A meta-analysis of the associations between insufficient sleep duration and antibody response to vaccination.

Vaccination is a major strategy to control a viral pandemic. Simple behavioral interventions that might boost vaccine responses have yet to be identified. We conducted meta-analyses to summarize the evidence linking the amount of sleep obtained in the days surrounding vaccination to antibody response in healthy adults. Authors of the included studies provided the information needed to accurately estimate the pooled effect size (ES) and 95% confidence intervals (95% CI) and to examine sex differences.1,2,3,4,5,6,7 The association between self-reported short sleep (<6 h/night) and reduced vaccine response did not reach our pre-defined statistical significant criteria (total n = 504, ages 18-85; overall ES [95% CI] = 0.29 [-0.04, 0.63]). Objectively assessed short sleep was associated with a robust decrease in antibody response (total n = 304, ages 18-60; overall ES [95% CI] = 0.79 [0.40, 1.18]). In men, the pooled ES was large (overall ES [95% CI] = 0.93 [0.54, 1.33]), whereas it did not reach significance in women (overall ES [95% CI] = 0.42 [-0.49, 1.32]). These results provide evidence that insufficient sleep duration substantially decreases the response to anti-viral vaccination and suggests that achieving adequate amount of sleep during the days surrounding vaccination may enhance and prolong the humoral response. Large-scale well-controlled studies are urgently needed to define (1) the window of time around inoculation when optimizing sleep duration is most beneficial, (2) the causes of the sex disparity in the impact of sleep on the response, and (3) the amount of sleep needed to protect the response.

Transportation noise impairs cardiovascular function without altering sleep: The importance of autonomic arousals.

AIMS: Chronic exposure to nocturnal transportation noise has been linked to cardiovascular disorders with sleep impairment as the main mediator. Here we examined whether nocturnal transportation noise affects the main stress pathways, and whether it relates to changes in the macro and micro structure of sleep. METHODS AND RESULTS: Twenty-six young healthy participants (12 women, 24.6 ± 0.7 years, mean ± SE) spent five consecutive 24-h days and one last morning in the laboratory. The first (baseline) and last (recovery) nights comprised a quiet ambient scenario. In-between, four different noise scenarios (low/medium/high intermittent road or rail scenarios with an identical equivalent continuous sound level of 45 dB) were randomly presented during the 8-h nights. Participants felt more annoyed from the transportation noise scenarios compared to the quiet ambient scenario played back during the baseline and recovery nights (F5,117 = 10.2, p < 0.001). Nocturnal transportation noise did not significantly impact polysomnographically assessed sleep macrostructure, blood pressure, nocturnal catecholamine levels and morning cytokine levels. Evening cortisol levels increased after sleeping with highly intermittent road noise compared to baseline (p = 0.002, noise effect: F4,83 = 4.0, p = 0.005), a result related to increased cumulative duration of autonomic arousals during the noise nights (F5,106 = 3.4, p < 0.001; correlation: rpearson = 0.64, p = 0.006). CONCLUSION: Under controlled laboratory conditions, highly intermittent nocturnal road noise exposure at 45 dB increased the cumulative duration of autonomic arousals during sleep and next-day evening cortisol levels. Our results indicate that, without impairing sleep macrostructure, nocturnal transportation noise of 45 dB is a physiological stressor that affects the hypothalamic-pituitary-adrenal axis during the following day in healthy young good sleepers.

Adverse impact of nocturnal transportation noise on glucose regulation in healthy young adults: Effect of different noise scenarios.

BACKGROUND: Epidemiological evidence indicates an association between transportation noise exposure and a higher risk of developing type 2 diabetes. Sleep disturbances are thought to be one of the mechanisms as it is well established that a few nights of short or poor sleep impair glucose tolerance and insulin sensitivity in healthy good sleepers. OBJECTIVES: The present study aimed to determine the extent to which exposure to nocturnal transportation noise affects glucose metabolism, and whether it is related to noise-induced sleep alterations. METHODS: Twenty-one young healthy volunteers (nine women) participated in a six-day laboratory study starting with a noise-free baseline night, then four nights sleeping with randomly-presented transportation noise scenarios (three road and one railway noise scenario) with identical average sound level of 45dB but differing in eventfulness and ending with a noise-free recovery night. Sleep was measured by polysomnography. Glucose tolerance and insulin sensitivity were measured after the baseline, the last noise night and the recovery nights with an oral glucose tolerance test using Matsuda and Stumvoll insulin sensitivity indexes. Eleven participants were assigned a less eventful noise scenario during the last noise night (LE-group), while the other ten had a more eventful noise scenario (ME-group). Baseline metabolic and sleep variables between the two intervention groups were compared using a non-parametric Mann-Whitney U test while mixed models were used for repeated measure analysis. RESULTS: All participants had increased glucoseAUC (mean±SE, 14±2%, p<0.0001) and insulinAUC (55±10%, p<0.0001) after the last noise night compared to the baseline night. 2h-glucose level tended to increase only in the ME-group between baseline (5.1±0.22mmol·L-1) and the last noise night (6.1±0.39mmol·L-1, condition: p=0.001, interaction: p=0.08). Insulin sensitivity assessed with Matsuda and Stumvoll indexes respectively decreased by 7±8% (p=0.001) and 9±2% (p<0.0001) after four nights with transportation noise. Only participants in the LE-group showed beneficial effects of the noise-free recovery night on glucose regulation (relative change to baseline: glucoseAUC: 1±2%, p=1.0 for LE-group and 18±4%, p<0.0001 for ME-group; Stumvoll index: 3.2±2.6%, p=1.0 for LE-group and 11±2.5%, p=0.002 for ME-group). Sleep was mildly impaired with increased sleep latency of 8±2min (<0.0001) and more cortical arousals per hour of sleep (1.8±0.6arousals/h, p=0.01) during the last noise night compared to baseline. No significant associations between sleep measures and glucose tolerance and insulin sensitivity were found. CONCLUSION: In line with epidemiological findings, sleeping four nights with transportation noise impaired glucose tolerance and insulin sensitivity. Based on the presented sound exposure, the eventfulness of the noise scenarios seems to play an important role for noise-induced alterations in glucose regulation. However, we could not confirm our hypothesis that transportation noise impairs glucose regulation via deterioration in sleep quality and quantity. Therefore, other factors, such as stress-related pathways, may need to be considered as potential triggers for noise-evoked glucose intolerance in future research.

Effects of Insufficient Sleep on Pituitary-Adrenocortical Response to CRH Stimulation in Healthy Men.

Study Objectives: Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Methods: Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Results: Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Conclusions: Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response.

The important role of sleep in metabolism.

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity.

Impact of obesity in children with narcolepsy.

AIMS: To evaluate the impact of obesity on clinical and sleep characteristics in a population of narcoleptic children. METHODS: Data from the children diagnosed with idiopathic narcolepsy in the National Reference Centers for Narcolepsy were collected between 2008 and 2011. Clinical and electrophysiological characteristics were compared between obese (body mass index [BMI] greater than P97) and nonobese children. RESULTS: The 117 children (65 boys, 59 de novo patients) had a mean age of 11.6 ± 3.1 years on diagnosis. Cataplexy was present in 81%, DQB1*0602 in 91%. Mean BMI was 23.2 ± 5.2 kg/m(2) and BMI z-score was 2.9 ± 2.6. Obesity was found in 60% with a similar prevalence in treated versus de novo patients and in patients with and without cataplexy. Sleepiness and cataplexy started earlier in obese children. Obese narcoleptic children had lower sleep efficiency, higher apnea hypopnea index and respiratory arousals index (RAI) than nonobese children. BMI z-score was positively correlated with RAI. Obese children were more tired and missed more often school than nonobese children. CONCLUSION: Obesity affects more than 50% of narcoleptic children, mostly younger at disease onset, and has a deleterious impact on sleep quality as well as on school attendance.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin.

OBJECTIVES: We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. DESIGN: Single-blind, randomized, crossover design study. METHODS: Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. RESULTS: Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 µV(2) respectively; P=0.048). CONCLUSIONS: Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

A phenomenological model for circadian and sleep allostatic modulation of plasma cortisol concentration.

Both circadian rhythmicity and sleep play significant roles in the regulation of plasma cortisol concentration by the hypothalamo-pituitary-adrenal (HPA) axis. Numerous studies have found links between sleep and changes in cortisol concentration, but the implications of these results have remained largely qualitative. In this article, we present a quantitative phenomenological model to describe the effects of different sleep durations on cortisol concentration. We constructed the proposed model by incorporating the circadian and sleep allostatic effects on cortisol concentration, the pulsatile nature of cortisol secretion, and cortisol's negative autoregulation of its own production and validated its performance on three study groups that experienced four distinct sleep durations. The model captured many disparate effects of sleep on cortisol dynamics, such as the inhibition of cortisol secretion after the wake-to-sleep transition and the rapid rise of cortisol concentration before morning awakening. Notably, the model reconciled the seemingly contradictory findings between studies that report an increase in cortisol concentration following total sleep deprivation and studies that report no change in concentration. This work provides a biomathematical approach to combine the results on the effects of sleep on cortisol concentration into a unified framework and predict the impact of varying sleep durations on the cortisol profile.

Sleep and metabolic function.

Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health.

Twenty-four-hour profiles of acylated and total ghrelin: relationship with glucose levels and impact of time of day and sleep.

CONTEXT: The acylation of ghrelin is essential for its stimulatory effects on GH release and appetite. Most of the physiology of ghrelin has been defined based on the assay of total ghrelin (TG), which mainly reflects levels of unacylated ghrelin. Whether levels of acylated ghrelin (AG) are influenced by circadian time and sleep and impact glucose regulation under physiologic conditions is not known. METHODS: Blood was sampled at 10- to 30-min intervals for 24 h in 14 healthy young lean men under controlled conditions of activity, light-dark cycle, and sleep-wake schedule. The subjects ingested three identical carbohydrate-rich meals at 5-h intervals. Sleep was polygraphically monitored. Levels of TG and AG were measured by RIA. The 24-h profiles of glucose and insulin levels were assessed simultaneously. RESULTS: Postprandial glucose concentrations were positively correlated with mean levels of AG but not TG, independently of insulin. Postprandial suppression and rebound of AG and TG occurred in parallel and were not impacted by time of day. The nocturnal elevation of AG and TG reflects the postdinner rebound curbed by an inhibitory effect of sleep. The ratio of AG to TG was lower during sleep than during wake, consistent with a reduction of orexigenic signal. CONCLUSIONS: Individual differences in AG levels may be an important predictor of overall glucose control under physiological conditions. Sleep, but not time of day, impacts postprandial TG and AG responses. The inhibitory effect of sleep on ghrelin release and acylation is consistent with the association between sleeping and fasting.

Role of sleep duration in the regulation of glucose metabolism and appetite.

Sleep curtailment has become a common behavior in modern society. This review summarizes the current laboratory evidence indicating that sleep loss may contribute to the pathophysiology of diabetes mellitus and obesity. Experimentally induced sleep loss in healthy volunteers decreases insulin sensitivity without adequate compensation 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.

Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency.

CONTEXT: Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. OBJECTIVE: The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. SUBJECTS: Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. METHODS: Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. RESULTS: Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. CONCLUSIONS: GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

Effects of poor and short sleep on glucose metabolism and obesity risk.

The importance of sleep to hormones and glucose metabolism was first documented more than four decades ago. Since then, sleep curtailment has become an endemic behavior in modern society. In addition, the prevalence of sleep disorders, particularly obstructive sleep apnea (OSA), has increased. OSA is very common in endocrine and metabolic disorders, but often remains undiagnosed. This Review summarizes the laboratory and epidemiologic evidence that suggests how sleep loss, either behavioral or disease-related, and poor quality of sleep might promote the development of obesity and diabetes mellitus, and exacerbate existing endocrine conditions. Treatment of sleep disorders has the potential to improve glucose metabolism and energy balance. Screening for habitual sleep patterns and OSA might be critically important for patients with endocrine and metabolic disorders.

Metabolic consequences of sleep and sleep loss.

Reduced sleep duration and quality appear to be endemic in modern society. Curtailment of the bedtime period to minimum tolerability is thought to be efficient and harmless by many. It has been known for several decades that sleep is a major modulator of hormonal release, glucose regulation and cardiovascular function. In particular, slow wave sleep (SWS), thought to be the most restorative sleep stage, is associated with decreased heart rate, blood pressure, sympathetic nervous activity and cerebral glucose utilization, compared with wakefulness. During SWS, the anabolic growth hormone is released while the stress hormone cortisol is inhibited. In recent years, laboratory and epidemiologic evidence have converged to indicate that sleep loss may be a novel risk factor for obesity and type 2 diabetes. The increased risk of obesity is possibly linked to the effect of sleep loss on hormones that play a major role in the central control of appetite and energy expenditure, such as leptin and ghrelin. Reduced leptin and increased ghrelin levels correlate with increases in subjective hunger when individuals are sleep restricted rather than well rested. Given the evidence, sleep curtailment appears to be an important, yet modifiable, risk factor for the metabolic syndrome, diabetes and obesity. The marked decrease in average sleep duration in the last 50 years coinciding with the increased prevalence of obesity, together with the observed adverse effects of recurrent partial sleep deprivation on metabolism and hormonal processes, may have important implications for public health.

The metabolic consequences of sleep deprivation.

The prevalence of diabetes and obesity is increasing at an alarming rate worldwide, and the causes of this pandemic are not fully understood. Chronic sleep curtailment is a behavior that has developed over the past 2-3 decades. Laboratory and epidemiological studies suggest that sleep loss may play a role in the increased prevalence of diabetes and/or obesity. Current data suggest the relationship between sleep restriction, weight gain and diabetes risk may involve at least three pathways: (1) alterations in glucose metabolism; (2) upregulation of appetite; and (3) decreased energy expenditure. The present article reviews the current evidence in support of these three mechanisms that might link short sleep and increased obesity and diabetes risk.

Impact of sleep and sleep loss on neuroendocrine and metabolic function.

BACKGROUND: Sleep exerts important modulatory effects on neuroendocrine function and glucose regulation. During the past few decades, sleep curtailment has become a very common behavior in industrialized countries. This trend toward shorter sleep times has occurred over the same time period as the dramatic increases in the prevalence of obesity and diabetes. AIMS: This article will review rapidly accumulating laboratory and epidemiologic evidence indicating that chronic partial sleep loss could play a role in the current epidemics of obesity and diabetes. CONCLUSIONS: Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes. Epidemiologic findings in both children and adults are consistent with the laboratory data.

Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes.

Chronic sleep loss as a consequence of voluntary bedtime restriction is an endemic condition in modern society. Although sleep exerts marked modulatory effects on glucose metabolism, and molecular mechanisms for the interaction between sleeping and feeding have been documented, the potential impact of recurrent sleep curtailment on the risk for diabetes and obesity has only recently been investigated. In laboratory studies of healthy young adults submitted to recurrent partial sleep restriction, marked alterations in glucose metabolism including decreased glucose tolerance and insulin sensitivity have been demonstrated. The neuroendocrine regulation of appetite was also affected as the levels of the anorexigenic hormone leptin were decreased, whereas the levels of the orexigenic factor ghrelin were increased. Importantly, these neuroendocrine abnormalities were correlated with increased hunger and appetite, which may lead to overeating and weight gain. Consistent with these laboratory findings, a growing body of epidemiological evidence supports an association between short sleep duration and the risk for obesity and diabetes. Chronic sleep loss may also be the consequence of pathological conditions such as sleep-disordered breathing. In this increasingly prevalent syndrome, a feedforward cascade of negative events generated by sleep loss, sleep fragmentation, and hypoxia are likely to exacerbate the severity of metabolic disturbances. In conclusion, chronic sleep loss, behavioral or sleep disorder related, may represent a novel risk factor for weight gain, insulin resistance, and Type 2 diabetes.

Impact of carbohydrate-rich meals on plasma epinephrine levels: dysregulation with aging.

CONTEXT: Plasma norepinephrine (NE) and epinephrine (E) levels are indicators of peripheral sympathetic and adrenomedullary activities, respectively. The sympathoadrenomedullary system is involved in the metabolic response to carbohydrate intake and is affected by aging; however, the relationship between glucose metabolism and adrenomedullary activity in older adults remains poorly defined. OBJECTIVE: The objective of this study was to examine the changes in the impact of carbohydrate-rich meals on circulating catecholamines with aging. DESIGN: After iv glucose tolerance testing and 1 d of habituation, blood samples were collected every 10-30 min for 24 h. Daytime hours were spent at bed rest. Sleep was scheduled between 2300 and 0700 h with polygraphic monitoring. SETTING: The study was performed at a general clinical research center. PARTICIPANTS: Nine young (age, 20-28 yr) and eight older (age, 50-69 yr) healthy men participated in this study. INTERVENTION: Identical mixed meals (62% carbohydrate) were given at 0900, 1400, and 1900 h. MAIN OUTCOME MEASURES: The main outcome measures were 24-h plasma E and NE measurements. RESULTS: The profiles of E and NE were characterized by clear day-night differences, which were preserved in the older group. Young subjects showed a clear dissociation between postprandial adrenomedullary and sympathetic activities characterized by a rapid decline in plasma E and increased NE levels. There was an overall increase in NE levels and markedly dampened postprandial variation in plasma E in the older men. CONCLUSIONS: In young adults, postprandial E levels follow a biphasic pattern that is inversely related to that of glucose and insulin. Aging is associated with a dysregulation of this response.