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Sleep Loss Alters Basal Metabolic Hormone Secretion and Modulates the Dynamic Counterregulatory Response to Hypoglycemia

Departments of Internal Medicine I (S.M.S., K.J.-C., N.B., B.S.) and Neuroendocrinology (M.H., J.B.), University of Luebeck, D-23538 Luebeck, Germany; and Interdisciplinary Obesity Center Eastern Switzerland (B.S.), Kantonsspital St. Gallen, CH-9400 Rorschach, Switzerland

Address all correspondence and requests for reprints to: Bernd Schultes, M.D., Interdisciplinary Obesity Center Eastern Switzerland, Kantonsspital St. Gallen, CH-9400 Rorschach, Switzerland. E-mail: schultes{at}kfg.uni-luebeck.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Sleep loss has immediate effects on metabolic function that in the long run may contribute to the development of obesity and type 2 diabetes.

Objective: Our objective was to explore the neuroendocrine mechanisms mediating the acute effects of sleep deprivation on blood glucose regulation under basal and hypoglycemic conditions.

Methods: In a randomized, crossover study in 10 healthy young men, plasma concentrations of relevant hormones were examined during basal rest, a subsequent stepwise hypoglycemic clamp after one night of total sleep deprivation (SD) and one night of regular sleep.

Results: Basal glucagon concentrations were decreased (P = 0.022) and C-peptide levels were slightly reduced after SD (P = 0.085), compared with regular sleep. During hypoglycemia after SD, the glucagon increase relative to baseline was enhanced (P = 0.034) and the relative decrease in C-peptide was reduced (P = 0.013). Also, the relative increase in norepinephrine was reduced (P = 0.031). SD did not affect epinephrine, ACTH, cortisol, lactate, ß-hydroxybutyrate, or nonesterified fatty acids during hypoglycemia, but overall, plasma nonesterified fatty acid levels were reduced after SD (P = 0.009). SD markedly increased rated hunger during basal rest (P < 0.008), resulting in a dampened relative increase during hypoglycemia (P < 0.009). Unexpectedly, despite distinct alterations in basal secretory activity, the absolute amplitude of hormonal counterregulation and hunger responses to hypoglycemia was not affected by SD.

Conclusion: Short-term SD distinctly alters hormonal glucose regulation, affecting especially pancreatic islet secretion, and also increases hunger. Immediate perturbations in the dynamic regulation of energy metabolism caused by acute sleep curtailment may contribute to the association between chronic sleep loss and metabolic disorders.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A GROWING BODY of data indicates that sleep considerably impacts the regulation of glucose metabolism (1, 2). Epidemiological studies (3, 4, 5, 6, 7, 8) suggest that a chronic sleep deficit can promote the development of type 2 diabetes. Experimental attempts to enlighten the causality of this relationship are still rare. A most compelling study on this issue was performed by Spiegel et al. (9) in healthy young men. In these experiments, a limitation of sleep to 4 h per night for 6 consecutive days markedly impaired glucose tolerance. The effect was accompanied by increased activity of the sympathetic nervous system and by increased evening plasma cortisol levels, suggesting a neuroendocrine mediation of the detrimental influence of sleep loss on glucose metabolism.

Beside its activating influence on neuroendocrine stress systems, sleep loss may affect glucose regulation by influencing cerebral glucose utilization and storage. Sleep, and especially slow wave sleep, i.e. the deepest form of non-rapid eye movement sleep, represents a state when the brain’s glucose demand is at a minimum (10, 11). Although data are not unequivocal (12), it has been proposed that brain glucose stores, in the form of astrocytic glycogen, are replenished during sleep (13, 14). Sleep loss characterized by a wake-associated globally increased energy demand may thus prevent replenishment and induce further depletion of energy stores. Accordingly, sleep loss is expected to promote neuroendocrine regulation toward hyperglycemia, thereby enhancing the supply of glucose to the brain via the bloodstream (15). Specifically, availability of blood glucose to the brain can be enhanced by reducing the release of insulin and increasing the release of glucagon and neuroendocrine stress hormones such as cortisol and catecholamines (16). In addition to these neuroendocrine adaptive processes, increases in hunger and food intake after sleep loss may serve to ensure sufficient energy supply to the brain (17). Such hormonal and behavioral responses to sleep loss may not only occur during basal rest conditions but might be particularly pronounced when the organism is challenged by additional metabolic stress such as hypoglycemia enforcing acute counterregulation.

Based on the assumption that sleep loss depletes brain glycogen stores and aggravates neuroglycopenia, we hypothesized that depriving subjects of sleep during a single night enhances basal activity of metabolic neuroendocrine systems as well as the counterregulatory response to hypoglycemia on the following day. To test this hypothesis, 10 healthy men were tested during a baseline period and a subsequent stepwise hypoglycemic clamp after one night of total sleep deprivation (SD) or a control night with 7 h of regular sleep.

	Subjects and Methods

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Subjects

We studied 10 healthy young men aged 20–40 yr (mean ± SEM, 25.3 ± 1.4 yr) with a mean body mass index between 20.7 and 25.0 kg/m² (23.8 ± 0.5 kg/m²). All subjects had a regular sleep-wake cycle during the last 4 wk before the experiment. Exclusion criteria were chronic or acute illness, current medication of any kind, smoking, alcohol or drug abuse, obesity, and diabetes in first-degree relatives. The study protocol was approved by the ethics committee of the University of Luebeck, and all participants gave written informed consent.

Study design and procedure

Participants were tested after a night of total SD and after a night with 7 h regular sleep. Conditions were spaced at least 2 wk apart and performed in a randomized and balanced order. After each night, subjects were exposed to a stepwise hypoglycemic clamp experiment performed as described below. Results of an additional experimental condition including partial SD (4.5 h sleep) are not reported because this condition essentially yielded intermediate effects that appear to be of minor relevance.

Participants arrived at the research unit at 2100 h. Before arriving, subjects had eaten a light dinner, and after 2100 h they were allowed to drink only water. After preparation of polysomnographic recordings participants went to bed. In the regular sleep condition, lights were turned off at 2200 h and subjects were allowed to sleep until 0600 h with concomitant polysomnographic sleep recordings that were scored offline according to standard criteria (18). During the SD condition, subjects were allowed to read and watch movies in a sitting position, whereas brisk physical activities and food intake were not allowed, and participants were monitored by the experimenter throughout the night. In the morning after both SD and regular sleep, participants went outside the building for a standardized 5-min walk in the company of an experimenter. Subsequently, preparations for the hypoglycemic clamp started (0630 h) with the subjects again sitting on the bed.

Hypoglycemic clamp procedure

The stepwise hypoglycemic clamp procedure followed a standardized protocol previously described in detail (19). Briefly, after a 30-min baseline period starting at 0700 h, a bolus of 0.01 IU/kg body weight human insulin (Insuman Rapid; Aventis, Strasbourg, France) was given over 2 min. Thereafter, insulin was infused at a constant rate of 1.8 mIU/kg body weight·min. A 20% dextrose solution was simultaneously infused at a variable rate to control blood glucose levels. Arterialized blood was drawn at 5-min intervals to measure blood glucose concentration (HemoCue B-Glucose-Analyzer; Ángelholm, Sweden). Blood glucose levels were reduced in a stepwise fashion to achieve four plateaus of 75, 65, 55, and 45 mg/dl (4.2, 3.6, 3.1, and 2.5 mmol/liter), respectively. Each plateau was maintained for a 30-min period with the next lower plateau gradually induced within the subsequent 30 min.

Blood samples were drawn twice during baseline and at the beginning and end of each hypoglycemic plateau. Insulin, C-peptide, glucagon, ACTH, cortisol, and GH were measured by ELISA, nonestified fatty acid (NEFA) concentrations were measured by enzymatic assays, and plasma catecholamines were measured by standard HPLC as previously described (20, 21). Plasma ß-hydroxybutyrate and lactate concentrations were measured by commercial enzymatic assays (Randox Laboratories Ltd., Antrim, UK, and Abbott, Wiesbaden, Germany) with the following intra- and interassay coefficients of variation: ß-hydroxybutyrate, less than 1.4%; lactate, less than 1.3% and less than 1.7%. Limit of sensitivity was 0.1 mmol/liter and 0.005 mg/dl, respectively. Subjective responses to hypoglycemia were assessed at the beginning and end of each hypoglycemic plateau by standard questionnaire (22). Subjects rated from 0 (not at all) to 9 (severely) on the following 11 symptoms: dizziness, tingling, blurred vision, difficulty in thinking, faintness, anxiety, palpitation, hunger, sweating, irritability, and tremor. Consistent with categories used by previous investigators (23), the first five symptoms are considered neuroglycopenic and the latter six autonomic symptoms.

Statistical analyses

Values are expressed as mean ± SEM. Analyses were generally based on ANOVA for repeated measures, including the factors sleep (for regular sleep vs. SD) and hypo (for the repeated measurements during the clamps). Baseline values were compared using Student’s t tests. To compare changes of hormone levels and symptom scores between conditions during the clamp with respect to potential baseline differences, data were transformed to relative changes from baseline (as percentage) and then included in the ANOVA models. A P value < 0.05 was considered significant. All calculations were done with SPSS 12.0 for Windows.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sleep, blood glucose, insulin, and dextrose infusion rates

On the regular sleep condition, subjects slept on average 423 ± 11 min (range, 374–462 min), whereas they stayed completely awake on the SD condition. During baseline, blood glucose levels were similar after SD and regular sleep [82 ± 3 mg/dl (4.6 ± 0.2 mmol/liter) vs. 85 ± 2 mg/dl (4.7 ± 0.1 mmol/liter), P = 0.22]. Basal serum insulin levels were likewise not affected [6.5 ± 1.0 µU/ml (39.1 ± 5.7 pmol/liter) vs. 6.7 ± 1.6 µU/ml (40.4 ± 9.8 pmol/liter), P = 0.88]. During the hypoglycemic clamp, the stepwise decrease in glucose levels was very similar in the two study conditions (Fig. 1A). As expected, serum insulin levels markedly increased during the hypoglycemic clamp without significant difference between conditions (P = 0.77; Fig. 1B). As shown in Fig. 1C, dextrose infusion rates required to achieve target glucose levels during the hypoglycemic clamp also did not differ between conditions. Thus, the total amount of dextrose infused during the clamp was almost identical between the SD and the regular sleep condition (131 ± 17 vs. 128 ± 11 g; P = 0.85).

View larger version (9K): [in this window] [in a new window]   FIG. 1. Mean ± SEM concentrations of blood glucose (A), serum insulin (B), and glucose infusion rate (C) during a 30-min baseline period and the subsequent 240-min stepwise hypoglycemic clamp. The clamps were performed in 10 healthy men after a night of regular (7 h) sleep () and after one night with SD (•). Target blood glucose plateaus were 4.2 mmol/liter (30–60 min), 3.6 mmol/liter (90–120 min), 3.1 mmol/liter (150–180 min), and 2.5 mmol/liter (210–140 min). (To convert values for blood glucose to mg/dl, multiply by 18.01; to convert values for insulin to µU/ml, multiply by 0.167.)

During baseline, C-peptide levels tended to be lower after SD than after regular sleep [1.03 ± 0.15 ng/ml (0.34 ± 0.04 nmol/liter) vs. 1.42 ± 0.21 ng/ml (0.47 ± 0.07 nmol/liter), P = 0.085; Fig. 2A]. Here, due to the relatively large interindividual variability in insulin levels, the C-peptide/insulin ratio, reflecting hepatic insulin clearance (24, 25), did not differ between the two conditions (10.5 ± 1.4 vs. 11.7 ± 2.2, P = 0.68). During the hypoglycemic clamp, C-peptide levels decreased (P = 0.005), with this decrease being distinctly less pronounced after SD than after regular sleep (P = 0.013 for the sleep x hypo interaction; Fig. 2A).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Mean ± SEM concentrations of plasma C-peptide (A) and plasma glucagon (B) during a 30-min baseline period and the subsequent 240-min stepwise hypoglycemic clamp. A' and B' show relative changes during the clamp with regard to respective baseline values. The clamps were performed in 10 healthy men after a night of 7 h sleep () and after one night with SD (•). (To convert values for C-peptide to ng/ml, multiply by 3.021; to convert values for glucagon to pg/ml, multiply by 1.0.)

Epinephrine, norepinephrine, ACTH, cortisol, and GH

Overall, there was no influence of SD on plasma epinephrine or norepinephrine concentrations during baseline and hypoglycemia (all P > 0.10; Fig. 3, A and B). However, baseline adjustment of the data revealed a reduced norepinephrine response to hypoglycemia after SD (P = 0.031 for the interaction sleep x hypo; Fig. 3B'). Although basal ACTH levels were similar after SD and regular sleep [44.5 ± 13.6 pg/ml (9.8 ± 3.0 pmol/liter) vs. 42.2 ± 7.3 pg/ml (9.3 ± 1.6 pmol/liter); P = 0.84; Fig. 3C], cortisol concentrations were significantly reduced after SD (18.24 ± 1.19 µg/dl (503 ± 33 mmol/liter) vs. 21.82 ± 1.54 µg/dl (602 ± 43 mmol/liter), P = 0.048; Fig. 3D]. ACTH and cortisol responses to hypoglycemia were not affected by SD (both P > 0.43 for the interaction sleep x hypo; Fig. 3, C' and D')

View larger version (16K): [in this window] [in a new window]   FIG. 3. A–E, Mean ± SEM concentrations of plasma epinephrine (A), plasma norepinephrine (B), plasma ACTH (C), serum cortisol (D), and serum GH (E) during a 30-min baseline period and the subsequent 240-min stepwise hypoglycemic clamp; A'–E', responses to hypoglycemia expressed as changes relative to baseline. The clamps were performed in 10 healthy men after a night of regular (7 h) sleep () and after one night with SD (•). (To convert values for epinephrine to pg/ml, multiply by 0.183; to convert values for norepinephrine to pg/ml, multiply by 169.18; to convert values for ACTH to pg/ml, multiply by 4.54; to convert values for cortisol to µg/dl, multiply by 0.0362; to convert values for GH to ng/ml, multiply by 1.0.)

Lactate, NEFA, and ß-hydroxybutyrate

Figure 4 shows the plasma levels of lactate, NEFA, and ß-hydroxybutyrate at baseline and at the end of the hypoglycemic clamp. SD had no effect on basal plasma lactate levels (0.99 ± 0.11 vs. 1.19 ± 0.15 mmol/liter, P = 0.27). During hypoglycemia, lactate levels increased (P = 0.004) with no difference between conditions (P = 0.19 for the interaction sleep x hypo; Fig. 4A). Also, SD had no significant effect on basal ß-hydroxybutyrate levels [0.87 ± 0.21 mg/dl (84.0 ± 20.3 µmol/liter) vs. 1.60 ± 0.63 mg/dl (153.9 ± 60.7 µmol/liter); P = 0.33]. During hypoglycemia, ß-hydroxybutyrate levels decreased (P = 0.015 for the main effect hypo) in both conditions (P = 0.41 for the interaction sleep x hypo; P = 0.26 for the main effect sleep). Pairwise comparison of ß-hydroxybutyrate levels at the end of the hypoglycemic clamp revealed significantly lower levels in the SD than regular sleep condition [0.31 ± 0.03 mg/dl (29.8 ± 3.1 µmol/liter) vs. 0.47 ± 0.06 mg/dl (44.7 ± 5.7 µmol/liter), P = 0.013; Fig. 4B]. Overall, NEFA levels were significantly lower after SD than regular sleep (P = 0.009 for the main effect sleep), with this difference reaching significance at the end of the hypoglycemic clamp (Fig. 4C). During hypoglycemia, NEFA levels generally decreased (P = 0.002), with the extent of this decrease being similar in both conditions (P = 0.77 for the interaction term sleep x hypo).

View larger version (7K): [in this window] [in a new window]   FIG. 4. Mean ± SEM concentrations of lactate (A), ß-hydroxybutyrate (B), and NEFA (C) during a 30-min baseline period and at the end of a subsequent 240-min stepwise hypoglycemic clamp (hypo). The clamps were performed in 10 healthy men after a night of regular (7 h) sleep (white bars) and after one night with SD (black bars). (To convert values for lactate to mEq/liter, multiply by 1.0.)

The pooled autonomic symptoms score during the baseline period tended to be higher after SD than after regular sleep (7.0 ± 1.1 vs. 4.6 ± 1.4; P = 0.084; Fig. 5A). However, the respective increase during hypoglycemia (P = 0.022 for the main effect hypo) was not affected by SD (P = 0.65 for the interaction term sleep x hypo; Fig. 5A'). The pooled neuroglycopenic symptoms score was higher after SD than regular sleep at baseline (6.8 ± 1.2 vs. 4.6 ± 1.0, P = 0.032), with this difference persisting throughout the hypoglycemic clamp (P = 0.008 for the main effect sleep, P = 0.61 for the interaction term sleep x hypo; Fig. 5, B and B'), which in both conditions was accompanied by a trend toward enhanced neuroglycopenic symptom perception (P = 0.097 for the main effect hypo).

View larger version (17K): [in this window] [in a new window]   FIG. 5. A–D, Mean ± SEM scores of autonomic symptoms (A), neuroglycopenic symptoms (B), feelings of hunger (C), and fatigue (D) during a 30-min baseline period and the subsequent 240-min stepwise hypoglycemic clamp; A'–D', responses to hypoglycemia expressed as difference values with regard to baseline levels. The clamps were performed in 10 healthy men after a night of regular (7 h) sleep () and after one night with SD (•).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We assessed the influence of one night of SD on basal morning secretory activity of glucose regulatory neuroendocrine systems as well as on the counterregulatory hormonal response to hypoglycemia in healthy men. We hypothesized that due to increased metabolic demands during extended periods of wakefulness, SD stimulates neuroendocrine stress systems that mobilize glucose and thereby ensure energy supply to the brain via the circulation. However, the observed alterations in different hormone levels after SD do not concur with this hypothesis. SD significantly decreased basal glucagon and tended to reduce basal C-peptide levels. Basal cortisol levels were even lower after SD than after awakening from regular sleep. Basal glucose, insulin, ACTH, catecholamines, lactate, ß-hydroxybutyrate, and NEFA levels remained unaffected by SD. Although relative counterregulatory responses of glucagon and GH to hypoglycemia were increased after SD, relative C-peptide and norepinephrine responses were reduced. After SD, subjects reported distinctly more hunger and fatigue, but the relative increase in rated hunger during hypoglycemia was reduced by SD. Contrary to our expectations absolute amplitudes of hormonal and hunger responses to hypoglycemia were not changed after SD. Although the present results in sum do not support our initial hypothesis of an increased activity of neuroendocrine stress systems after SD, the observed endocrine, metabolic, and neurocognitive effects of SD shed new light on the regulatory influence of sleep on metabolic functions by pointing toward a particular sensitivity of pancreatic islet secretion to the immediate effect of SD.

A most remarkable finding of our study is the clear-cut reduction of glucagon levels after SD. The release of this hormone by the pancreatic -cells is well known to depend on endocrine and neuronal signals primarily related to energy homeostasis (26). To the best of our knowledge, this is the first observation indicating a dependence of glucagon release on prior sleep. As a consequence of lowered basal glucagon levels, the relative counterregulatory response to hypoglycemia was enhanced after SD. This finding is particularly surprising in conjunction with the attenuated decrease in C-peptide levels during hypoglycemia, which reflects that the suppression of endogenous insulin secretion is reduced. Because the acute reduction in ß-cell insulin secretion during hypoglycemia is a crucial signal for counterregulatory -cell glucagon release (27, 28, 29, 30), glucagon levels should be expected to be attenuated rather than enhanced in the presence of markedly elevated C-peptide levels during hypoglycemia. Hence, our data point to a differential influence of SD on - and ß-cell secretory activity and presumably also on the interplay between both cell types. Whether this surprising effect of sleep loss on pancreatic islet functions is established via autonomic nervous system pathways or relies on other mediators remains to be investigated.

Contrary to expectations, SD exerted only weak influences on the activity of neuroendocrine stress systems, i.e. the sympathico-adrenal system and the hypothalamic-pituitary-adrenal axis. Rather than being increased, basal cortisol levels were reduced after SD. In this context, it has to be considered that in the regular sleep condition, the first cortisol sample was collected approximately 30 min after awakening. Because awakening is tightly associated with a strong rise in circulating cortisol levels (31, 32), reduced basal cortisol levels after SD most probably reflect the missing sleep-wake transition, i.e. there was no awakening in this condition. Norepinephrine levels showed a slightly attenuated response to hypoglycemia after SD. However, absolute levels at the end of the hypoglycemic clamp were comparable between conditions (Fig. 3B), suggesting that the diminished response was largely due to the slightly elevated (P = 0.10) baseline levels after SD. At first glance, our findings revealing essentially similar activity of the neuroendocrine stress systems after SD are at odds with those of previous studies indicating increased neuroendocrine stress system activity (9, 33, 34). However, in contrast with these studies, in our experiments, the neuroendocrine stress response was not assessed in the evening but in the morning when effects of sleep loss may not have fully developed. Also, our data do not rule out that sleep restriction for a longer period might amplify counterregulatory activity. Despite these limitations, the present data suggest that the hypothalamic-pituitary-adrenal response to a strong stressor like hypoglycemia is regulated by mechanisms independent of slight fluctuations in the basal tone. It is well known that a modulation of baseline activity of the stress systems is not obligatorily linked to changes in the acute response to strong stressors (35, 36). Short-term sleep loss appears to be a metabolic stressor strong enough to modulate the basal tone, but its effects become blurred if a strong stressor calls for an immediate response, as in the case of an imminent lack of brain energy supply during hypoglycemia.

Effects of SD on lactate, NEFA, and ß-hydroxybutyrate have so far not been investigated. Lactate levels in general as well as basal levels of NEFA and ß-hydroxybutyrate were not affected by SD, but there was a reduction of NEFA levels in response to hypoglycemia after SD. Plasma ß-hydroxybutyrate levels revealed a comparable, although less pronounced, pattern. This result may be taken as an indication that already decreased lipolysis after SD is further promoted by hypoglycemia. Alternatively, hypoglycemia after SD might trigger increased utilization of lipolytic products. Clearly, these observations are in need of further investigation.

The distinct increase in rated hunger assessed after SD, unlike the hormonal changes, is in line with the view of central nervous energy depletion after sleep loss that has to be compensated for by increased food intake. This finding also fits well with previous observations by Spiegel and co-workers (17) of increased hunger and appetite in healthy men after sleep curtailment during two nights. Notably, although absolute values in response to hypoglycemia reached the same level, the relative increase in rated hunger during the clamp period was flattened after SD. This finding may be of clinical relevance, assuming that it also pertains to diabetic patients who are at high risk of severe hypoglycemia episodes (37). Hunger represents an important warning signal of emerging hypoglycemia, eliciting food intake that counteracts a further decline in circulating glucose levels. A reduced ability to adequately perceive hypoglycemia-triggered increases in hunger that add to the orexigenic impact of sleep loss per se might thus elevate the risk of severe hypoglycemia in these patients under conditions of sleep debt.

In sum, the present data show distinct alterations in metabolic endocrine signaling and feelings of hunger due to short-term sleep loss that are particularly manifest under basal rest conditions. Although maximal neuroendocrine responses to hypoglycemia are not affected, relative changes with regard to baseline levels are likewise modulated by SD. Contrasting with the minor changes in activity of neuroendocrine stress system after SD, our results reveal a particular sensitivity of glucagon secretion to sleep loss that has not been scrutinized in previous studies. The physiological significance of our findings and their relationship to the interplay between chronic sleep debt and metabolic disorders like obesity and type 2 diabetes remain to be established. However, our results strongly support the notion that sleep plays a pivotal role in the regulation of metabolic functions in humans.

	Acknowledgments

 
We are grateful to Christiane Otten and Ingrid von Lützau for their expert and invaluable laboratory assistance.

	Footnotes

 
Experiments were supported by the Deutsche Forschungsgemeinschaft (SFB–654 Plasticity and Sleep).

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 22, 2007

Abbreviations: NEFA, Nonesterified fatty acid; SD, sleep deprivation.

Received December 18, 2006.

Accepted May 11, 2007.

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