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Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism.
Skene, DJ, Skornyakov, E, Chowdhury, NR, Gajula, RP, Middleton, B, Satterfield, BC, Porter, KI, Van Dongen, HPA, Gaddameedhi, S
Proceedings of the National Academy of Sciences of the United States of America. 2018;(30):7825-7830
Abstract
Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day-shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN-melatonin, cortisol, and PER3 expression-maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders.
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Chronopathophysiological implications of orexin in sleep disturbances and lifestyle-related disorders.
Tsuneki, H, Wada, T, Sasaoka, T
Pharmacology & therapeutics. 2018;:25-44
Abstract
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus. Central levels of orexin oscillate with the daily rhythm and peak at the awake phase. Orexin plays a major role in stabilizing the wakefulness state. Orexin deficiency causes sleep/wake-state instability, resulting in narcolepsy. Hyper-activation of the orexin system also causes sleep disturbances, such as insomnia, and hence, suvorexant, an orexin receptor antagonist, has been clinically used to treat insomnia. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating the central-autonomic nervous systems and endocrine systems. These multiple actions of orexin maintain survival. However, it remains unknown whether chronopharmacological interventions targeting the orexin system ameliorate sleep-related disorders as well as sleep in humans. To understand the significance of adequate orexin action for prevention of these disorders, this review summarizes the physiological functions of daily orexin action and pathological implications of its mistimed or reduced action in sleep disturbances and sleep-related disorders (lifestyle-related physical and neurological disorders in particular). Timed administration of drugs targeting the orexin system may prevent lifestyle-related diseases by improving the quality of life in patients with sleep disturbances.
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Effects of daytime versus night-time cesarean deliveries on Stage II lactogenesis.
İlhan, G, Atmaca, FV, Çümen, A, Zebitay, AG, Güngör, ES, Karasu, AFG
The journal of obstetrics and gynaecology research. 2018;(4):717-722
Abstract
AIM: The circadian timing system has a rhythm and one of the roles of this system is the mediation of hormonal and metabolic adaptations to lactation. This study was conducted to determine whether the time to stage II lactogenesis differed in women who underwent cesarean section (CS) in the daytime (DT) or night-time (NT). METHODS This study was conducted at Süleymaniye Research and Education Hospital between June and December 2016. Two hundred and eighty-eight mothers who had a cesarean delivery and their healthy singleton neonates were included. Clinical and demographic data of the mothers and neonates, time of initiation of breastfeeding and time to stage II lactogenesis were analyzed according to DT or NT CS groups. RESULTS There were no statistically significant differences in age, gravida, parity, body mass index, week of gestation at birth, postoperative hemoglobin level, cesarean indications, anesthesia type, previous history of breastfeeding, transfusion need, Apgar scores or birth weight-height of neonates between the DT and NT CS groups. While the time of initiation of breastfeeding did not differ statistically in terms of DT or NT CS groups, the time to stage II lactogenesis was significantly longer in the NT CS group. CONCLUSIONS NT cesarean delivery is a risk factor for the delayed onset of lactogenesis. The results of this study may be useful to clinical practitioners counseling mothers who undergo NT cesarean delivery.
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Links between the circadian rhythm, obesity and the microbiome.
Rácz, B, Dušková, M, Stárka, L, Hainer, V, Kunešová, M
Physiological research. 2018;(Suppl 3):S409-S420
Abstract
Obesity is linked to a wide range of serious illnesses. In addition to the important impact on the health of the individual, obesity also has a substantial impact on the economy. Disruption of physiological day-night cycles could contribute to the increased incidence of obesity. According to the American National Sleep Federation, the percentage of the people who reported a sleep duration of six hours or less increased from 12 to 37 % over ten years. Insufficient sleep leads not only to an increase of the total calorie intake but changes the meal preference in favor of palatable foods and meals with high carbohydrate content. A decrease of leptin and increase of ghrelin levels caused by sleep deficiency can also play a role. In addition to the higher caloric intake, the timing of food consumption should be taken into account. The same meal eaten during the night versus the day is associated with increased postprandial glucose and triglyceride levels. The gut microbiome has also been recently understood as an endocrine system, with links between the gut microbiome and circadian rhythm changes possibly influencing increased obesity.
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Diurnal distribution of carbohydrates and fat affects substrate oxidation and adipokine secretion in humans.
Kessler, K, Hornemann, S, Petzke, KJ, Kemper, M, Markova, M, Rudovich, N, Grune, T, Kramer, A, Pfeiffer, AFH, Pivovarova-Ramich, O
The American journal of clinical nutrition. 2018;(6):1209-1219
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BACKGROUND A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes. OBJECTIVE We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers. DESIGN In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). During a 12-h clinical investigation day after each intervention period, 2 meal tolerance tests were performed, at 0900 and 1540, respectively. Substrate oxidation and concentrations of circulating lipids, adipokines, and cytokines were assessed pre- and postprandially. The postprandial inflammatory response in leukocytes was analyzed ex vivo. RESULTS Fasting carbohydrate oxidation decreased (P = 0.004) and lipid oxidation increased (P = 0.012) after the HC/HF diet. Fasting concentrations of blood markers did not differ between diets. The diets modulated the daily profiles of carbohydrate oxidation, lipid oxidation, and β-hydroxybutyrate, although the average daily values of these parameters showed no difference between the diets, and no interaction between diet and glucose tolerance status. Diurnal patterns of triglycerides, low-density lipoprotein cholesterol, leptin, visfatin, and of LPS-induced cytokine secretion in blood leukocytes were also modulated by the diets. Average daily concentrations of leptin (P = 0.017) and visfatin (P = 0.041) were lower on the HF/HC diet than on the HC/HF diet. CONCLUSIONS Diurnal distribution of carbohydrates and fat affects the daily profiles of substrate oxidation, circulating lipids, and cytokine secretion, and alters the average daily concentrations of adipokine secretion in nonobese nondiabetic humans. The study was registered at clinicaltrials.gov as NCT02487576.
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Modifying the Impact of Eveningness Chronotype ("Night-Owls") in Youth: A Randomized Controlled Trial.
Harvey, AG, Hein, K, Dolsen, EA, Dong, L, Rabe-Hesketh, S, Gumport, NB, Kanady, J, Wyatt, JK, Hinshaw, SP, Silk, JS, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2018;(10):742-754
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OBJECTIVE To determine whether an intervention to reduce eveningness chronotype improves sleep, circadian, and health (emotional, cognitive, behavioral, social, physical) outcomes. METHOD Youth aged 10 to 18 years with an evening chronotype and who were "at risk" in 1 of 5 health domains were randomized to: (a) Transdiagnostic Sleep and Circadian Intervention for Youth (TranS-C; n = 89) or (b) Psychoeducation (PE; n = 87) at a university-based clinic. Treatments were 6 individual, weekly 50-minute sessions during the school year. TranS-C addresses sleep and circadian problems experienced by youth by integrating evidence-based treatments derived from basic research. PE provides education on the interrelationship between sleep, stress, diet, and health. RESULTS Relative to PE, TranS-C was not associated with greater pre-post change for total sleep time (TST) or bed time (BT) on weeknights but was associated with greater reduction in evening circadian preference (pre-post increase of 3.89 points, 95% CI = 2.94-4.85, for TranS-C, and 2.01 points, 95% CI = 1.05-2.97 for PE, p = 0.006), earlier endogenous circadian phase, less weeknight-weekend discrepancy in TST and wakeup time, less daytime sleepiness, and better self-reported sleep via youth and parent report. In terms of functioning in the five health domains, relative to PE, TranS-C was not associated with greater pre-post change on the primary outcome. However, there were significant interactions favoring TranS-C on the Parent-Reported Composite Risk Scores for cognitive health. CONCLUSION For at-risk youth, the evidence supports the use of TranS-C over PE for improving sleep and circadian functioning, and improving health on selected outcomes. CLINICAL TRIAL REGISTRATION INFORMATION Triple Vulnerability? Circadian Tendency, Sleep Deprivation and Adolescence. https://clinicaltrials.gov; NCT01828320.
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[Thermal and Lighting Housing Environments and Circadian Blood Pressure Variability: Findings from the HEIJO-KYO Cohort].
Obayashi, K, Saeki, K
Nihon eiseigaku zasshi. Japanese journal of hygiene. 2018;(2):138-142
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The purpose of this short review is to describe the influence of housing environment temperature and lighting on circadian blood pressure (BP) variability using data from the HEIJO-KYO cohort, a community-based cohort study launched in 2010. Increased excess mortality from cardiovascular disease in winter is a worldwide problem. Previous studies showed higher conventional BP and higher daytime ambulatory BP in winter; however, the relationship between indoor cold exposure and circadian BP variability remained unknown. In our cohort, we found a significant inverse relationship between indoor temperature and morning BP surge, independent of potential confounding factors. In addition, we found the tertile group with the lowest daytime indoor temperatures showed significantly higher urinary sodium excretion than the tertile group with the highest daytime indoor temperatures. Higher sodium intake caused by indoor cold exposure may partly explain the higher BP in winter. Physiologically, light exposure is the most important environmental cue for the circadian timing system and melatonin secretion. In our cohort, we observed that an increase in nighttime short-wave length light exposure and a decrease in daytime light exposure were significantly associated with lower melatonin secretion. Furthermore, lower melatonin levels were significantly related to higher nighttime BPs and parameters of atherosclerosis, which are predictors of cardiovascular disease incidence. Further longitudinal studies of the influence of housing environment temperature and lighting on cardiovascular disease incidence are required.
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Sleep in Normal Aging.
Li, J, Vitiello, MV, Gooneratne, NS
Sleep medicine clinics. 2018;(1):1-11
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Sleep patterns change with aging, independent of other factors, and include advanced sleep timing, shortened nocturnal sleep duration, increased frequency of daytime naps, increased number of nocturnal awakenings and time spent awake during the night, and decreased slow wave sleep. Most of these changes seem to occur between young and middle adulthood; sleep parameters remain largely unchanged among healthy older adults. The circadian system and sleep homeostatic mechanisms become less robust with normal aging. The amount and pattern of sleep-related hormone secretion change as well. The causes of sleep disturbances in older adults are multifactorial.
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Association Between Change in Central Nocturnal Blood Pressure and Urine Albumin-Creatinine Ratio by a Valsartan/Amlodipine Combination: A CPET Study.
Fujiwara, T, Yano, Y, Hoshide, S, Kanegae, H, Hashimoto, J, Kario, K
American journal of hypertension. 2018;(9):995-1001
Abstract
BACKGROUND We aimed to assess the association of changes in brachial or central nocturnal systolic blood pressure (SBP) with change in urine albumin-creatinine ratio (UACR) by a valsartan/amlodipine combination (80/5 mg) therapy in hypertensive patients. METHODS Twenty-three patients (age range, 47-78 years; mean, 68.0 years; 35% men, 65% with chronic kidney disease) with clinic brachial BP ≥140/90 mm Hg were treated with valsartan/amlodipine combination therapy for 16 weeks. At baseline and 16 weeks later, we measured brachial and central nocturnal SBP using an oscillometric Mobil-O-Graph device and UACR by spot urine in 23 patients. RESULTS The changes in brachial nocturnal SBP (r = 0.445, P = 0.033) and those in central nocturnal SBP (r = 0.616, P = 0.002) were significantly associated with change in UACR by intervention. In multivariable-adjusted multiple regression analyses including changes in both brachial and central nocturnal SBP jointly, only central nocturnal SBP change retained a statistically significant association with change in UACR (β = 0.919, P = 0.020). CONCLUSIONS Lowering central nocturnal SBP by a valsartan/amlodipine combination therapy was associated with reduction of UACR, independently of brachial nocturnal SBP reduction. Central nocturnal SBP may be a therapeutic target to protect the kidney. A larger scale interventional study will be needed to confirm the kidney protection conferred by lowering central nocturnal SBP. CLINICAL TRIALS REGISTRATION Trial Number UMIN000013519.
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Effect of canagliflozin on nocturnal home blood pressure in Japanese patients with type 2 diabetes mellitus: The SHIFT-J study.
Kario, K, Hoshide, S, Okawara, Y, Tomitani, N, Yamauchi, K, Ohbayashi, H, Itabashi, N, Matsumoto, Y, Kanegae, H
Journal of clinical hypertension (Greenwich, Conn.). 2018;(10):1527-1535
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on several cardiometabolic biomarkers, but this is not sufficient to fully explain the significant reduction in cardiovascular risk and mortality reported with SGLT2 inhibitor treatment in patients with diabetes mellitus. The 8-week, randomized, open-label SHIFT-J study investigated the effects of adding canagliflozin vs intensified antihyperglycemic therapy on nocturnal home blood pressure (BP) in patients with poorly controlled type 2 diabetes and nocturnal BP on existing therapy. Patients were randomized to oral canagliflozin 100 mg/d or control (increased hypoglycemic dosage/addition of another hypoglycemic agent). The efficacy analysis included 78 patients (mean 69 years; 59% male). Nocturnal home systolic BP [HSBP] decreased by 5.23 mm Hg in the canagliflozin group and by 1.04 mm Hg in the control group (P = 0.078 for between-group difference in change from baseline to week 8 [primary endpoint]); corresponding decreases in HSBP from baseline to week 4 were 5.08 and 1.38 mm Hg, respectively (P = 0.054). Reductions in morning HSBP from baseline to week 4 (-6.82 mm Hg vs -1.26 mm Hg, P = 0.038) and evening HSBP from baseline to week 8 (-8.74 mm Hg vs -2.36 mm Hg, P = 0.012) were greater in the canagliflozin group than in the control group. Body mass index (P < 0.001) and N-terminal pro B-type natriuretic peptide level (NT-proBNP; P = 0.023) decreased more in the canagliflozin group than in the control group. Glycemic control improved comparably in both groups. Reduction of HSBP and NT-proBNP level may be potential mechanism by which SGLT2 inhibitors reduce cardiovascular event risk.