesting an impact of sleep duration on appetite regulation (reviewed in chapter 12 “Sleep and
metabolism: role of hypothalamic neuronal circuitry”).
The first laboratory studies examining the adverse impact of sleep deprivation on metabolic and
endocrine functions concluded that the alterations occurring during one or two nights of acute total
sleep deprivation were reversed during recovery sleep. Because these results suggested that persistent
adverse effects of sleep loss are unlikely, but also because the degree of sleep deprivation in these
studies was not commonly occurring on a recurring basis in the general population, little attention was
paid to these findings. Since then, recurrent partial sleep deprivation, i.e. the result of a voluntary
behavior reflecting the demands and opportunities of modern society, has become increasingly
common. The impact of such sleep deprivation, which affects all age groups, was first investigated
10–15 years ago. Fig. 1 summarizes the sleep duration on week nights for US and French adults and
adolescents as assessed in years 2005–2008.6–9 Data from the 2008 “Sleep in America” poll of the

Fig. 1. Self-reported sleep duration (hours) for US and French adults (panel A) and adolescents (panel B). For adolescents, a sleep
duration of <8 h is considered insufficient, from 8 to 9 h borderline, and 9 h optimal. Adapted from.6–9
 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702 689

National Sleep Foundation indicate that although working adults report a sleep need of an average of
7 h and 18 min to function at best, the average sleep duration is 6 h and 40 min, with 44% of them
sleeping less than 7 h on a typical week-night (as opposed to only 15.6% in 196010), and 16% less than
6 h (Fig. 1A right panel6). Sleep times in European countries follow a similar trend; a survey conducted
in France among adults aged 18–55 years reported that, on work-nights, the average sleep duration was
6 h and 58 min and that 33% of the respondents slept less than 7 h per night (Fig. 1A left panel8). Among
the pediatric population, adolescents carry the strongest sleep debt. While laboratory studies have
shown that physiological sleep need is about 9 h across all ages of adolescence,11 sleep duration on
school nights is 7 h and 12 min for 9–12th grade American teens7 and 7 h and 45 min for 15–19 years
old French adolescents.9 In both countries the amount of sleep that adolescents believe they need to
feel their best during the day is higher than the amount of sleep that they actually achieve (9 h and
02 min in France, 8 h and 00 min in the US), with the optimal sleep duration reported by French
adolescents matching findings on sleep need obtained in laboratory studies.11 In France, 78% of
adolescents get an insufficient (<8 h) or borderline sufficient (8 h to 9 h) amount of sleep on school
nights and this proportion reaches a striking 87% for US adolescents (Fig. 1B7,9). Not surprisingly, in
both countries, adults and adolescents who report insufficient sleep are much more likely to also report
sleepiness, tiredness, irritability, depressed mood, and higher intake of caffeinated beverages.
To date, an ever-increasing number of cross-sectional as well as prospective epidemiologic studies
(reviewed in chapter 5 “Sleep duration and cardiometabolic risk: a review of the epidemiologic
evidence”) have provided evidence for an association between short sleep and the prevalence or
incidence of obesity or diabetes, after controlling for age, body mass index (BMI) and various other
confounders. The present review will summarize the current laboratory evidence indicating that
recurrent sleep curtailment is associated with a constellation of metabolic and endocrine alterations,
strongly suggesting that short sleep is an important, though still widely underestimated, non-tradi-
tional lifestyle factor involved in the current epidemic of diabetes and obesity.

Sleep duration and glucose metabolism

Total sleep deprivation studies

The first studies evaluating the impact of sleep deprivation on human health involved various
durations of total sleep deprivation (TSD) (Table 1). In the late 1960s, Kuhn et al. compared glucose
tolerance in 28 young healthy volunteers after 4–5 control nights with normal bedtimes and after
72–126 h of TSD: the glucose response to an oral glucose tolerance test (OGTT) was higher in the latter
condition, indicating reduced glucose tolerance.12 In another early study,13 the effect of 120-h TSD on
the activity of selected enzymes of energy metabolism in skeletal muscle was studied in 7 healthy
volunteers: the activity of all the enzymes assayed was decreased, with those involved in the Krebs
cycle and in anaerobic glycolysis reaching statistical significance. These results are suggestive of
a “prediabetic” type of muscle metabolism during sleep deprivation. Furthermore, fasting blood
glucose levels were increased at the end of the sleep deprivation period.13 In another study,14 compared
to results obtained after a 7-h night, 60 h of TSD in young healthy male volunteers was shown to
increase fasting insulin levels, as well as the insulin response to OGTT, while no change was observed
for glucose levels, suggesting that TSD induced insulin resistance.14 In yet another study, one night of
TSD was found to increase steady state glucose levels during an insulin suppression test modified with
octreotide, while steady state insulin levels were unchanged, suggesting again decreased insulin
sensitivity (SI).15 In contrast, Schmid et al. reported no alteration of SI after a similar duration of sleep
deprivation; however, surprisingly, baseline glucagon levels were decreased and the relative glucagon
response to a stepwise hypoglycemic clamp was enhanced, compared to a 7-h night; the clinical
significance of these results remains to be investigated.16

Partial sleep deprivation studies

The second part of Table 1 summarizes the results of studies that investigated the impact of partial
sleep deprivation (PSD) on glucose metabolism in healthy lean, overweight or obese adults. The first
Table 1

690
Impact of total (upper panel) and partial sleep deprivation (lower panel) on glucose metabolism.

Subjects Study conditions Changes with sleep deprivation

Time in bed Method used to assess glucose metabolism

Total sleep deprivation

L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702
Kuhn et al. 196912 28 men 72–126 h TSD vs. 4–5 OGTT Z glucose tolerance
20–30 yo “control” nights
BMI n.a.

Vondra et al. 198113 7 men 120 h TSD Muscle biopsy and Prediabetic type of muscle metabolism
21–23 yo vs. energy metabolism \ fasting glucose
BMI n.a. 3 “normal” nights -related enzymatic activity

VanHelder et al. 199314 10 men 60 h TSD OGTT \ insulin response

22  3 yo vs. 5 glucose tolerance
12.6  5.9% body fat 17h

Gonzalez-Ortiz 28 men and women 24 h TSD Insulin suppression \ steady state glucose
et al. 200015 19–23 yo vs. test modified with octreotide 5 steady state insulin
BMI < 26 kg/m2 1 night of “normal sleep”

Schmid et al. 200716 10 men 1 night TSD Stepwise hypoglycemic clamp Z baseline glucagon
25  1 yo vs. \ relative glucagon response
BMI 23.8  0.5 kg/m2 17h to hypoglycemia

Partial sleep deprivation

Spiegel et al. 199917 11 men 64h ivGTT Z glucose tolerance
18–27 yo vs. Z glucose effectiveness
BMI 23.4  0.5 kg/m2 6  12 h Z AIRg

Spiegel et al. 200525 12 men 24h Daytime blood sampling \ glucose

22  2 yo vs. (q20 min) Z insulin
BMI 23.6  2 kg/m2 2  10 h

Leproult et al. 200626 10 men and 2 women 75h ivGTT Z insulin sensitivity
24  1 yo vs.
BMI 23.4  0.6 kg/m2 2  10 h

Buxton et al. 200827 20 men 75h Euglycemic hyperinsulinemic Z insulin sensitivity

20–35 yo vs. clamp
BMI 21–30 kg/m2 3  10 h

Bosy-Westphal et al. 14 women 1  7 h, 2  6 h, OGTT 5 Insulin sensitivity (HOMA index)

200828 28–38 yo 1  4 h (5.5h sleep) 5 Insulin sensitivity (Matsuda index)
BMI 20–36.6 kg/m2 vs.
2  >8 h (9h sleep)
 Zielinski et al. 200829 Restriction: 6 men and Restriction: 8 weeks of 6.6  0.6 h OGTT 5 glucose tolerance
16 women vs. 2 weeks of 7.6  0.7 h 5 Insulin sensitivity (QUICKI index)
60  5 yo Controls: 8 weeks of 6.8  1.1 h
BMI 24.7  3 kg/m2 vs. 2 weeks of 7.2  1.1 h
Controls: 6 men and
12 women

L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702
61  5 yo
BMI 26.6  3.4 kg/m2

Schmid et al. 200931 10 men 1  4.5 h Stepwise hypoglycemic Z baseline glucagon

20–40 yo vs. clamp Z glucagon during hypoglycemia
BMI 23.8  0.5 kg/m2 17h

Nedeltcheva et al. 200932 6 men and 5 women 14  5.5 h OGTT Z oral glucose tolerance
39  5 yo vs. ivGTT Z insulin sensitivity
BMI 26.5  1.5 kg/m2 14  8.5 h \ glucose effectiveness

Donga et al. 201033 5 men and 4 women 14h Euglycemic hyperinsulinemic Z peripheral and hepatic
23–62 yo vs. clamp insulin sensitivity
BMI < 26 kg/m2 1  8.5 h [6,6-2H2]-glucose infusion

Van Leeuwen et al. 201034 23 men (15 sleep Restriction: 5  4 h Single fasting blood sample 5 glucose
restriction, vs. 2  8 h (7.30 am) \ fasting insulin
8 controls) Controls: 8 h
19–29 yo
BMI 23.2  2.7 kg/m2

TSD: Total sleep deprivation; OGTT: Oral Glucose Tolerance Test; ivGTT: Intravenous Glucose Tolerance Test; AIRg: Acute insulin response to glucose.

691
692 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

study that investigated the effect of sleep debt on metabolic and endocrine functions assessed
carbohydrate metabolism, 24-h profiles of the counterregulatory hormones cortisol and GH, and
cardiac sympathovagal balance in 11 young men after time in bed had been restricted to 4 h for 5–6
nights.17–19 The sleep-debt condition was compared with measurements taken at the end of a sleep-
recovery period when participants were allowed 12 h in bed for 5–6 nights. Glucose tolerance, assessed
during an intravenous glucose tolerance test (ivGTT) and a high carbohydrate breakfast, was lower in
the sleep-debt condition than in the fully rested condition. Importantly, glucose tolerance quantified
from the decline of glucose levels during the ivGTT was in the range typical for older adults with
impaired glucose tolerance in the state of sleep debt.20 The ivGTT is a validated tool that also provides
assessments of SI, pancreatic beta-cell responsiveness (referred to as “acute insulin response to
glucose”, AIRg), and glucose effectiveness (SG), a measure of non-insulin dependent glucose disposal.21
SG was 30% lower in the state of sleep debt. AIRg was reduced by more than 30% after sleep restriction
despite a trend for decreased SI. The disposition index (DI), i.e. the product of SI and AIRg, is a validated
marker of diabetes risk.22,23 In the state of sleep debt, the DI was decreased by an average of about 40%
as compared to the fully rested state, and 3 of the 11 subjects had DI values <1.000, indicating a high
risk of diabetes.24 Sleep loss was also associated with increased evening cortisol concentrations,
increased duration of elevated GH concentrations during the waking period, and increased cardiac
sympathovagal balance (Fig. 2; panels B, C, and E).17–19 Thus, semi-chronic PSD appears to have
a clinically significant deleterious impact on glucose metabolism and cardiometabolic risk. In
a subsequent study from the same group of investigators, a randomized cross-over design with 2 nights

4 HOURS IN BED 8 HOURS IN BED 12 HOURS IN BED

A 40 3h48' OF SLEEP 6h52' OF SLEEP 8h52' OF SLEEP

HOMA 30
(INSULIN (mU/L) * 20
GLUCOSE(mmol/L)
/ 22.5) 10
0

B 15
CORTISOL 10
( µg/dL)
5

18
C
12
GROWTH
HORMONE
(ng/ml) 6

6.5
D 5.5
LEPTIN 4.5
(ng/ml) 3.5
2.5
1.5

E 0.80

CARDIAC 0.75
SYMPATHOVAGAL
BALANCE 0.70
(rRR) 0.65
0.60
9 13 17 21 1 5 9 9 13 17 21 1 5 9 9 13 17 21 1 5 9
CLOCK TIME CLOCK TIME CLOCK TIME

Fig. 2. Relationship between sleep duration and the 24 h profiles of HOMA, cortisol, growth hormone, leptin and cardiac sym-
pathovagal balance. Adapted from.18,19 The bars represent the sleep periods. The shaded areas represent the response to breakfast for
HOMA and the evening levels for cortisol profiles.
 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702 693

of 10 h vs. 2 nights of 4 h in bed was used to examine the impact of short-term PSD on glucose
metabolism.25 After the second night of each condition, caloric intake was replaced by an intravenous
glucose infusion at a constant rate and blood samples were collected every 20 min. Even though sleep
duration was manipulated for only 2 nights, glucose tolerance was decreased, partly as a result of
inadequate insulin secretion.
In another study involving a baseline period of 3 days with 10-h bedtimes followed by 8 nights of
5-h bedtimes, an ivGTT was performed in 12 young healthy individuals after the second baseline night
and after 7 short nights. Preliminary findings indicate that, following sleep restriction, the subjects
experienced a 40% decrease in SI, without adequate compensation by insulin release. The DI was thus
markedly decreased after sleep loss.26 In a separate study in non-obese healthy men, sleep restriction
to 5 h per night for one week resulted in a significant reduction in SI as assessed by hyperinsulinemic
euglycemic clamp, considered the gold standard method for SI determination.27
In a study focusing only on women, no impact of progressive sleep curtailment over 4 nights was
reported on measures of glucose tolerance and SI.28 Zielinski et al. assessed the impact of semi-chronic
(8 weeks) sleep curtailment on glucose tolerance in self-reported older long sleepers (8.5 h/night),
compared to a control group; the authors observed no effect of sleep restriction on glucose tolerance, as
assessed by OGTT.29 However, contrasting with the self-reported long sleep, objective sleep duration
assessed by actigraphy was approximately 7.5 h at baseline. Bedtime curtailment resulted in a decrease
in total sleep time by only 1 h on average. Furthermore, sleep duration was also decreased in the
control group, and the final difference in total sleep time between the two groups was only approxi-
mately 16 min.30 The negative findings regarding glucose tolerance are thus not unexpected.
Schmid et al. reported the effect of one single night of sleep restriction (4.5 h in bed vs. normal
bedtime of 7 h) on insulin-induced hypoglycemia in healthy young subjects. Similar to previous
findings,17 fasting glucose, insulin levels or HOMA levels (the normalized product of glucose and insulin
levels, a validated index of SI), were not altered by sleep deprivation. Also, the glucose infusion rate, as
well as the hypoglycemia-induced decrease in C-peptide levels, were similar to those observed in the
normal sleep condition. However, a decrease in glucagon levels both at baseline and during hypo-
glycemia was observed after the night of sleep restriction. The authors speculate that this could be
mediated by the autonomic nervous system. These results suggest that sleep deprivation could also
affect alpha-cell function, but await further confirmation.31
Another study reported that semi-chronic sleep restriction (2 weeks of 5.5 h vs. 8.5 h in bed) in
middle-aged overweight adults was associated with decreased SI during ivGTT without appro-
priate compensatory beta-cell release, as AIRg was not affected by the sleep condition, resulting
in reduced oral glucose tolerance.32 However, the increase in diabetes risk, as assessed by the DI,
did not reach statistical significance. In addition, SG was increased. Donga et al. evaluated SI in
middle-aged men and women after one single night of partial sleep restriction (4 h in bed, from
1:00 to 5:00) with the euglycemic hyperinsulinemic clamp.33 The authors observed a reduction in
glucose infusion and disposal rates, indicating a deterioration of glucose tolerance and peripheral
SI. They also assessed endogenous hepatic glucose production rate, by continuous infusion of
[6,6-2H2]-glucose, which was increased by approximately 22% after sleep restriction. Free fatty
acid levels were also increased, a sign of higher insulin resistance at the adipose tissue level.
Cortisol and glucagon levels (both at baseline and during the clamp), in contrast, were unchanged.
Finally, Van Leeuwen et al. simulated a cumulative sleep restriction as it can occur during five
working days (4 h in bed), in healthy young men. Compared to 2 nights of 8 h in bed, morning
fasting glucose levels were unchanged after sleep loss, while morning fasting insulin concen-
trations were increased, indicating reduced SI. After 2 nights of recovery sleep (8 h in bed), fasting
glucose was lower than at baseline, while insulin returned to baseline levels, suggesting that the
effects of weekday sleep restriction may be reversed by recovery sleep on weekends. 34 Lastly, in
a study that did not intent to manipulate sleep duration but focused instead on the metabolic
consequences of circadian misalignment, by submitting healthy young volunteers to 28-h sleep/
wake cycles for 7 consecutive nights, sleep efficiency was reduced to 67% at the peak of circadian
misalignment (vs. 84% at baseline), and the glucose and insulin responses to breakfast were
increased.35
694 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

Sleep duration and appetite regulation

A large number of epidemiologic studies have demonstrated associations between short sleep and
higher BMI. One pathway linking short sleep to obesity is increased caloric intake in short sleepers. The
following section will present results from laboratory studies that have used TSD paradigms to
delineate the respective role of sleep and circadian rhythmicity in the 24-h pattern of hormones
involved in the neuroendocrine regulation of appetite, i.e. leptin and ghrelin. We then summarize the
results from a growing number of laboratory studies that have explored the effects of PSD on leptin,
ghrelin, caloric intake and weight gain. Table 2 summarizes the results of these studies.

Total sleep deprivation studies

Leptin, a hormone released by the adipocytes, provides information about energy status to regu-
latory centers in the hypothalamus.36 Circulating leptin levels in humans show a rapid decline or
increase in response to acute caloric shortage or surplus, respectively.37,38 These changes in leptin
concentrations have been associated with reciprocal changes in hunger.38 The 24-h leptin profile,
which is strongly dependent on meal intake, shows increasing levels during the daytime that culmi-
nate in a nocturnal maximum.39 Nevertheless, a study using an abrupt 8-h shift of bedtimes and
continuous enteral nutrition to eliminate the impact of meal intake demonstrated that leptin levels are
modulated by both sleep and circadian rhythmicity.40 Under these experimental conditions, a sleep-
related leptin elevation was apparent when sleep was allowed during the daytime after the night of
TSD, and a circadian-related leptin elevation was observed during the night of TSD. The stimulating
impact of sleep on leptin levels was also evidenced in a subsequent study that showed decreased
amplitude of the leptin diurnal variation during prolonged TSD.41
Ghrelin, a peptide produced predominantly by the stomach, is also involved in energy balance
regulation, but, in contrast to leptin, ghrelin stimulates appetite.42 The 24-h profile of ghrelin levels
shows a marked nocturnal rise which reflects at least partly the rebound of ghrelin following
suppression by the evening meal. The impact of TSD on the nocturnal ghrelin profile has been
examined in only one study and it was reported that the nocturnal ghrelin elevation is dampened when
subjects are sleep deprived.43
Recently, Schmid et al. reported that a night of TSD resulted in increased subjective hunger the
following morning.16 Leptin and ghrelin levels were not assessed in this study.

Partial sleep deprivation studies

In a randomized cross-over design study involving 2 nights of 4 h in bed vs. 2 nights of 10 h in bed,
the daytime profiles of leptin and ghrelin were assessed while the subjects completed validated scales
for hunger and appetite for various food categories.44 Overall leptin levels were decreased by 18%,
while ghrelin increased by 28%, and the ghrelin:leptin ratio increased by more than 70% when sleep
was restricted. Hunger showed a 23% increase and appetite for nutrients with high carbohydrate
content was increased by more than 30%. Importantly, these differences in appetite regulation between
the 2 bedtime conditions occurred despite identical amounts of caloric intake, similar sedentary
conditions, and stable weight. By comparison, in a study where caloric intake, rather than sleep
duration, was manipulated, 3 days of underfeeding by approximately 900 cal/day in healthy lean
volunteers resulted in a 22% decrease of leptin levels.38 Thus the decrease in leptin resulting from sleep
restriction appears to have functional significance. Indeed, if this increase in hunger during sleep
restriction were to translate into a commensurate increase in food intake, weight gain would be
expected to occur over time. In accordance with this hypothesis, anecdotal evidence for an increase in
food intake in subjects confined to the laboratory and permitted ad libitum access to food during 3 days
of TSD had already been reported in 1997.45 Since then, careful evaluations of food intake have been
performed in subjects submitted to PSD. In healthy young men, one night of 4 h in bed, in comparison
with one night of 8 h in bed, resulted in a 22% increase in caloric intake during the subsequent day.46
Similarly, preliminary data by Tasali et al. reported a 14% increase in caloric intake, particularly for
carbohydrate-rich nutrients, during an ad libitum buffet after 4 nights of 4.5 h in bed, compared to after
Table 2
Impact of total (upper panel) and partial sleep deprivation (lower panel) on appetite regulation.

Subjects Study conditions Changes with sleep deprivation

Time in bed Caloric intake Weight Leptin Ghrelin Hunger Caloric intake
Total sleep deprivation

L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702
Simon et al. 199840 7 men 8 h (23:00–7:00) 24 h continuous enteral nutrition n/a Z during n/a n/a n/a
21–25 yo vs. TSD followed by night
BMI 22.2  0.6 kg/m2 daytime 8 h (7:00–15:00)

Mullington et al. 200341 10 men 3  8 h þ recovery 3 meals þ optional 5 Z during n/a n/a n/a
22–37 yo vs. 88 h TSD evening snack/24 h night
BMI 20–34.5 kg/m2 vs. 4 meals þ optional
evening snack/24 h

Dzaja et al. 200443 10 men 10 h vs. TSD Matched standardized n/a n/a Z during n/a n/a
28  3 yo meals (1800 kcal/24 h) night
BMI 20.5–29.5 kg/m2

Schmid et al. 200716 10 men 1  7 h sleep No food from 21:00 to n/a n/a n/a \ n/a
20–40 yo vs. TSD hypoglycemic clamp
BMI 20.7–25 kg/m2

Partial sleep deprivation

Guilleminault 8 men 1  ad libitum Standardized diet n/a Z n/a n/a n/a
et al. 200354 18–25 yo þ 2  8.5 h
BMI 22.9  0.7 kg/m2 vs. 7  4 h

Spiegel et al. 200419 11 men 6  12 h Matched meals on 5 Z n/a n/a n/a

22  1 yo vs. 6  4 h the day preceding and
BMI 23.4  0.5 kg/m2 on the day of blood
sampling

Spiegel et al. 200444 12 men 2  10 h Matched dinner on the 5 Z \ \ n/a

22  2 yo vs. 2  4 h second night/Matched
BMI 23.6  2 kg/m2 glucose infusion during
blood sampling

Schmid et al. 200855 9 men 1  7 h sleep No food from 21:00 to n/a 5 \ \ n/a
20–40 yo vs. 1  4.5 h sleep single morning
BMI 20.7–25.0 kg/m2 vs. TSD blood draw

Bosy-Westphal 14 women 2  >8 h (9 h sleep) ad libitum diet prior to OGTT \ þ 0.4 kg \ 5 5 \ þ 20% by
et al. 200828 23–38 yo vs. 7 h, 6 h, 6 h, 4 h dietary records
BMI 20–36.6 kg/m2 (5.5 h sleep)

(continued on next page)

695
Table 2 (continued)

696
Subjects Study conditions Changes with sleep deprivation
Time in bed Caloric intake Weight Leptin Ghrelin Hunger Caloric intake
Schmid et al. 200931 10 men 1  7 h sleep No food from 21:00 to n/a n/a n/a 5 n/a
20–40 yo vs. 1  4.5 h sleep hypoglycemic clamp

L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702
BMI 20.7–25.0 kg/m2

Schmid et al. 200950 15 men 2  8 h 15 min Uncontrolled food intake n/a 5 5 5 \ 60% more
20–40 yo vs. 2  4 h 15 min until the morning than usual in
BMI 22.9  0.3 kg/m2 of the 2nd night when both sleep
blood sampling was conditions
initiated and ad libitum
food offered

Tasali et al. 200974 10 men and 4  8.5 h Matched meals/ad libitum 5 n/a n/a n/a \ during ad
women vs. 4  4.5 h buffet at the end libitum buffet
18–28 yo
BMI 20–25 kg/m2

Nedeltcheva et al. 200948 5 women, 6 men 14  8.5 h ad libitum diet/identical Similar \ 5 5 n/a \ snacks
34–49 yo vs. 14  5.5 h meals on the in both sleep
BMI 24–29 kg/m2 blood sampling day conditions

Brondel et al. 201046 12 men 14h Similar food intake n/a n/a n/a \ \
18–29 yo vs. 1  8 h the day before
BMI 19–24.6 kg/m2 sleep restriction.
Ad libitum food intake
after sleep restriction.

Omisade et al. 201052 15 women 2  10 h Matched meals n/a \ n/a 5 n/a

18–25 yo vs. 1  3 h
BMI 18.3–51.9 kg/m2

van Leeuwen et al. 201034 15 men 28h Matched meals and n/a \ n/a 5 n/a
19–29 yo vs. 5  4 h snacks/þone
BMI 23.3  2.7 kg/m2 more snack (fruit;
50 kcal) at
0:30 during sleep
restriction

Simpson et al. 201051 136 men and 2  10 h Ad libitum food access n/a \ n/a n/a n/a
women vs. 5  4 h
22–45 yo
BMI 17.7–32.6 kg/m2

TSD: Total sleep deprivation; OGTT: Oral Glucose Tolerance Test.

 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702 697

4 nights of 8.5 h in bed, in young healthy men and women.47 Of note, in the above studies, caloric intake
was identical under both sleep conditions prior to access to ad libitum food. In yet another study,28
when young women were exposed to an ad libitum diet during 2 bedtime conditions, i.e. 4 nights of
w5.5 h of sleep vs. 2 nights of w9 h of sleep, a 20% increase in self-reported food consumption was
observed in the sleep restriction condition and weight gain (þ0.4 kg) occurred.28 In overweight
middle-aged adults who had ad libitum access to palatable food during 2 weeks of sleep extension
(þ1.5 h/night) vs. 2 weeks of sleep restriction (1.5 h/night), an increase in snack consumption,
particularly in the evening, was observed in the short sleep condition.48 In this study, weight gain was
observed under both sleep conditions, a result somehow expected, as food intake is critically depen-
dent on the amount and palatability of food provided to the subject.49
Results obtained for the neuroendocrine regulation of appetite in studies providing ad libitum
access to food can seem contradictory at first sight. For instance, in the two studies that observed
increased food consumption and weight gain, ghrelin levels were unchanged48 and leptin levels were
either unchanged48 or increased28 by sleep restriction. However, as leptin levels are enhanced by food
intake and correlate with the degree of obesity,38 these endocrine results are the expected conse-
quence of the positive energy balance achieved by increased food intake and weight gain. Along the
same lines, daytime leptin, ghrelin, hunger and caloric intake were unchanged after 2 nights of 4 h vs. 3
nights of 8 h sleep in a study that proposed ad libitum highly palatable food 1 h after awakening under
both conditions. In this study, food intake was increased by 60% regardless of the bedtime condition.50
Similarly, a study that measured morning leptin levels in 136 healthy subjects (49% women, 56%
African Americans) after 2 nights of baseline sleep and after 5 subsequent nights of 4 h in bed, while
allowing free access to food, found increased leptin levels after sleep restriction, particularly in women
and in participants with elevated BMI.51
However, two studies observed increased, rather than decreased, morning leptin levels after sleep
restriction eventhough food intake was similar in both sleep conditions; sleep restriction did not result
in changes in hunger, appetite or satiety.34,52 Methodological differences may contribute to this
discrepancy. For example, in the study by van Leeuwen et al., a single assessment of satiety and leptin
levels was performed at 7:30 after 5 nights of 4 h in bed (bedtimes from 3:00 to 7:00) and after 5 nights
of habitual sleep (bedtimes from 23:00 to 7:00).34 As the nocturnal elevation in leptin levels is influ-
enced both by sleep and circadian rhythmicity,40 a shift towards the morning of the nocturnal elevation
of leptin levels may have occurred due to the shifted short bedtimes, resulting in higher morning leptin
levels. In the study by Omisade et al., bedtimes were restricted to 3 h for only one day and leptin levels
were measured only at 2 time points during daytime.52
Finally, a recent report described the impact of 2 nights of 5 h in bed on PYY, ghrelin, glucagon-like
peptide-1, adiponectin and leptin in young healthy males.53 Compared to a fully rested night (8–10 h in
bed), satiety was reduced and levels of PYY, an anorexigenic peptide produced by the gastro-intestinal
tract in response to food intake, were lower in the sleep loss condition. The other hormones were not
affected by the study conditions. Although sleep was not monitored and hormonal levels were assessed
at a single time point upon awakening, it is the first report of decreased PYY levels after sleep
restriction in humans, which could represent another mechanism underlying the reduced feeling of
satiety consistently reported by sleep-deprived individuals.
Lastly, young healthy men and women studied in a forced desynchrony protocol involving a 28-h
sleep-wake and dark-light cycle with 4 isocaloric meals exhibited lower leptin levels when they ate and
slept 12 h out of phase from their usual schedule.35 Although the relative contributions of circadian
misalignment and sleep loss in such a protocol can not be unequivocally dissected, sleep efficiency was
67% with circadian disruption, compared to 84% when circadian alignment occurred, suggesting that
sleep loss per se may contribute to lower leptin levels.
Evidence for a dose-response relationship between sleep duration and the neuroendocrine regu-
lation of appetite has also been obtained. In a study that assessed the 24-h leptin profiles after 6 days of
4-h, 8-h, and 12-h bedtimes in healthy lean young men under conditions of stable caloric intake and
activity levels, all characteristics of the 24-h leptin profile (overall mean, nocturnal maximum,
amplitude) gradually increased from the 4-h to the 12-h bedtime condition19 (Fig. 2; panel D). These
findings confirmed and extended the observations of an earlier study that assessed leptin levels at 6
time points of the 24-h cycle in volunteers studied after 7 days of 4-h bedtimes and reported a decrease
698 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

in peak leptin levels.54 A dose-response relationship between amounts of sleep, hunger ratings and
ghrelin levels was also reported in a study involving TSD, 4.5-h and 7-h bedtimes.55 In this study, which
involved only one night of manipulation of sleep duration, leptin levels were not affected.

Sleep duration and energy expenditure

Beside the changes in neurohormones involved in the regulation of food intake, reduced energy
expenditure (EE) during sleep loss could represent another mechanism contributing to the link
between short sleep and increased weight consistently reported in epidemiologic studies.
Relatively few studies have evaluated the impact of sleep restriction on EE. Bosy-Westphal et al.
studied 14 healthy lean and obese women after 4 nights of w5.5 h in bed, by indirect calorimetry;
compared to the rested condition (w9 h sleep for 2 nights), there was no change in resting EE, even
when adjusted for fat-free mass or total EE.28 In a protocol involving a more prolonged sleep restriction
(14 nights of 5.5 h vs. 14 nights of 8.5 h in bed) in healthy overweight subjects, total EE assessed by the
gold standard doubly labeled water method, resting metabolic rate assessed by indirect calorimetry,
and the thermic effect of food were not affected by the bedtime condition.48 To note, this study was
conducted under sedentary conditions and the results may have been different if the subject had been
allowed physical activity.
Subjects with sleep problems and/or excessive daytime sleepiness report a significant reduction in
their levels of physical activity,56,57 which could reduce activity-related EE. The only three studies that
examined the impact of behavioral sleep restriction on physical activity have yielded contradictory
results; the possible involvement of reduced activity-related EE in the link between short sleep and
increased obesity risk remains to be determined. In comparison with a rested night (7 to >8 h in bed),
Schmid et al. reported decreased physical activity after 2 nights of 4 h sleep,50 Brondel et al. observed
increased physical activity after one night of partial sleep deprivation46 and no change in physical
activity was documented by Bosy-Westphal et al. after 2 nights of 6 h in bed and 1 night of 4 h in bed.28
Thus, from evidence obtained so far, it appears that short sleep affects energy balance because of an
up-regulation of orexigenic hormones and a down-regulation of anorexigenic hormones associated
with increased hunger and caloric intake, rather than because of a reduced EE.

Pathways linking sleep loss and increased risk of diabetes and obesity

Multiple pathways are likely to mediate the adverse effect of sleep loss on the risk of obesity and
diabetes. Several of these pathways interact with one another. An up-regulation of the activity of orexin
neurons may be a primary mechanism linking sleep deprivation and adverse metabolic effects.4,5
Another important mechanism, considering that brain is a major user of glucose, is brain glucose
utilization, which appears to be reduced after sleep deprivation, as shown by PET studies.58
Fig. 2 illustrates the fact that sleep duration affects multiple facets of normal human physiology. The
24-h profiles of HOMA, cortisol, GH, leptin and cardiac sympathovagal balance observed in normal
young men are shown after 6 days of 4 h, 8 h and 12 h in bed. For all these variables, clear changes are
observed in a dose-response relationship with sleep duration. HOMA levels post-breakfast increased
from the 12-h to the 4-h in bed condition indicating a decrease in glucose tolerance and/or a decrease
in SI proportional to the severity of sleep loss (Fig. 2; panel A). Changes in the activity of the autonomic
nervous system and of counterregulatory hormones may play a role in these alterations (Fig. 2; panels
B, C, and E). Panel E of Fig. 2 shows progressive higher values of the coefficient of autocorrelation of
successive beat-to-beat intervals (rRR) with increasing amounts of sleep loss, reflecting lower levels of
heart rate variability due to an elevation of cardiac sympathetic activity and/or a decrease in para-
sympathetic activity.59–61 Sympathetic activation inhibits, and parasympathetic activation stimulates,
insulin release; the lack of compensatory hyperinsulinemia in response to the reduced SI associated
with sleep loss may therefore be related to an alteration of the autonomic regulation of the beta-cells.
In addition, sleep loss-related changes in counterregulatory hormones (increased evening cortisol
levels,19,62 extended duration of daytime elevated GH concentrations,18 and elevated ghrelin levels)
also favor glucose intolerance and hyperinsulinemia63,64 (Fig. 2; panels B and C).
 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702 699

Sleep loss also impacts hormones involved in appetite regulation, in the direction of promotion of
food intake. For instance, Panel D of Fig. 2 shows that all characteristics of the 24-h leptin profile
(overall mean, nocturnal maximum, amplitude) gradually increased from the 4-h to the 12-h bedtime,
signaling the brain an unnecessary need for extra caloric intake in a state of sleep debt. Since leptin
secretion is inhibited by sympathetic activity65 and ghrelin secretion is inhibited by parasympathetic
activity,66 the changes in the activity of autonomic nervous system observed with sleep loss may be
involved in the simultaneous reduction of leptin and increase of ghrelin. Furthermore, insulin and
leptin appear to negatively modulate the food rewarding system,67 whereas ghrelin exerts opposite
effects68; the changes in these hormonal concentrations following sleep restriction could therefore
contribute to the increased hedonic, rather than homeostatic, eating, that may be typical of short
sleepers. In addition, the increased opportunity to eat, due to longer waking time, probably also plays
a role in the generation of a positive energy balance in short sleepers. Reduced EE is to date a poorly
explored pathway that could also link short sleep and the risk of overweight and obesity. Sleep loss is
associated with sleepiness and fatigue that may result in reduced EE through decreased physical
exercise but also through decreases in non-exercise activity thermogenesis.
Furthermore, sleep loss is associated with increased levels of proinflammatory cytokines and low-
grade inflammation (reviewed in chapter 9 “Sleep loss and inflammation”), a condition that may
predispose to insulin69–71 and leptin resistance.72
Finally, obesity is in itself a major risk factor for diabetes mellitus and has been shown to be crucial
in the pathogenesis of sleep-disordered breathing (SDB), a reported independent risk factor for insulin
resistance.73 The detrimental effects of sleep loss are likely to be exacerbated in overweight and obese
individuals.

Summary

Sleep curtailment has become a common behavior in modern society. This review summarizes the
current laboratory evidence indicating that recurrent sleep restriction is associated with a constellation
of metabolic and endocrine consequences that may contribute to the pathophysiology of obesity and
diabetes mellitus. Recommending sufficient amounts of habitual sleep in these patients may therefore
be of great importance. Intervention studies are warranted to determine if strategies aiming at
increasing sleep duration in short sleepers with metabolic alterations have the potential of improving
glucose metabolism and appetite regulation.

Research agenda

 The impact of sleep loss in children, in older adults and in patients with metabolic and
endocrine disorders needs to be documented
 Studies are warranted to evaluate the putative therapeutic impact of bedtime extension in
habitual short sleepers with metabolic conditions

Practice points

 Due to the deleterious impact of short sleep on glucose metabolism and appetite regulation,
habitual sleep patterns and sleep disorders should be routinely assessed in clinical practice
 If sleep-disordered breathing (SDB) is present in obese or diabetic patients, treat with
continuous positive airway pressure (CPAP)
 Obtain measures of sleep duration and quality on the night preceding diabetes screening
 Monitor and ensure adequate sleep duration in weight loss programs
700 L. Morselli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 687–702

Conflict of interest

The authors have no conflict of interest.

Acknowledgments

Some of the research described in this article was supported by US National Institute of Health
grants P01 AG-11412, U54 RR023560, P60 DK-20595, R01 DK-0716960, R01 HL-075025 and P50-
HD057796, by US Department of Defense award W81XWH-07-2-0071, by Belgian “CARE Foundation”
grants, by INSERM U628, and by Claude Bernard University of Lyon, France.

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