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OBJECTIVE Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or CONCLUSIONS In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.

OBJECTIVE: Poor sleep may increase obesity and type 2 diabetes (T2D) risk in youth. We explored whether subjective sleep duration, sleep quality, or risk for obstructive sleep apnea (OSA) are associated with glycemia, body mass index (BMI), or blood pressure (BP) in overweight/obese youth. METHODS: Two-hundred and fourteen overweight/obese youth of 10 to 19 years of age at risk for or recently diagnosed with T2D who were screened for the Restoring Insulin Secretion (RISE) Study had a 2-hour oral glucose tolerance test (OGTT) and completed a Cleveland Adolescent Sleepiness questionnaire and a Sleep Disturbances Scale questionnaire. Independent associations between sleep variables and measures of glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 67% female, 14.1 ± 2.1 years, and BMI 35.9 ± 6.5 kg/m(2). Habitual sleep duration

Evidence suggests that sleep disorders are common in individuals with CKD, but the influence of sleep duration and quality on CKD progression is unknown. We examined the association of habitual sleep duration and quality with CKD progression in 431 Chronic Renal Insufficiency Cohort (CRIC) Study participants, of whom 48% were women and 50% had diabetes (mean age of 60 years old, mean eGFR =38 ml/min per 1.73 m2, and median urine protein-to-creatinine ratio [UPCR] =0.20 g/g). We assessed sleep duration and quality by 5–7 days of wrist actigraphy and self-report. Primary outcomes were incident ESRD, eGFR slope, log-transformed UPCR slope, and all-cause death. Participants slept an average of 6.5 hours per night; mean sleep fragmentation was 21%. Over a median follow-up of 5 years, we observed 70 ESRD events and 48 deaths. In adjusted analyses, greater sleep fragmentation associated with increased ESRD risk (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07 per 1% increase in fragmentation). In adjusted mixed effects regression models, shorter sleep duration (per hour less) and greater sleep fragmentation (per 1% more) each associated with greater eGFR decline (−1.12 and −0.18 ml/min per 1.73 m2 per year, respectively; P=0.02 and P

Context The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day. Objective We sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant. Design With fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900. Participants Twelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied. Results We observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants. Conclusions Obesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.

OBJECTIVE Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS Our cohort included 962 overweight/obese adults ages 20–65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting 8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and CONCLUSIONS In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.

STUDY OBJECTIVES: Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. METHODS: Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. RESULTS: Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (−2.1 ± 1.0 vs. −4.3 ± 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Δ21 ± 11 vs. Δ14 ± 8 mm Hg; time × group = 0.04) and total MSNA reactivity (Δ127%, 54%–208% vs. Δ52%, 30%–81%; time × group = 0.02) were augmented in chronic insomnia. CONCLUSIONS: Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. CLINICAL TRIAL REGISTRATION: NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878

Obstructive sleep apnea (OSA) is associated with hypertension.We aimed to quantify the independent association of OSA during REM sleep with prevalent and incident hypertension.We included adults enrolled in the longitudinal community-based Wisconsin Sleep Cohort Study with at least 30 minutes of REM sleep obtained from overnight in-laboratory polysomnography. Studies were repeated at 4-year intervals to quantify OSA. Repeated measures logistic regression models were fitted to explore the association between REM sleep OSA and prevalent hypertension in the entire cohort (n = 4,385 sleep studies on 1,451 individuals) and additionally in a subset with ambulatory blood pressure data (n = 1,085 sleep studies on 742 individuals). Conditional logistic regression models were fitted to longitudinally explore the association between REM OSA and development of hypertension. All models controlled for OSA events during non-REM sleep, either by statistical adjustment or by stratification.Fully adjusted models demonstrated significant dose-relationships between REM apnea-hypopnea index (AHI) and prevalent hypertension. The higher relative odds of prevalent hypertension were most evident with REM AHI greater than or equal to 15. In individuals with non-REM AHI less than or equal to 5, a twofold increase in REM AHI was associated with 24% higher odds of hypertension (odds ratio, 1.24; 95% confidence interval, 1.08-1.41). Longitudinal analysis revealed a significant association between REM AHI categories and the development of hypertension (P trend = 0.017). Non-REM AHI was not a significant predictor of hypertension in any of the models.Our findings indicate that REM OSA is cross-sectionally and longitudinally associated with hypertension. This is clinically relevant because treatment of OSA is often limited to the first half of the sleep period leaving most of REM sleep untreated.

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.

OBJECTIVE Severity of obstructive sleep apnea (OSA) has been associated with poorer glycemic control in type 2 diabetes. It is not known whether obstructive events during rapid eye movement (REM) sleep have a different metabolic impact compared with those during non-REM (NREM) sleep. Treatment of OSA is often limited to the first half of the night, when NREM rather than REM sleep predominates. We aimed to quantify the impact of OSA in REM versus NREM sleep on hemoglobin A1c (HbA1c) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS All participants underwent polysomnography, and glycemic control was assessed by HbA1c. RESULTS Our analytic cohort included 115 subjects (65 women; age 55.2 ± 9.8 years; BMI 34.5 ± 7.5 kg/m2). In a multivariate linear regression model, REM apnea–hypopnea index (AHI) was independently associated with increasing levels of HbA1c (P = 0.008). In contrast, NREM AHI was not associated with HbA1c (P = 0.762). The mean adjusted HbA1c increased from 6.3% in subjects in the lowest quartile of REM AHI to 7.3% in subjects in the highest quartile of REM AHI (P = 0.044 for linear trend). Our model predicts that 4 h of continuous positive airway pressure (CPAP) use would leave 60% of REM sleep untreated and would be associated with a decrease in HbA1c by approximately 0.25%. In contrast, 7 h of CPAP use would cover more than 85% of REM sleep and would be associated with a decrease in HbA1c by as much as 1%. CONCLUSIONS In type 2 diabetes, OSA during REM sleep may influence long-term glycemic control. The metabolic benefits of CPAP therapy may not be achieved with the typical adherence of 4 h per night.

OBJECTIVE To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA1c values and whether this association was mediated by a higher proportion of caloric intake at dinner. RESULTS We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner. CONCLUSIONS Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.

Studies examining the impact of CPAP treatment on glycaemic control have yielded conflicting results, partly because of insufficient nightly CPAP use. We examined the 24-hour profiles of glucose, insulin and counter-regulatory hormones in 12 subjects with type 2 diabetes and OSA before and after 1 week of effective in-laboratory CPAP therapy over an entire 8-hour night thus ensuring optimal CPAP compliance. Blood samples were collected every 15 to 30 minutes for 24 hours under controlled conditions. The 24-hour mean glucose decreased from 153.2 ± 33.0 to 139.7 ± 24.2 mg/dL with CPAP (-13.5 ± 13.5 mg/dL; P = .005) without change in insulin levels. Morning fasting glucose levels decreased by 14.6 ± 3 mg/dL (P = .001) and the dawn phenomenon decreased by 7.8 ± 9.8 mg/dL (P = .019). CPAP treatment decreased norepinephrine levels while the 24-hour profiles of growth hormone and cortisol remained unchanged. In conclusion, 1 week of effective treatment of OSA over an entire 8-hour night results in a clinically significant improvement in glycaemic control via an amelioration of evening fasting glucose metabolism and a reduction in the dawn phenomenon, a late-night glucose increase that is not adequately treated by oral medications. Clinical Trials Information: ClinicalTrials.gov Identifier: NCT01136785.

OBJECTIVE To determine whether inpatient sleep duration and efficiency are associated with a greater risk of hyperglycemia in hospitalized patients with and without diabetes. RESEARCH DESIGN AND METHODS In this retrospective analysis of a prospective cohort study, medical inpatients ≥50 years of age were interviewed, and their charts were reviewed to obtain demographic data and diagnosis. Using World Health Organization criteria, patients were categorized as having normal blood glucose, impaired fasting blood glucose, or hyperglycemia based on morning glucose from the electronic health record. Wrist actigraphy measured sleep. Multivariable ordinal logistic regression models, controlling for subject random effects, tested the association between inpatient sleep duration and proportional odds of hyperglycemia versus impaired fasting blood glucose or impaired fasting blood glucose versus normal blood glucose in hospitalized adults. RESULTS A total of 212 patients (60% female and 74% African American) were enrolled. Roughly one-third (73, 34%) had diabetes. Objective inpatient sleep measures did not differ between patients with or without diabetes. In ordinal logistic regression models, each additional hour of in-hospital sleep was associated with an 11% (odds ratio 0.89 [95% CI 0.80, 0.99]; P = 0.043) lower proportional odds of a higher glucose category the next morning (hyperglycemia vs. elevated and elevated vs. normal). Every 10% increase in sleep efficiency was associated with an 18% lower proportional odds of a higher glucose category (odds ratio 0.82 [95% CI 0.74, 0.89]; P < 0.001). CONCLUSIONS Among medical inpatients, both shorter sleep duration and worse sleep efficiency were independently associated with greater proportional odds of hyperglycemia and impaired fasting glucose.

Insufficient sleep and circadian rhythm disturbances have been each associated with adverse cardiovascular outcomes in epidemiological studies, but experimental evidence for a causal link is scarce. The present study compares the impact of circadian misalignment (CM) to circadian alignment (CA) on human autonomic function using a nonrandomized parallel group design to achieve the same total sleep time in both conditions. After baseline assessments (3 days with 10-hour bedtimes), 26 healthy young adults were assigned to sleep restriction (SR; eight 5-hour bedtimes) with either fixed nocturnal bedtimes (CA; n=13) or bedtimes delayed by 8.5 hours on 4 of the 8 days (CM; n=13). Daytime ambulatory blood pressure and heart rate (HR; CA, n=11; CM, n=10) and 24-hour urinary norepinephrine levels (CA, n=13; CM, n=13) were assessed at baseline and the end of SR. Nocturnal HR and HR variability were analyzed during sleep at baseline and during the fourth and seventh nights of SR (CA, n=8; CM, n=12). SR resulted in a significant increase in daytime HR in both groups, without changes in blood pressure. SR increased 24-hour urinary norepinephrine in the CM group (30±4 versus 21±2 μg), but not in the circadian alignment group (group×condition, P =0.005). In contrast to the lack of detectable impact of CM on daytime autonomic function, SR with CM elicited greater increases in nocturnal HR, as well as greater reductions in vagal indices of HR variability, than SR without CM (group×condition, P

OBJECTIVES Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. DESIGN Observational study. SETTING Academic medical intensive care unit. PATIENTS Critically ill patients receiving MV and intravenous sedation. METHODS Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. MEASUREMENTS AND RESULTS We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). CONCLUSIONS The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

Rationale: Obstructive sleep apnea (OSA), a treatable sleep disorder that is associated with alterations in glucose metabolism in individuals without diabetes, is a highly prevalent comorbidity of type 2 diabetes. However, it is not known whether the severity of OSA is a predictor of glycemic control in patients with diabetes. Objectives: To determine the impact of OSA on hemoglobin A1c (HbA1c), the major clinical indicator of glycemic control, in patients with type 2 diabetes. Methods: We performed polysomnography studies and measured HbA1c in 60 consecutive patients with diabetes recruited from outpatient clinics between February 2007 and August 2009. Measurements and Main Results: A total of 77% of patients with diabetes had OSA (apnea–hypopnea index [AHI] ≥5). Increasing OSA severity was associated with poorer glucose control, after controlling for age, sex, race, body mass index, number of diabetes medications, level of exercise, years of diabetes and total sleep time. Compared with patients without OSA, the adjusted mean HbA1c was increased by 1.49% (P = 0.0028) in patients with mild OSA, 1.93% (P = 0.0033) in patients with moderate OSA, and 3.69% (P < 0.0001) in patients with severe OSA (P < 0.0001 for linear trend). Measures of OSA severity, including total AHI (P = 0.004), rapid eye movement AHI (P = 0.005), and the oxygen desaturation index during total and rapid eye movement sleep (P = 0.005 and P = 0.008, respectively) were positively correlated with increasing HbA1c levels. Conclusions: In patients with type 2 diabetes, increasing severity of OSA is associated with poorer glucose control, independent of adiposity and other confounders, with effect sizes comparable to those of widely used hypoglycemic drugs.

To assess objectively measured daytime physical activity and sleep duration and efficiency in hospitalized older adults and explore associations with demographic characteristics and disease severity.Prospective cohort study.University of Chicago Medical Center general medicine wards.Community-dwelling inpatients aged 50 and older (N = 120) MEASUREMENTS: Physical activity and sleep were measured using wrist accelerometers. Information on Charlson Comorbidity Index and length of stay was collected from charts. Random-effects linear regression analysis was used to examine the association between in-hospital sleep and physical activity.From March 2010 to May 2013, 120 participants wore wrist actigraphy monitors for at least 2 nights and 1 intervening day. Median activity level over the waking period was 77 counts/min (interquartile range 51-121 counts/min), an activity level that approximately corresponds to sitting while watching television (65 counts/min). Mean sleep duration the night before the activity interval was 289 ± 157 minutes, and mean sleep efficiency the night before the activity interval was 65.2 ± 26.9%. Mean activity counts/min were lowest for the oldest participants (oldest quartile 62, 95% confidence interval (CI) = 50-75; youngest quartile 121, 95% CI = 98-145, trend test P.001) and those with highest Charlson Comorbidity Index (highest tertile 71, 95% CI = 60-83; lowest tertile 125, 95% CI = 104-147, trend test P = .01). Controlling for severity of illness and demographic characteristics, activity declined by 3 counts/min (95% CI = -5.65 to -0.43, P = .02) for each additional hour of inpatient sleep.Older, sicker adults are less physically active during hospitalization. In contrast to studies in the community, inpatients who slept more were not more active. This may highlight that need for sleep is greater in the hospital than in the community.

Study objectives To examine sex differences in nocturnal growth hormone and prolactin release in older adults. Design Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled at frequent intervals during the last 24 hours. Setting The University of Chicago Clinical Research Center. Participants Two groups of healthy nonobese older subjects: 10 men (59 +/- 2 years, mean +/- SEM), and 10 postmenopausal women (63 +/- 2 years). Interventions N/A. Measurements and results A spectral analysis of the electroencephalogram was performed in the delta and alpha bands. When delta activity was normalized for the activity in rapid eye movement sleep, women had lower delta activity than men. Growth hormone secretion was estimated by deconvolution. The prolactin profile was quantified by a best-fit curve. In both sexes, growth hormone was released both before and after sleep onset. In men, there was no relationship between presleep growth hormone release and subsequent sleep quality and postsleep growth hormone release correlated with delta activity. In women, presleep growth hormone release appeared to inhibit both postsleep growth hormone release and sleep consolidation. Prolactin release was related to rapid eye movement sleep and was lower in men than in women. Women with poor sleep maintenance had a lower prolactin acrophase. Conclusions Major sex differences in the nocturnal profiles of growth hormone and prolactin and their relationship to sleep electroencephalogram variables are present in healthy older adults. Our analyses suggest that lower sleep-onset release of growth hormone in women as compared with men could be related to lower levels of delta activity. Improvements in the homeostatic control of sleep could have hormonal benefits in older adults.

Summary Objective Older adults are less responsive to the phase-shifting effects of light than younger subjects and may have difficulties adapting to abrupt time shifts. This study aims to determine whether the potent melatonin agonist agomelatine (S-20098) is capable of phase-shifting overt circadian rhythms in older adults. Subjects and design Eight healthy elderly men participated in a double-blind, two-period, cross-over study of 15 days of daily administration of either agomelatine (50 mg) or placebo at 1830 h. Measurements At the end of each treatment period, the 24-h profiles of body temperature and of the plasma levels of GH, PRL, cortisol and TSH were collected and sleep was monitored polygraphically. Results Phase-advances, averaging nearly 2 h, were observed for the temperature profile and for the variables characterizing the temporal organization of cortisol secretion following agomelatine administration. A similar trend was observed for the circadian rise of plasma TSH. There was no effect of agomelatine on any of the sleep variables. Agomelatine stimulated GH secretion during the wake period and was associated with a transient elevation of PRL levels. Conclusions Melatonin agonists such as agomelatine may be useful to phase-shift at least some overt circadian rhythms in older adults.

Objective Two studies using cross-sectional designs explored four possible mechanisms by which loneliness may have deleterious effects on health: health behaviors, cardiovascular activation, cortisol levels, and sleep. Methods In Study 1, we assessed autonomic activity, salivary cortisol levels, sleep quality, and health behaviors in 89 undergraduate students selected based on pretests to be among the top or bottom quintile in feelings of loneliness. In Study 2, we assessed blood pressure, heart rate, salivary cortisol levels, sleep quality, and health behaviors in 25 older adults whose loneliness was assessed at the time of testing at their residence. Results Total peripheral resistance was higher in lonely than nonlonely participants, whereas cardiac contractility, heart rate, and cardiac output were higher in nonlonely than lonely participants. Lonely individuals also reported poorer sleep than nonlonely individuals. Study 2 indicated greater age-related increases in blood pressure and poorer sleep quality in lonely than nonlonely older adults. Mean salivary cortisol levels and health behaviors did not differ between groups in either study. Conclusions Results point to two potentially orthogonal predisease mechanisms that warrant special attention: cardiovascular activation and sleep dysfunction. Health behavior and cortisol regulation, however, may require more sensitive measures and large sample sizes to discern their roles in loneliness and health.

We are grateful to Drs. Scarlata and Antonelli-Incalzi (1) for their interest in our recent publication in Diabetes Care (2). We respectfully have to disagree with their statement that our study focused on “how rapid eye movement (REM) sleep deprivation due to obstructive sleep apnea [OSA] affects glycemic control in type 2 diabetes.” Indeed, our study was a cross-sectional analysis and did not include an experimental paradigm of REM sleep deprivation. In fact, the median duration of REM sleep in our cohort was 20.3% of the total sleep time—well within the normal range (Supplementary Table 1 in ref. 2). The primary aim of our study was to estimate the impact of OSA in REM sleep and in non-REM sleep on glycemic control (as assessed by HbA1c) in patients with …

Shift workers, who are exposed to irregular sleep schedules resulting in sleep deprivation and misalignment of circadian rhythms, have an increased risk of diabetes relative to day workers. In healthy adults, sleep restriction without circadian misalignment promotes insulin resistance.To determine whether the misalignment of circadian rhythms that typically occurs in shift work involves intrinsic adverse metabolic effects independently of sleep loss, twenty-six healthy adults were studied using a parallel group design. Both interventions involved 3 inpatient days with 10-h bedtimes followed by 8 inpatient days of sleep restriction to 5 hours, either with fixed nocturnal bedtimes (circadian alignment) or with bedtimes delayed by 8.5 hours on 4 of the 8 days (circadian misalignment). Daily total sleep time during the intervention was nearly identical in the aligned and misaligned conditions (4h48min[5min] vs. 4h45min[6min]). In both groups, insulin sensitivity significantly decreased after sleep restriction, without compensatory increase in insulin secretion, and inflammation increased. In male participants exposed to circadian misalignment, both the reduction in insulin sensitivity and the increase in inflammation doubled, compared to those who maintained regular nocturnal bedtimes.Circadian misalignment as occurs in shift work may increase diabetes risk and inflammation, independently of sleep loss., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

To systematically determine the effects of daytime exposure to sleep in darkness on human circadian phase, four groups of subjects participated in 4-day studies involving either no nap (control), a morning nap (0900–1500), an afternoon nap (1400–2000), or an evening nap (1900–0100) in darkness. Except during the scheduled sleep/dark periods, subjects remained awake under constant conditions, i.e., constant dim light exposure (36 lx), recumbence, and caloric intake. Blood samples were collected at 20-min intervals for 64 h to determine the onsets of nocturnal melatonin and thyrotropin secretion as markers of circadian phase before and after stimulus exposure. Sleep was polygraphically recorded. Exposure to sleep and darkness in the morning resulted in phase delays, whereas exposure in the evening resulted in phase advances relative to controls. Afternoon naps did not change circadian phase. These findings indicate that human circadian phase is dependent on the timing of darkness and/or sleep exposure and that strategies to treat circadian misalignment should consider not only the timing and intensity of light, but also the timing of darkness and/or sleep.

This article discusses the hypothesis that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. In a recent study, we examined carbohydrate metabolism, endocrine function, and sympatho-vagal balance in young, healthy adults studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bedtime period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo-pituitary-adrenal function were qualitatively and quantitatively similar to those observed in normal aging. These results indicate that sleep loss can increase the “allostatic load” and facilitate the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups.

To delineate the contributions of genetic and environmental factors in the regulation of human prolactin (PRL) secretion, the 24-h profile of plasma PRL was obtained at 15-min intervals in 10 pairs of monozygotic and 10 pairs of dizygotic twins. Sleep was monitored polygraphically. PRL secretory rates were derived from plasma concentrations by deconvolution. Diurnal (24-h) variations were quantified by a regression curve to define nadir, acrophase, and amplitude. Pulses of PRL secretion were identified using a computerized algorithm. A procedure specifically developed for twin studies was used to partition the variance into genetic and environmental contributions. Significant genetic effects were identified for daytime PRL concentrations, rhythm amplitude, and overall waveshape of the daily PRL profile. In contrast, environmental effects were dominant for mean concentrations during sleep, total secretory output during sleep, overall 24-h concentrations, and total 24-h secretion. However, when interindividual variations in sleep fragmentation were taken into account, the estimates of genetic variance for PRL concentrations and secretion during sleep approached statistical significance. Significant genetic influences were identified for slow-wave sleep (SWS). Because SWS is associated with increased nocturnal PRL secretion, it is possible that genetic effects on PRL secretion during sleep reflect genetic influences on SWS. In conclusion, genetic factors determine partially both the basal daytime concentrations of PRL and the temporal organization of PRL secretion over the 24-h cycle in normal young men.

The temporal profiles of subjective fatigue (as assessed by the Stanford Sleepiness Scale), of cognitive performance (on a digit symbol substitution test and a symbol copying task), of body temperature, and of the peripheral concen trations of melatonin, thyroid-stimulating hormone (TSH), and cortisol were obtained simultaneously at frequent intervals in 17 normal young subjects submitted to a 43-h period of constant routine conditions involving continuous wakefulness at bed rest in dim indoor light. The subjects had knowledge of time of day. Caloric intake was exclusively in the form of an intravenous glucose infusion, and plasma glucose levels were monitored continuously in 8 of the 17 subjects. Under these conditions, fluctuations in plasma glucose reflect primarily changes in glucose use because endogenous glucose production is suppressed by the exogenous infusion. Following the completion of a baseline constant routine study, the volunteers participated in two subsequent studies using the same protocol to determine the immediate psychophysiological effects of expo sure to a 3-h pulse of bright light or to a 3-h pulse of physical exercise. Sleepiness and performance varied in a mirror image, with significant negative correlations. Sleepiness scores were minimal around noon and then increased at a modest rate throughout the rest of the normal waking period. Staying awake during usual bedtime hours was associated with an acceleration in the rate of increase in sleepiness, which coincided with decreasing body temperature, rapidly rising cortisol concentrations, and maximal levels of melatonin and TSH. When body temperature reached its nadir, a further major increase in sleepiness occurred in parallel with a pronounced decrease in plasma glucose (reflecting increased glucose use). Recovery from maximal sleepiness started when blood glucose levels stopped falling and when significant decreases in cortisol and melatonin concentrations were initiated. Lower levels of subjective sleepiness resumed when glucose concentrations and body temperature had returned to levels similar to those observed prior to sleep deprivation and when melatonin and TSH concentrations had returned to daytime levels. The synchrony of behav ioral, neuroendocrine, and metabolic changes suggests that circulating hormonal levels could exert modulatory influences on sleepiness and that metabolic altera-tions may underlie the sudden increase in fatigue consistently occurring at the end of a night of sleep deprivation. Effects of bright light or exercise exposure on subjective sleepiness appeared to be critically dependent on the timing of exposure.

ObjectivesWe 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.DesignSingle-blind, randomized, crossover design study.MethodsFourteen 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.ResultsValid 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 μV2respectively;P=0.048).ConclusionsFour 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.

OBJECTIVE To examine whether sleep duration and quality are associated with fasting glucose, fasting insulin, or estimated insulin resistance in a community-based sample of early middle-aged adults. RESEARCH DESIGN AND METHODS This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Habitual sleep duration and fragmentation were estimated from 6 days of wrist actigraphy collected in 2003–2005. Insomnia was defined as self-reported difficulty falling asleep or waking up in the night three or more times per week plus average sleep efficiency of

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.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.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.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.

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.The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients.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.Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured.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.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.

To determine (1) whether short sleep has increased over 31 years; (2) whether trends in short sleep differed by employment status; (3) which sociodemographic factors predict short sleep; and (4) how short sleepers spend their time.Time diaries from eight national studies conducted between 1975 and 2006.U.S. adultsor = 18 years.Short sleepers were defined as those reporting6 hours of sleep in their time diary. Unadjusted percentages of short sleepers ranged from 7.6% in 1975 to 9.3% in 2006. The 1998-99 study had the highest odds of short sleep. The odds ratio for the 31-year period predicting short sleep was 1.14 (95% CI: 0.92, 1.50, P = 0.22), adjusting for age, sex, education, employment, race, marital status, income, and day of week. When stratified by employment, there was a significant increase for full-time workers (P = 0.05), who represented over 50% of participants in all studies, and a significant decrease for students (P = 0.01), who represented5% of participants. The odds of short sleep were lower for women, thoseor = 65 years, Asians, Hispanics, and married people. The odds were higher for full-time workers, those with some college education, and African Americans. Short sleepers in all employment categories spent more time on personal activities. Short sleepers who were full- and part-time workers spent much more time working.Based on time diaries, the increase in the odds of short sleep over the past 31 years was significant among full-time workers only. Work hours are much longer for full-time workers sleeping6 hours.

Epidemiological studies have reported an association between self-reported short sleep duration and high blood pressure (BP). Our objective was to examine both cross-sectional and longitudinal associations between objectively measured sleep and BP.This study is ancillary to the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. Blood pressure was measured in 2000 and 2001 and in 2005 and 2006. Sleep was measured twice using wrist actigraphy for 3 consecutive days between 2003 and 2005. Sleep duration and sleep maintenance (a component of sleep quality) were calculated. Analyses included 578 African Americans and whites aged 33 to 45 years at baseline. Outcome measures were systolic BP (SBP) and diastolic BP (DBP) levels, 5-year change in BP, and incident hypertension.After we excluded the patients who were taking antihypertensive medications and adjusted for age, race, and sex, shorter sleep duration and lower sleep maintenance predicted significantly higher SBP and DBP levels cross-sectionally as well as more adverse changes in SBP and DBP levels over 5 years (all P.05). Short sleep duration also predicted significantly increased odds of incident hypertension (odds ratio, 1.37; 95% confidence interval, 1.05-1.78). Adjustment for 16 additional covariates, including snoring and daytime sleepiness, slightly attenuated the associations between sleep and BP. Sleep duration appeared to mediate the difference between African Americans and whites in DBP change over time (P = .02).Reduced sleep duration and consolidation predicted higher BP levels and adverse changes in BP, suggesting the need for studies to investigate whether interventions to optimize sleep may reduce BP.

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.The objective of this study was to examine the changes in the impact of carbohydrate-rich meals on circulating catecholamines with aging.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.The study was performed at a general clinical research center.Nine young (age, 20-28 yr) and eight older (age, 50-69 yr) healthy men participated in this study.Identical mixed meals (62% carbohydrate) were given at 0900, 1400, and 1900 h.The main outcome measures were 24-h plasma E and NE measurements.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.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.

Sleep plays an important role in energy homeostasis. The present study tests the hypothesis that circulating levels of leptin, a hormone that signals energy balance to the brain, are influenced by sleep duration. We also analyzed associations between leptin and sympathovagal balance, cortisol, TSH, glucose, and insulin under different bedtime conditions. Twenty-four-hour hormonal and glucose profiles were sampled at frequent intervals, and sympathovagal balance was estimated from heart rate variability in 11 subjects studied after 6 d of 4-h bedtimes (mean +/- sem of sleep duration during last 2 d: 3 h and 49 +/- 2 min) and after 6 d of 12-h bedtimes (sleep: 9 h and 03 +/- 15 min). A study with 8-h bedtimes was performed 1 yr later (sleep: 6 h and 52 +/- 10 min). Caloric intake and activity levels were carefully controlled in all studies. Mean levels, maximal levels, and rhythm amplitude of leptin were decreased (-19%, -26%, and -20%, respectively) during sleep restriction compared with sleep extension. The decrease in leptin levels was concomitant with an elevation of sympathovagal balance. The effects of sleep duration on leptin were quantitatively associated with alterations of the cortisol and TSH profiles and were accompanied by an elevation of postbreakfast homeostasis model assessment values. Measures of perceived stress were not increased during sleep restriction. During the study with 8-h bedtimes, hormonal and metabolic parameters were intermediate between those observed with 4-h and 12-h bedtimes. In conclusion, sleep modulates a major component of the neuroendocrine control of appetite., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Objective: To compare noninvasive measures of cardiac autonomic activity during sleep. Methods: The absolute and normalized (n.u.) high and low frequency peaks from the spectral analysis of R-R intervals (HF, LF, HFn.u., LFn.u.), LF/HF ratio, pre-ejection period (PEP) from impedance cardiography, and the autocorrelation coefficient (rRR) as illustrated in Poincareplots were measured during night-time sleep in 9 young healthy subjects. Heart rate and blood pressure were also recorded. Results: Heart rate was significantly associated with cardiac sympathetic activity (PEP, average r ¼ 20:46), but not with cardiac parasympathetic activity (HF, average r ¼ 20:17). rRR was significantly associated with heart rate (average r ¼ 0:41), and LF/HF (average r ¼ 0:69), but not with PEP or HF. From NREM to REM sleep, heart rate, LFn.u., LF and rRR significantly increased, HFn.u. significantly decreased, LF/HF showed an increasing trend (P ¼ 0:07) and PEP showed a decreasing trend (P ¼ 0:06). Blood pressure and HF were highly variable without significant changes from NREM to REM sleep. Conclusions: Cardiac parasympathetic activity (HF) does not vary greatly between sleep stages. Cardiac sympathetic activity (PEP) decreases linearly during sleep. rRR and LF/HF can track sympathovagal changes during sleep, but cannot differentiate between changes in cardiac parasympathetic and sympathetic activity. The relative advantages and disadvantages of the different measures are discussed. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20–30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (±SD) 42 ± 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed ( P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 ± 15 min (SE) compared with the phase delays observed in the no-exercise group (−25 ± 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.

This study examines the individual reproducibility of alterations of subjective, objective, and EEG measures of alertness during 27 h of continuous wakefulness and analyzes their interrelationships. Eight subjects were studied twice under similar constant-routine conditions. Scales and performance tasks were administered at hourly intervals to define temporal changes in subjective and objective alertness. The wake EEG was recorded every 2 h, 2 min with eyes open and 2 min with eyes closed. Plasma glucose and melatonin levels were measured to estimate brain glucose utilization and individual circadian phase, respectively. Decrements of subjective alertness and performance deficits were found to be highly reproducible for a given individual. Remarkably, there was no relationship between the impairments of subjective and objective alertness. With increased duration of wakefulness, EEG activity with eyes closed increased in the delta range and decreased in the alpha range, but the magnitudes of these changes were also unrelated. These findings indicate that sleep deprivation has highly reproducible, but independent, effects on brain mechanisms controlling subjective and objective alertness.

To investigate the adaptation of plasma cortisol profiles to an abrupt phase advance of the rest-activity cycle, eight normal young subjects were submitted in a sleep laboratory to an 8-h advance shift of their sleep-wake and dark-light cycles. The shift was achieved by advancing bedtimes from 2300–0700 to 1500–2300. Blood samples were obtained at 20-min intervals for 68 consecutive hours. The shift resulted within 6–9 h in a 3- to 4-h advance of timings of the nadir of the cortisol profile and of the end of the quiescent period but had no immediate effect on the timing of cortisol acrophase. The quiescent period of cortisol secretion was shortened and fragmented. Thus a major advance shift achieved without enforcing sleep deprivation results in a rapid partial adaptation of the temporal profiles of cortisol but also in a marked disruption of the cortisol quiescent period. Sleep onset was consistently followed by a decrease in cortisol concentrations. Conversely, both sleep-wake and dark-light transitions were consistently associated with cortisol secretory pulses.

ContextIn young adults, sleep affects the regulation of growth hormone (GH) and cortisol. The relationship between decreased sleep quality in older adults and age-related changes in the regulation of GH and cortisol is unknown.ObjectiveTo determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.Design and SettingData combined from a series of studies conducted between 1985 and 1999 at 4 laboratories.SubjectsA total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.Main Outcome MeasuresTwenty-four–hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings.ResultsThe mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep. The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (−24 minutes per decade; P

Chronic sleep debt is becoming increasingly common and affects millions of people in more-developed countries. Sleep debt is currently believed to have no adverse effect on health. We investigated the effect of sleep debt on metabolic and endocrine functions.We assessed carbohydrate metabolism, thyrotropic function, activity of the hypothalamo-pituitary-adrenal axis, and sympathovagal balance in 11 young men after time in bed had been restricted to 4 h per night for 6 nights. We compared the sleep-debt condition with measurements taken at the end of a sleep-recovery period when participants were allowed 12 h in bed per night for 6 nights.Glucose tolerance was lower in the sleep-debt condition than in the fully rested condition (p0.02), as were thyrotropin concentrations (p0.01). Evening cortisol concentrations were raised (p=0.0001) and activity of the sympathetic nervous system was increased in the sleep-debt condition (p0.02).Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.

To investigate the adaptation of melatonin secretion to an abrupt time shift and the effects of sleep facilitation with a hypnotic, eight subjects were submitted to an 8-h advance shift achieved by advancing bedtimes from 2300–0700 to 1500–2300. Each subject participated in two studies (i.e., placebo and zolpidem). Each study included a baseline period with dim light during waking hours and 2300–0700 bedtimes in total darkness. Blood samples for determination of plasma melatonin were obtained at 20-min intervals for 68 h. Advanced exposure to sleep and darkness resulted in a nearly 2-h advance of melatonin onset, which appeared within 6 h after lights-out during the first shifted night, and an almost 1-h advance of the melatonin offset. No further adaptation occurred during the second shifted sleep period. Zolpidem had no beneficial effects on the adaptation of the melatonin profile. There was no relationship between sleep parameters and the magnitude of the melatonin shifts. Thus the overall advance of melatonin profiles was primarily achieved during the initial exposure to an 8-h period of darkness. The present data suggest that exposure to dark affects human circadian phase.

A complex interrelationship exists between sleep and somatotropic activity. In humans, intravenous injections of growth hormone-releasing hormone (GHRH) given during sleep consistently stimulate slow-wave (SW) sleep, particularly when given in the latter part of the night. In the present study, the possible somnogenic effects induced under similar conditions by GH-releasing peptide (GHRP) were investigated in seven young healthy men. Bolus intravenous injections of GHRP-2 (1 μg/kg body wt) or saline, in randomized order, were given after 60 s of the third rapid-eye-movement period. All GHRP injections were immediately followed by transient prolactin elevations and by GH pulses of a magnitude within or around the upper limit of the physiological range. Except for a nonsignificant tendency to increased amounts of wakefulness during the 1st h after the injection, no effects of GHRP-2 administration on sleep were detected. There was in particular no enhancement of SW sleep. Thus, in contrast to GHRH, late-night single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep. The present data provide evidence against the involvement of the GHRP axis in human SW sleep regulation.

Sleep curtailment constitutes an increasingly common condition in industrialized societies and is thought to affect mood and performance rather than physiological functions. There is no evidence for prolonged or delayed effects of sleep loss on the hypothalamo-pituitary-adrenal (HPA) axis. We evaluated the effects of acute partial or total sleep deprivation on the nighttime and daytime profile of cortisol levels. Plasma cortisol profiles were determined during a 32-hour period (from 1800 hours on day 1 until 0200 hours on day 3) in normal young men submitted to three different protocols: normal sleep schedule (2300-0700 hours), partial sleep deprivation (0400-0800 hours), and total sleep deprivation. Alterations in cortisol levels could only be demonstrated in the evening following the night of sleep deprivation. After normal sleep, plasma cortisol levels over the 1800-2300-hour period were similar on days 1 and 2. After partial and total sleep deprivation, plasma cortisol levels over the 1800-2300-hour period were higher on day 2 than on day 1 (37 and 45% increases, p = 0.03 and 0.003, respectively), and the onset of the quiescent period of cortisol secretion was delayed by at least 1 hour. We conclude that even partial acute sleep loss delays the recovery of the HPA from early morning circadian stimulation and is thus likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess.

To define the physiological relationships between cardiovascular function, glucose regulation, and insulin secretion, we submitted nine young normotensive subjects to ambulatory blood pressure monitoring and blood sampling at 20-minute intervals for 24 hours to measure glucose, insulin, C peptide, cortisol, and growth hormone. Subjects ingested three identical carbohydrate-rich meals in the morning (8:30 am ), early afternoon (2 pm ), and evening (8 pm ). On the following day, they underwent an intravenous glucose tolerance test for quantification of insulin sensitivity. Significant postmeal increases in systolic pressure averaging 18±10 mm Hg in the morning, 18±8 mm Hg in the early afternoon, and 26±19 mm Hg in the evening were observed. Postprandial variations in diastolic pressure and heart rate were significant only for the morning meal. The magnitude of the postprandial increases in systolic pressure was correlated with the amount of insulin secreted in the morning but not later in the day. Pulses of growth hormone consistently occurred 3 to 4 hours after the morning and midday meals, as well as after the onset of sleep. Our findings indicate that under normal conditions, there is a quantitative relationship between postprandial insulin secretion and blood pressure.

The temporal relation between the first few hours of sleep and the secretion of growth hormone (GH), which is present in normal persons of both sexes from early childhood until late adulthood, is reviewed. In adults the most reproducible pulse of GH secretion occurs shortly after the onset of sleep in association with the first phase of slow-wave sleep (SWS) (stages III and IV). In men approximately 70% of the GH pulses during sleep coincide with SWS, and the amount of GH secreted during these pulses correlates with the concurrent amount of SWS. Sleep-related secretion of GH appears to be primarily dependent on the release of growth hormone-releasing-hormone. Rodent and human studies have shown that growth hormone-releasing hormone injections decrease wakefulness and increase SWS. During the fourth decade of life (ages 30 to 40 years) the total amount of GH secreted over a 24-hour span decreases by two- to threefold. Similarly, the amount of SWS decreases dramatically over the same narrow age range. Because the sleep-onset GH pulse is often the major secretory output in adults, age-related decrements in sleep-related GH secretion likely play a major role in the hyposomatotropism of senescence.

Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown.To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance.Randomized, 2-period, 2-condition, crossover clinical study.University of Chicago Clinical Resource Center.Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m(2) (SD, 1.6).Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity.Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt-tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test.The insulin concentration for the half-maximal pAkt-tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt-tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.This was a single-center study with a small sample size.Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues.National Institutes of Health.

Objective: To characterize sleep and the 24-hour profiles of cortisol, prolactin (PRL), and growth hormone (GH) secretion in mania. Methods: Blood was sampled at 15-minute intervals, and sleep was polygraphically recorded in eight unmedicated male patients with pure mania and the results compared with those from a group of 14 healthy age-matched controls. The circadian, sleep-related, and pulsatile hormonal variations were quantitatively characterized using specially designed computer algorithms. Results: The manic state was associated with alterations of corticotropic activity and circadian rhythmicity partially overlapping those previously observed in acute endogenous depression, consisting of an elevation of nocturnal cortisol levels and an early timing of the nadir of the circadian variation. Sleep onset was delayed and the sleep period was reduced. A trend for short rapid eye movement latencies was apparent in the adult patients. Both the amount and the temporal organization of PRL and GH secretion were normal. Conclusion: The manic state seems to be characterized by similar but less severe neuroendocrine and circadian abnormalities, compared with major depression.

To the Editor: Chronic sleep curtailment is endemic in modern societies. The majority of the daily testosterone release in men occurs during sleep.1 Sleep fragmentation and obstructive sleep apnea are associated with reduced testosterone levels.2 In older men, morning testosterone levels are partly predicted by total sleep time.3 Testosterone is critical in male sexual behavior and reproduction, but also has important beneficial effects on muscle mass and strength, adiposity, bone density, and vigor and well-being.4 We investigated the effect of 1 week of sleep restriction on testosterone levels in young healthy men.