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Introduction Circadian misalignment increased systemic inflammation in sleep experiments and in those performing shift work. Milder degree of circadian misalignment such as day-to-day shift in sleep timing, i.e. sleep variability, was related to inflammation in population studies. Further, other sleep disturbances and glycemic control can contribute to inflammation. This pilot study explored if sleep variability was associated with inflammation in type 2 diabetes (T2D). Methods Subjects included 35 non-shift working T2D patients with and without diabetic retinopathy (DR) who were participating in a clinical study (NCT04547439). Sleep pattern was assessed by 14-day actigraphy, yielding sleep duration and efficiency. Standard deviation of sleep duration across the night was used to represent sleep variability. Sleep apnea severity was assessed by an overnight home monitor. Neuropathy pain, statin use, serum creatinine, low-density lipoprotein (LDL), HbA1C and by high-sensitivity c-reactive protein (hs-CRP) were collected. Spearman’s correlation analyses and multiple regression analysis (using natural-log transformed values) were performed to establish an independent association between sleep variability and hs-CRP. Results Mean (SD) age was 54.3 (6.4) years, 54.3% were female and 62.9% had DR. Median (interquartile range) of sleep variability was 69 (56,84) minutes. Median A1C was 7.5 (6.6, 8.7)% and hs-CRP was 2.4 (1.4, 4.6) mg/L. Higher hs-CRP was significantly associated with higher sleep variability (r=0.342, p=0.04), HbA1c (r=0.431, p=0.01) and LDL (r=0.379, p=0.03), but not with sleep duration, sleep efficiency, sleep apnea severity, DR status or other variables. Multiple regression analysis showed that higher sleep variability (B = 0.91, p=0.034) and higher HbA1c (B = 1.51, p=0.035), but not LDL, contributed to higher hs-CRP. Conclusion Higher sleep variability in non-shift working T2D patients was shown to be independently associated with higher systemic inflammation, conferring higher cardiovascular risk. This data supports the role of even a mild degree of circadian misalignment on systemic inflammation. Further investigations are needed to determine whether sleep intervention to increase sleep regularity can reduce systemic inflammation and improve cardiometabolic health. Support (if any) NEI R01EY029782 The University of Illinois Chicago Center for Clinical and Translational Science, which is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002003.”

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

Circadian rhythmicity is an approximately 24-h cell-autonomous period driven by transcription–translation feedback loops of specific genes, which are referred to as ‘circadian clock genes’. In mammals, the central circadian pacemaker, which is located in the hypothalamic suprachiasmatic nucleus, controls peripheral circadian clocks. The circadian system regulates virtually all physiological processes, which are further modulated by changes in the external environment, such as light exposure and the timing of food intake. Chronic circadian disruption caused by shift work, travel across time zones or irregular sleep–wake cycles has long-term consequences for our health and is an important lifestyle factor that contributes to the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamic–pituitary–thyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer., ファイル公開：2020/04/01

The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(−) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(−) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(−), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(−) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(−) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

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 beta-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with beta-cell function in overweight/obese adults with prediabetes or recently-diagnosed, treatment-naïve type 2 diabetes. Research Design and Methods: 221 adults (57.5% men, age 54.5±8.7 years, BMI 35.1±5.5 kg/m2) completed one week of wrist actigraphy and one 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 and clamp-derived outcomes were evaluated with adjusted regression models. Results: Mean±SD objective sleep duration by actigraphy was 6.6±1.0 hours/night. OSA defined as an apnea-hypopnea index (AHI) ≥5 events per hour was present in 89% of the participants; 20% mild, 28% moderate and 41% severe. Higher AHI was associated with higher HbA1c (p =0.007). However, OSA severity, measured by either AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or Conclusion: 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 beta-cell responses.

The prevalence of prediabetes and diabetes is substantially higher in PCOS women with obstructive sleep apnea (OSA) compared to PCOS women without OSA1,2,3. Prior studies, however, did not examine the complex interaction between race and OSA on metabolic function in PCOS. We sought to determine if the impact of OSA on glucose and insulin metabolism is affected by race. We studied non-Hispanic white (NHW) (n=53) and African-American (AA) (n=48) women with PCOS. Following an overnight polysomnogram (PSG), PCOS women (NHW without OSA n=40; NHW with OSA n=13; AA without OSA n=36; AA with OSA n=12) had a 2-h 75-g oral glucose tolerance test (OGTT) with blood sampling every 30 minutes for measurement of glucose, insulin, and C-peptide concentrations. OSA severity was measured by the Apnea-Hypopnea Index (AHI). Only women without OSA (AHI < 5) or with moderate-to-severe OSA (AHI > 15) were included in these analyses; women with mild OSA were excluded. Insulin secretion rates (ISR) during the OGTT were derived by deconvolution of C-peptide levels 4. Area under the curve (AUC) response to the glucose challenge was calculated using the trapezoidal method. BMI and age did not differ between races in PCOS women without OSA (BMI [kg/m2]: 36.3±1.2 vs. 37.2±1.1, p=0.58; Age [yr]: 27.7±0.8 vs. 27.2±0.8, p=0.65; for NHW and AA respectively), or in PCOS women with OSA (BMI [kg/m2]: 42.8±1.7 vs. 44.7±2.0, p=0.50; Age [yr]: 31.4±1.6 vs. 28.6±1.6, p=0.18; for NHW and AA respectively). OSA severity was similar in NHW and AA PCOS women without OSA (AHI: 1.5±0.2 vs 2.1±0.2, p=0.076), and PCOS women with OSA (AHI: 32.0±4.9 vs. 28.3±4.4, p=0.26). Higher glucose responses during the OGTT were observed in NHW PCOS women with OSA compared to both NHW (AUC: 18,965±648 vs. 15,797±371, p=0.0004) and AA (AUC: 18,965±648 vs. 15,801±497, p=0.0005) PCOS women without OSA. Glucose responses did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 17,104±965 vs. 15,801±497, p=0.15). Similarly, ISR was higher in NHW PCOS women with OSA compared to both NHW (AUC: 5,648±488 vs. 3,907±231, p=0.0006) and AA (AUC: 5,648±488 vs. 3,981±235, p=0.0011) PCOS women without OSA. ISR did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 4,827±461 vs. 3,981±235, p=0.09). CONCLUSIONS: OSA has a greater impact on glucose and ISR during an oral glucose challenge in NHW compared to AA women with PCOS. Future studies would benefit from including race when evaluating metabolic outcomes in women with PCOS. References: 1Fogel et al., J Clin Endocrinol Metab. 2001: 86:1175–1180. 2Kapsimalis et al., Sleep. 2002; 25:499–506. 3Kapsimalis et al., Sleep. 2002; 25:412–419. 4Polonsky et al., J Clin Invest. 1986 Jan; 77(1):98–105.

A large body of epidemiologic evidence has linked insufficient sleep duration and quality to the risk of obesity, insulin resistance and type 2 diabetes. To address putative causal mechanisms, this review focuses on laboratory interventions involving several nights of experimental sleep restriction, fragmentation or extension and examining metabolically relevant outcomes. Sleep restriction has been consistently shown to increase hunger, appetite and food intake, with the increase in caloric intake in excess of the energy requirements of extended wakefulness. Findings regarding decreases in hormones promoting satiety or increases in hormones promoting hunger have been less consistent, possibly because of confounding effects of changes in adiposity when energy intake was not controlled and sampling protocols that did not cover the entire 24-h cycle. Imaging studies revealed alterations in neuronal activity of brain regions involved in food reward. An adverse impact of experimental sleep restriction on insulin resistance, leading to reduced glucose tolerance and increased diabetes risk, has been well-documented. There is limited evidence indicating that sleep fragmentation without reduction in sleep duration also results in a reduction in insulin sensitivity. The adverse metabolic outcomes of sleep disturbances appear to involve multiple mechanistic pathways acting in concert. Emerging evidence supports the benefits of behavioral, but not pharmacological, sleep extension on appetite and glucose metabolism. Further research should focus on the feasibility and efficacy of strategies to optimize sleep duration and quality on obesity and diabetes risk in at-risk populations as well as those with established diseases. Further work is needed to identify mechanistic pathways.

Introduction The importance of diet for health has been recognized for centuries, yet, the focus has mostly been on what someone eats. Recently, however, focus has expanded to include when someone eats. Experimental studies that manipulated timing of food intake demonstrated effects on metabolic function. Most population-based studies have had to rely on self-reported methods to assess dietary behavior, including food logs or dietary recall, but self-report is subjective, error-prone, and burdensome. The goal of this analysis was to identify an objective estimate of dietary timing in clock time format. Further, we planned to examine whether sleep “chronotype” and this dietary “chronotype” are correlated. Methods We used continuous glucose monitoring (CGM), which involves inserting a small sensor into the back of a participant’s upper arm. It measures interstitial glucose levels every 5 minutes continuously for up to 2 weeks. We had 13 participants wear a CGM device for 2–10 days. We characterized dietary timing by simply identifying the clock time at which glucose levels were the highest. We identified this time point for each day and then calculated the mean clock time for each participant. Participants also wore wrist actigraphy for approximately one week and we calculated mean sleep start, sleep end, and midpoint times. We calculated intervals between highest glucose and sleep timing measures. Results The mean time of highest glucose was 16:57 (SD 3:05) and ranged from 11:16 to 22:27. The mean (SD) intervals were 10.4 (2.9) hours for sleep end to highest glucose, 13.5 (2.8) hours for midpoint to highest glucose, and 5.8 (2.8) hours for highest glucose to sleep start. The correlations between highest glucose and sleep timing were .13 (p=.70) for sleep start, .05 (p=.88) for sleep end, and -.19 (p=.55) for midpoint. Conclusion There was a wide range in the timing of highest glucose values in this sample, Further, the timing of highest glucose does not correlate with sleep timing, which indicates that these two timing measures are not redundant with one another. The timing of highest glucose from CGM may provide an objective, simple circadian biomarker of dietary behavior. Support (if any) P01A1011412-18A1

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

Sleep disturbances [short (6 h) and long (8 h) sleeping time, insomnia (initiating or maintaining sleep), obstructive sleep apnea (OSA) and abnormal sleep timing] have been associated with increased diabetes risk but the effect size relative to that of traditional risk factors is unknown. We conducted a systematic review and meta-analysis to compare the risk associated with sleep disturbances to traditional risk factors. Studies were identified from Medline and Scopus. Cohort studies measuring the association between sleep disturbances and incident diabetes were eligible. For traditional risk factors (i.e., overweight, family history, and physical inactivity), systematic reviews with or without meta-analysis were included. Thirty-six studies (1,061,555 participants) were included. Pooled relative risks (RRs) of sleep variables were estimated using a random-effect model. Pooled RRs of sleeping ≤5 h, 6 h, and ≥9 h/d were respectively 1.48 (95%CI:1.25,1.76), 1.18 (1.10,1.26) and 1.36 (1.12,1.65). Poor sleep quality, OSA and shift work were associated with diabetes with a pooled RR of 1.40 (1.21,1.63), 2.02 (1.57, 2.61) and 1.40 (1.18,1.66), respectively. The pooled RRs of being overweight, having a family history of diabetes, and being physically inactive were 2.99 (2.42,3.72), 2.33 (1.79,2.79), and 1.20 (1.11,1.32), respectively. In conclusion, the risk of developing diabetes associated with sleep disturbances is comparable to that of traditional risk factors. Sleep disturbances should be considered in clinical guidelines for type 2 diabetes screening.

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.

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

Poor sleep may be associated with an increased risk of obesity and T2D in youth. We explored whether subjective sleep duration, sleep quality or risk factors for obstructive sleep apnea (OSA) are associated with BMI, glycemia or blood pressure (BP) in youth. Between 2013 and 2016, 236 overweight and obese youth (10-19 years old) at risk for or with recently diagnosed T2D were screened for the Restoring Insulin Secretion (RISE) Study. Data from a 2 hour OGTT and validated Sleep Disturbances Scale and Cleveland Adolescent Sleepiness questionnaires were available for 214 youth. Regression models explored the independent association between sleep variables and outcomes of fasting glucose, 2-h glucose, HbA1c, BMI and BP. The cohort consisted of 67% females, 33% males; 26% white, 26% black, 33% hispanic; age 14.1±2.1 years and BMI 35.9±6.5 kg/m2 (mean±SD). Based on the ADA criteria, 20% had normal glucose tolerance, 60% had prediabetes and 20% had T2D. Sleep duration Disclosure B. Mokhlesi: None. K.A. Temple: None. A.N. Hogan: None. S. Edelstein: None. K.J. Nadeau: None. S. Sam: None. T. Hannon: Consultant; Self; Eli Lilly and Company. K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. E. Barengolts: None. S. Manchanda: None. D.A. Ehrmann: None. E. Van Cauter: Research Support; Self; AstraZeneca. R. Consortium: None.

Abnormal sleep and circadian misalignment (e.g., social jetlag, late chronotype, or shift work) have been associated with abnormal glucose metabolism. These associations have not been well established in adults who meet the ADA criteria for prediabetes. We hypothesized that self-reported short sleep, poor sleep quality or circadian misalignment are associated with worse glycemia, BP and BMI in adults with prediabetes or early untreated T2D. We screened 1,355 overweight/obese men and women age 20-65 y for the Restoring Insulin Secretion (RISE) Study. Completed data from a 2-h OGTT, HbA1c and sleep questionnaires were available for 704 adults with prediabetes and 258 with early untreated T2D. We used a modified Pittsburgh Sleep Quality Index to assess usual bedtime, wake time, and sleep duration on workdays and days off, and the Berlin questionnaire to assess the risk of obstructive sleep apnea (OSA). Regression models explored the independent associations of sleep variables with glycemic variables, BMI and BP. The cohort was 55% men, 45% women; 42% white, 36% black, 16% Hispanic; age 52.2±9.5 years and BMI 34.7±5.5 kg/m2 (mean±SD). Sleep duration was 6.6±1.3 h, poor sleep quality was reported by 54%, high risk for OSA in 64% and 20% did shift work. After adjusting for age, sex, and race/ethnicity, shift work was associated with 1.32 kg/m2 higher BMI (p=0.0043). After adjusting for age, sex, race/ethnicity and BMI, no sleep or circadian variables (sleep duration, sleep quality, OSA risk, shift work, social jetlag and chronotype) were associated with HbA1c, fasting or 2-h glucose, or BP. In this cohort with prediabetes or early untreated T2D, subjective measures of sleep duration, quality and circadian misalignment were not associated with measures of glycemia or BP. Shift workers were more obese. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia. Disclosure B. Mokhlesi: None. K.A. Temple: None. A.N. Hogan: None. S. Edelstein: None. K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. K.J. Nadeau: None. T. Hannon: Consultant; Self; Eli Lilly and Company. S. Sam: None. E. Barengolts: None. S. Manchanda: None. D.A. Ehrmann: None. E. Van Cauter: Research Support; Self; AstraZeneca. R. Consortium: None.

Objectives: Obstructive sleep apnea (OSA) is more prevalent in men and is an independent risk factor for type 2 diabetes. We aimed to determine if there are sex differences in the impact of OSA on glucose metabolism in nondiabetic overweight and obese adults. Methods: One hundred and forty-five men and women (age 33.4 ± 0.6, BMI 37.2 ± 0.7, 70.3% blacks) from the community underwent in-laboratory polysomnography. Severity of OSA was assessed by the apnea-hypopnea index (AHI). Glucose tolerance was assessed using fasting glucose, 1-h glucose, 2-h glucose and the area under the curve (AUC) during the 2-h oral glucose tolerance test (OGTT). Fasting insulin resistance was assessed by HOMA-IR, and insulin sensitivity during the OGTT was assessed by the Matsuda Index. Pancreatic beta-cell function was assessed by fasting HOMA-%B and by AUCinsulin/glucose, insulinogenic index, and oral disposition index (DIoral) during the OGTT. All comparisons were adjusted for age, BMI, race and severity of OSA. Results: There were no significant demographic differences between men and women without OSA. Men and women with OSA were similar in age, BMI, and severity of OSA, but there were more black women with OSA. Compared to women with OSA, men with OSA had significantly higher fasting glucose, 1-h glucose levels, AUCglucose, and AUC for insulin secretion rate (AUCISR) but similar 2-h glucose levels. These differences persisted in adjusted analyses. Men with OSA secreted significantly more insulin than women with OSA in order to achieve similar glucose levels. Men with OSA had significantly worse beta cell function as measured by the DIoral than women with OSA. In contrast, there were no significant sex differences in measures of glucose tolerance and beta-cell function in participants without OSA. Conclusion: Men with OSA secreted more insulin compared to women with OSA in order to maintain glucose homeostasis. The adverse impact of OSA on beta-cell responsiveness was larger in men, which may result in an overall greater risk of type 2 diabetes compared to women.

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.

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.

Context: Questionnaire studies linked symptoms of obstructive sleep apnea (OSA) to the risk of gestational diabetes mellitus (GDM). Whether this association is present when OSA is assessed objectively by polysomnography is not known. Objective: The objective of the study was to assess the relationship between pregnancy, OSA, and GDM. Design, Setting, and Participants: We conducted observational case-control studies using polysomnography in 15 nonpregnant, nondiabetic women (NP-NGT), 15 pregnant women with normal glucose tolerance (P-NGT), and 15 pregnant women with GDM (P-GDM). The groups were frequency matched for age and race/ethnicity. Pregnant women were studied during the late second to early third trimester. Main Outcome Measures: Comparisons of OSA diagnosis and sleep parameters between NP-NGT and P-NGT to assess the impact of pregnancy and between P-NGT and P-GDM to explore the association between GDM and OSA were measured. Results: Compared with NP-NGT, P-NGT women had a higher apnea hypopnea index (AHI) (median 2.0 vs 0.5, P = .03) and more disrupted sleep as reflected by a higher wake time after sleep onset (median 66 vs 21 min, P < .01) and a higher microarousal index (median 16.4 vs 10.6, P = .01). Among the pregnant women, P-GDM had markedly lower total sleep time (median 397 vs 464 min, P = .02) and a higher AHI (median 8.2 vs 2.0, P = .05) than P-NGT women. OSA was more prevalent in P-GDM than in P-NGT women (73% vs 27%, P = .01). After adjustment for prepregnancy body mass index, the diagnosis of GDM was associated with a diagnosis of OSA [odds ratio 6.60 (95% confidence interval 1.15–37.96)]. In pregnancy, after adjusting for prepregnancy body mass index, higher microarousal index significantly associated with higher hemoglobin A1c and fasting glucose levels. Higher oxygen desaturation index was associated with higher fasting glucose levels. Conclusion: Pregnancy is associated with sleep disturbances. Sleep is more disturbed in GDM than in P-NGT women. There is a strong association between GDM and OSA.

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.

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.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

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 RESULTS There was no association between sleep measures and fasting glucose, insulin, or HOMA in the 115 subjects without diabetes. Among the 40 subjects with diabetes, after adjustment for covariates, 10% higher sleep fragmentation was associated with a 9% higher fasting glucose level, a 30% higher fasting insulin level, and a 43% higher HOMA level. Insomnia was associated with a 23% higher fasting glucose level, a 48% higher fasting insulin level, and an 82% higher HOMA level. CONCLUSIONS The observed association between poor sleep quality and higher glucose, insulin, and estimated insulin resistance among subjects with diabetes warrants further examination of the effect of sleep disturbances on glucose control in type 2 diabetes.

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.

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.

Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory and epidemiological studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympathovagal balance, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. We also review cross-sectional epidemiological studies associating short sleep with increased body mass index and prospective epidemiological studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.

Type 2 diabetes is a major public health concern with high morbidity, mortality, and health-care costs. Recent reports have indicated that the majority of patients with type 2 diabetes also have obstructive sleep apnea (OSA). There is compelling evidence that OSA is a significant risk factor for cardiovascular disease and mortality. Rapidly accumulating data from both epidemiologic and clinical studies suggest that OSA is also independently associated with alterations in glucose metabolism and places patients at an increased risk of the development of type 2 diabetes. Experimental studies in humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in OSA, exert adverse effects on glucose metabolism. Based on the current evidence, clinicians need to address the risk of OSA in patients with type 2 diabetes and, conversely, evaluate the presence of type 2 diabetes in patients with OSA. Clearly, there is a need for further research, using well-designed studies and long-term follow-up, to fully demonstrate a causal role for OSA in the development and severity of type 2 diabetes. In particular, future studies must carefully consider the confounding effects of central obesity in examining the link between OSA and alterations in glucose metabolism. The interactions among the rising epidemics of obesity, OSA, and type 2 diabetes are likely to be complex and involve multiple pathways. A better understanding of the relationship between OSA and type 2 diabetes may have important public health implications.

There is convincing evidence that, in humans, discrete sleep stages are important for daytime brain function, but whether any particular sleep stage has functional significance for the rest of the body is not known. Deep non-rapid eye movement (NREM) sleep, also known as slow-wave sleep (SWS), is thought to be the most “restorative” sleep stage, but beneficial effects of SWS for physical well being have not been demonstrated. The initiation of SWS coincides with hormonal changes that affect glucose regulation, suggesting that SWS may be important for normal glucose tolerance. If this were so, selective suppression of SWS should adversely affect glucose homeostasis and increase the risk of type 2 diabetes. Here we show that, in young healthy adults, all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk. SWS suppression reduced delta spectral power, the dominant EEG frequency range in SWS, and left other EEG frequency bands unchanged. Importantly, the magnitude of the decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS. These findings demonstrate a clear role for SWS in the maintenance of normal glucose homeostasis. Furthermore, our data suggest that reduced sleep quality with low levels of SWS, as occurs in aging and in many obese individuals, may contribute to increase the risk of type 2 diabetes.

Sleep exerts modulatory effects on components of the endocrine system; depending on the endocrine axis hormonal secretion may be stimulated or inhibited during sleep. Reciprocally, several hormones have effects on sleep architecture. The sleep-wake cycle is under dual control of a centrally generated endogenous circadian signal and of a homeostatic mechanism relating sleep duration and intensity to the duration of prior wakefulness. This dual control affects the temporal organization of hormonal release. The physiological response of hormonal secretions to sleep is disturbed during sleep deprivation and when sleep is shallow and/or fragmented. Part of the hormonal and metabolic changes observed in older adults could be secondary to the decreases in sleep duration and quality that characterize aging.

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.

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.

Context Women with polycystic ovary syndrome (PCOS) are insulin resistant and are at increased risk for sleep apnea, which, in turn, may contribute to insulin resistance. Objective The objective of this study was to determine relationships between risk and severity of obstructive sleep apnea (OSA) and glucose metabolism in PCOS. Design and setting This study included two cohorts of women with PCOS in a tertiary care hospital. Patients and main outcome measures Cohort 1 included 40 nondiabetics who completed the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality, and the Berlin Questionnaire to assess risk of OSA; 32 of the 40 women had an oral glucose tolerance test. Cohort 2 included eight women who had a sleep study, glycosylated hemoglobin level, and an oral glucose tolerance test. Results In cohort 1, 62.5% of the women had poor sleep quality by Pittsburgh Sleep Quality Index, and 18 (45%) had chronic daytime sleepiness by Epworth Sleepiness Scale. Thirty of the 40 women had a high risk of OSA by Berlin Questionnaire. Women with high OSA risk had higher fasting insulin levels and homeostasis model assessment index compared with those with low OSA risk (168.2 +/- 17.3 vs. 97.2 +/- 6.4 pmol/liter, P = 0.011; 6.3 +/- 0.7 vs. 3.6 +/- 0.3 mg/dl x microU/ml, P = 0.014, respectively). Among women with normal glucose tolerance, insulin levels were significantly higher in those at high vs. low OSA risk, independently of body mass index. Women in cohort 2 had rapid eye movement (REM)-predominant OSA with lower sleep efficiency, longer sleep latency, and less REM sleep than controls. Glycosylated hemoglobin levels and the area under the glucose curve positively correlated with the apnea-hypopnea index (rP = 0.82, P = 0.013; rP = 0.96, P = 0.0008, respectively) and the number of oxygen desaturations in REM sleep (rP = 0.97, P = 0.0009; rP = 0.97, P = 0.005, respectively). Conclusion PCOS is associated with poor sleep quality, daytime sleepiness, and increased risk for OSA. Insulin levels and measures of glucose tolerance in PCOS are strongly correlated with the risk and severity of OSA.

Study objectives To examine sex effects on sleep stages and electroencephalogram (EEG) spectral power in older adults. Design Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled 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), and 10 postmenopausal women (63 +/- 2 years). Interventions N/A. Measurements and results A spectral analysis of the EEG was performed in the delta and alpha bands. There were no sex differences in sleep stages. Blood sampling resulted in reductions of total sleep time, sleep maintenance, slow-wave sleep, and absolute delta activity that were all larger in women than in men. In absolute values, delta and alpha activities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were higher in women than in men, but, for delta activity, the sex differences were larger in REM than in NREM sleep. In women, but not in men, absolute delta activity in REM was decreased during blood sampling and was strongly correlated with absolute delta activity in NREM. Delta activity in REM did not dissipate across the night in either group. When normalized for the activity in REM sleep, the sex difference in delta activity in NREM sleep was reversed, with lower activity in women. Conclusions Sex differences in sleep EEG variables are present in older adults. When normalized, delta activity in older women is lower than in older men, which may be more consistent with sex differences in subjective complaints, in fragility of sleep in the presence of environmental disturbances, and in the relationship to growth-hormone release.

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.

For more than 30 years, growth hormone (GH) has been observed to be preferentially secreted during deep, slow-wave sleep (SWS). However, the mechanisms that underlie this robust relationship that links anabolic processes in the body with behavioral rest and decreased cerebral metabolism remain to be elucidated. Current evidence indicates that GH secretion during the beginning of sleep appears to be primarily regulated by GH-releasing hormone (GHRH) stimulation occurring during a period of relative somatostatin withdrawal, which also is associated with elevated levels of circulating ghrelin. Apparently, two populations of GHRH neurons need to be simultaneously active to stimulate, in a coordinated fashion, SWS and pituitary GH release. Pharmacological interventions that are capable of increasing the duration and/or the intensity of SWS such as oral administration of gamma-hydroxybutyrate (GHB), also increase the rate of GH release. Because the normal negative feedback exerted by GH on central GHRH is inoperative in patients with GH deficiency, it is possible that the decreased energy levels and fatigue often reported by GH-deficient adults partly reflect an alteration in sleep-wake regulation. Preliminary data from a sleep study of adults with GH deficiency using wrist actigraphy for 6 nights at home and polysomnography in the laboratory indeed show decreased total sleep time and increased sleep fragmentation in GH-deficient patients as compared with normal controls.

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.

Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk. Well-controlled laboratory studies have provided insights regarding the underlying mechanisms. Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health. Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies are discussed.

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