Article

Daytime eating prevents internal circadian misalignment and glucose intolerance in night work

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Abstract

Night work increases diabetes risk. Misalignment between the central circadian “clock” and daily behaviors, typical in night workers, impairs glucose tolerance, likely due to internal misalignment between central and peripheral circadian rhythms. Whether appropriate circadian alignment of eating can prevent internal circadian misalignment and glucose intolerance is unknown. In a 14-day circadian paradigm, we assessed glycemic control during simulated night work with either nighttime or daytime eating. Assessment of central (body temperature) and peripheral (glucose and insulin) endogenous circadian rhythms happened during constant routine protocols before and after simulated night work. Nighttime eating led to misalignment between central and peripheral (glucose) endogenous circadian rhythms and impaired glucose tolerance, whereas restricting meals to daytime prevented it. These findings offer a behavioral approach to preventing glucose intolerance in shift workers.

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... The identification of this important modifiable factor highlights the urgent need for evidence-based circadian interventions to prevent mood vulnerability in this at-risk population. Daytime eating-despite mistimed sleep-can maintain internal circadian alignment and prevent glucose intolerance during simulated night work (6). As impaired glycemic control is a risk factor for mood disruption (7), we tested the prediction that daytime eating prevents mood vulnerability, despite simulated night work. ...
... Conversely, in the DMI group, no significant effects were observed (À3.1 to 9.9%; P = n.s.) (Fig. 1F). Importantly, we tested whether increased mood vulnerability during simulated night work was associated with the degree of internal circadian misalignment (i.e., change in the phase difference between the acrophase of circadian glucose rhythms and the bathyphase of circadian body temperature rhythms [expressed as the difference from baseline constant routine to postmisalignment constant routine protocol in hours]) (6). Accordingly, a larger degree of internal circadian misalignment was robustly associated with more depression-like and anxiety-like mood levels during simulated night work (linear regression models: r = 0.77; P = 0.001 and r = 0.67; P = 0.002, respectively) ( Fig. 1 G and H). ...
... However, the causal role of the timing of food intake on mental health remains to be tested. Nighttime work with daytime and nighttime eating (using identical test meals with ∼50% carbohydrate intake) impaired glucose tolerance, whereas no such effects occurred in nighttime work with daytime-only eating (6). Therefore, the beneficial effects of daytime eating on glucose tolerance may extend to mood perception; however, future studies are required to establish the effects of meal timing on individuals experiencing depressive and/or anxiety/anxiety-related disorders (SI Appendix has additional discussion). ...
Article
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Shift workers have a 25 to 40% higher risk of depression and anxiety partly due to a misalignment between the central circadian clock and daily environmental/behavioral cycles that may negatively affect mood and emotional well-being. Hence, evidence-based circadian interventions are required to prevent mood vulnerability in shift work settings. We used a stringently controlled 14-d circadian paradigm to assess mood vulnerability during simulated night work with either daytime and nighttime or daytime-only eating as compared with simulated day work (baseline). Simulated night work with daytime and nighttime eating increased depression-like mood levels by 26.2% (p-value adjusted using False Discovery Rates, pFDR = 0.001; effect-size r = 0.78) and anxiety-like mood levels by 16.1% (pFDR = 0.001; effect-size r = 0.47) compared to baseline, whereas this did not occur with simulated night work in the daytime-only eating group. Importantly, a larger degree of internal circadian misalignment was robustly associated with more depression-like (r = 0.77; P = 0.001) and anxiety-like (r = 0.67; P = 0.002) mood levels during simulated night work. These findings offer a proof-of-concept demonstration of an evidence-based meal timing intervention that may prevent mood vulnerability in shift work settings. Future studies are required to establish if changes in meal timing can prevent mood vulnerability in night workers.
... For instance, in humans, eating at night activates the liver clock at a time when the SCN wants to rest. In a simulated night shift study, researchers observed that nighttime eating can lead to a misalignment between the endogenous central clock (core body temperature) and peripheral clocks (glucose) [9]. ...
... Next, we assume the light-dark cycle of each day consists of 12 hours of light and 12 hours of darkness. Empirical evidence shows that the feed-fast cycle is more important than the light-dark cycle for circadian oscillations in peripheral clocks, so we minimize the effect of the feeding cues by providing scheduled feeding four times per day at equally spaced intervals, as in the constant routine experiments [9,48]. Under this condition, we study the effect of an abrupt shift of light schedule (e.g., caused by traveling across time zones) on the circadian system. ...
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The mammalian circadian system comprises a network of cell-autonomous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects which have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following a perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.
... Interestingly, there was no difference between mean insulin and leptin levels between dayshift nurses and nightshift nurses who ate predominantly during the daytime on workdays, suggesting that eating predominantly at night was driving the increases in insulin and leptin, not the nightshift work itself. These finding are consistent with another recent study using an acute circadian misalignment protocol, which found that eating during the daytime during simulated nightshift work may prevent internal circadian misalignment and glucose intolerance (38). Our findings are also consistent with both laboratory and field studies establishing a connection between nighttime food intake and metabolic outcomes (38)(39)(40). ...
... These finding are consistent with another recent study using an acute circadian misalignment protocol, which found that eating during the daytime during simulated nightshift work may prevent internal circadian misalignment and glucose intolerance (38). Our findings are also consistent with both laboratory and field studies establishing a connection between nighttime food intake and metabolic outcomes (38)(39)(40). However, since our sample size was small, our findings should be viewed with caution and interpreted as hypothesis-generating, until it is replicated. ...
Article
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Background Circadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers. Methods Female nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels. Results Mean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 – 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 – 21:00). Conclusions In our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health.
... Research in this area is of particular interest for night workers who typically eat during the night [55]. Recent laboratory research has demonstrated the beneficial effect for glucose metabolism of maintaining a daytime eating window even while working (simulated) night shifts [85][86][87][88]. To extend this research, additional consideration of TRE for those working night shifts is needed; in particular, this would determine the impact In shortening the eating window, TRE reduces the amount of time the body is required to metabolise food and lengthens the daily fast period, arguably allowing for greater metabolic recovery [14,16,22,41,50]. ...
... Research in this area is of particular interest for night workers who typically eat during the night [55]. Recent laboratory research has demonstrated the beneficial effect for glucose metabolism of maintaining a daytime eating window even while working (simulated) night shifts [85][86][87][88]. To extend this research, additional consideration of TRE for those working night shifts is needed; in particular, this would determine the impact and feasibility of shortening the daytime eating window while supporting the need to sleep during the day (Figure 2). ...
Article
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Cardiovascular disease (CVD) poses a serious health and economic burden worldwide. Modifiable lifestyle factors are a focus of research into reducing the burden of CVD, with diet as one of the most investigated factors. Specifically, the timing and regularity of food intake is an emerging research area, with approaches such as time-restricted eating (TRE) receiving much attention. TRE involves shortening the time available to eat across the day and is associated with improved CVD outcomes compared with longer eating windows. However, studies that have examined TRE have not considered the impact of sleep on CVD outcomes despite recent evidence showing that sleep duration can influence the timing and amount of food eaten. In this article, we argue that as TRE and sleep influence each other, and influence the same cardiometabolic parameters, experiencing inadequate sleep may attenuate any positive impact TRE has on CVD. We examine the relationship between TRE and CVD, with sleep as a potential mediator in this relationship, and propose a research agenda to investigate this relationship. This will provide necessary evidence to inform future interventions aimed at reducing the burden of CVD.
... Variation in meal timing appears to influence glucose metabolism (4). Studies performed in highly controlled laboratory conditions have found that eating during the biological night causes metabolic changes, including increased postprandial glucose (8,9,10). The postprandial responses of some healthy individuals during the biological night are equivalent to the responses of individuals with prediabetes (6). ...
... There exist conflicting data regarding the effects of melatonin and MTNR1B genotype on glucose control (9)(10)(11) and disagreement on whether melatonin increases or decreases fasting glucose, glucose tolerance, and T2D risk. While some studies show that elevated melatonin concentrations are associated with improved glucose control (12)(13)(14), others show associations with impaired glucose control (15,19,20). ...
Article
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OBJECTIVE We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes–associated G allele in the melatonin receptor-1b gene (MTNR1B). RESEARCH DESIGN AND METHODS In a Spanish natural late-eating population, a randomized, crossover study was performed. Each participant (n = 845) underwent two evening 2-h 75-g oral glucose tolerance tests following an 8-h fast: an early condition scheduled 4 h prior to habitual bedtime (“early dinner timing”) and a late condition scheduled 1 h prior to habitual bedtime (“late dinner timing”), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responsesbetween early and late dinner timing were determined using incremental area under the curve (AUC) calculated by the trapezoidal method. RESULTS Melatonin serum levels were 3.5-fold higher in the late versus early condition, with late dinner timing resulting in 6.7% lower insulin AUC and 8.3% higher glucose AUC. In the late condition, MTNR1B G-allele carriers had lower glucose tolerance than noncarriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (P for interaction, Pint glucose area under the curve = 0.009, Pint corrected insulin response = 0.022, and Pint Disposition Index = 0.018). CONCLUSIONS Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impairs glucose tolerance, especially in MTNR1B G-risk allele carriers, attributable to insulin secretion defects.
... «En kort blund på omkring 20 minutter er vist å redusere søvnigheten og bedre prestasjonsevnen» Det er hensiktsmessig å forsøke å oppre holde sin faste døgnrytme, med mindre man jobber flere ne er i strekk. Søvn på formiddagen bør derfor begrenses til 4-5 timer, og hovedmåltidene holdes til dagtid istedenfor om na en, noe som også reduserer risikoen for glukoseintoleranse (20). Å unngå sterkt lys og sollys på morgenen e er na evakt, å ha kjølig temperatur på soverommet, ørepropper for å stenge ute støy og sovemaske for å skjerme seg for dagslys er kanskje åpenbare, men likevel ny ige tiltak for å bedre søvnkvaliteten på dagtid (17,19). ...
... Though these results indicate that TRF is a potential solution in mediating the improvement of muscle under circadian disruption, there is still relatively insufficient information regarding TRF's effects on circadian disruption and skeletal muscle in other models. There is, however, a study that has examined glucose tolerance, a trait commonly associated with a muscle parameter, where daytime eating has been shown to prevent circadian misalignment and glucose intolerance under conditions of night work [109]. Additionally, a study although focusing on pancreatic β cells, acknowledged that beneficial effects including insulin-mediated glucose uptake were observed, this may have also been attributed to TRF effects in skeletal muscle [110]. ...
Article
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Nearly 50% of adults will suffer from obesity in the U.S. by 2030. High obesity rates can lead to high economic and healthcare burdens in addition to elevated mortality rates and reduced health span in patients. Emerging data demonstrate that obesity is a multifactorial complex disease with various etiologies including aging, a lifestyle of chronic high-fat diets (HFD), genetic predispositions, and circadian disruption. Time-restricted feeding/eating (TRF; TRE in humans) is an intervention demonstrated by studies to show promise as an effective alternative therapy for ameliorating the effects of obesity and metabolic disease. New studies have recently suggested that TRF/TRE modulates the skeletal muscle which plays a crucial role in metabolism historically observed to be impaired under obesity. Here we discuss recent findings regarding potential mechanisms underlying TRF’s modulation of skeletal muscle function, metabolism, and structure which may shed light on future research related to TRF as a solution to obesity.
... The FD protocol has also been used to examine sleep loss and circadian disruption of metabolic, cardiovascular and pulmonary function, oral microbiota, bone outcomes, and disease risk factors [101][102][103][104][105][106][107][108][109][110] ; to assess the effects of circadian rhythmicity and mistimed sleep on gene expression in whole blood 111 ; and to examine genetic variants associated with intrinsic circadian period 112,113 . It also has been used to test the impact of sleep-promoting and wake-promoting compounds when they are given at different circadian phases 40,52,53 . ...
Article
Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep-wake state and associated behaviors, such as changes in posture, light levels, fasting or eating, rest or activity and social interactions; thus, it is often important to quantify the relative contributions of these factors. Yet, circadian rhythms and these evoked effects cannot be separated under typical 24-h day conditions, because circadian phase and the length of time awake or asleep co-vary. Nathaniel Kleitman's forced desynchrony (FD) protocol was designed to assess endogenous circadian rhythmicity and to separate circadian from evoked components of daily rhythms in multiple parameters. Under FD protocol conditions, light intensity is kept low to minimize its impact on the circadian pacemaker, and participants have sleep-wake state and associated behaviors scheduled to an imposed non-24-h cycle. The period of this imposed cycle, Τ, is chosen so that the circadian pacemaker cannot entrain to it and therefore continues to oscillate at its intrinsic period (τ, ~24.15 h), ensuring circadian components are separated from evoked components of daily rhythms. Here we provide detailed instructions and troubleshooting techniques on how to design, implement and analyze the data from an FD protocol. We provide two procedures: one with general guidance for designing an FD study and another with more precise instructions for replicating one of our previous FD studies. We discuss estimating circadian parameters and quantifying the separate contributions of circadian rhythmicity and the sleep-wake cycle, including statistical analysis procedures and an R package for conducting the non-orthogonal spectral analysis method that enables an accurate estimation of period, amplitude and phase.
... 87 Conversely, night-time eating results in misalignment between central and peripheral (glucose) endogenous circadian rhythms and impairs glucose tolerance to increase diabetes risk. 150 Moreover, deficiency of the specific circadian clock regulators Tim and Per has been reported to lead to changes in cellular respiration through an increase in the uncoupling protein UCP4C in the gut and eventually contributes to prolonging the lifespan of male Drosophila. 151 How nutrient signals affect circadian clock genes is worth investigating. ...
Article
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Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.
... The data strongly suggest that canonical circadian clock rhythms and physiological rhythms are regulated by distinct oscillator mechanisms. Lifestyles and disease that disrupt and misalign circadian and physiological rhythms have been shown to increase cardiovascular risk in humans (Scheer et al., 1999;Scheer et al., 2009;Chellappa et al., 2021). Understanding the impact that time of feeding has on cardiovascular homeostasis in animal models and humans will enable the development of novel targeted approaches to mitigate cardiovascular disease risk. ...
Article
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Circadian rhythms are approximate 24-h biological cycles that optimize molecular and physiological functions to predictable daily environmental changes in order to maintain internal and organismal homeostasis. Environmental stimuli (light, feeding, activity) capable of altering the phase of molecular rhythms are important tools employed by circadian biologists to increase understanding of the synchronization of circadian rhythms to the environment and to each other within multicellular systems. The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus is largely responsive to light and is thought to entrain the phase of peripheral clocks via neurohumoral signals. Mice are nocturnal and consume most of their food during the dark cycle. Early studies demonstrated that altered metabolic cues in the form of time restricted feeding, specifically, feeding mice during the light cycle, resulted in an uncoupling of molecular clocks in peripheral tissues with those from the SCN. These studies showed as much as a 12-h shift in gene expression in some peripheral tissues but not others. The shifts occurred without corresponding changes in the central clock in the brain. More recent studies have demonstrated that changes in cardiac physiology (heart rate, MAP) in response to time of food intake occur independent of the cardiac molecular clock. Understanding differences in the physiology/function and gene expression in other organs both independently and in relation to the heart in response to altered feeding will be important in dissecting the roles of the various clocks throughout the body, as well as, understanding their links to cardiovascular pathology.
... The "sdijuno" practice, consistently followed for decades, might have tuned the endogenous response to daily meals, optimizing both immune and metabolic responses to dietary stressors, playing a role in Abruzzo's longevity rates. However, despite recent findings on the importance of meal timing for health (15,16), no evidence is available on the meal timing of nonagenarians and centenarians. The aim of this study was to survey, in a cross-sectional study, mealtime, adherence to comply with "sdijuno" practice, as well as general dietary habits and the level of physical activity throughout life, of nonagenarians and centenarians of the Abruzzo region. ...
Article
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Recent findings showed the role of late-night eating in metabolic disorders, highlighting the importance of meal timing for health. No evidence is available on the role of meal timing for longevity. The aim of this study was to survey, in a cross-sectional study, meal timing and dietary habits of 68 nonagenarians and centenarians of the Abruzzo region, Italy. Results showed an early dinner (7:13 p.m.) and a calorie restriction lapse of 17.5 h between dinner and the following lunch. The frequency of consumption was high for cereals, vegetables, fruits, and legumes; low for meat, processed meat, and eggs; and negligible for sweets. Subjects were physically active throughout life. Our results support the importance of a daily caloric restriction lapse, hampering nocturnal postprandial stress and optimizing metabolic response, associated with high consumption of plant-based foods and physical activity for the longevity of centenarians from Abruzzo.
... The benefits of acutely reducing insulin secretion on b-cell health and function for T2DM gained prominence in the 1970s when Greenwood, Mahler, and Hales suggested that b-cell overstimulation leads to impaired GSIS when they found that diazoxide treatment, a potent inhibitor of insulin secretion, restored b-cell function in T2DM subjects (143). This was followed by a series of studies demonstrating that "b-cell rest" or acute inhibition of insulin secretion, could restore b-cell function (first phase insulin secretion), insulin/Ca 2+ pulsatility, and insulin content in obesity and T2DM (144)(145)(146)(147)(148). Chronic bcell stimulation common to high fat feeding/obesity (149) and circadian disruption (21,22) result in both b-cell dysfunction and apoptosis which have been shown to be reversed by ADF (49,150), tRF (47,151,152), and a FMD (153). Specifically, a 12-week ADF regimen protected mice from HF diet induced b-cell dysfunction and failure (49), which was associated with enhanced GSIS, restored islet insulin content, and reduced apoptosis contingent on ADF activation of the autophagy-lysosome pathway. ...
Article
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Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in “what” and “when” we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism’s glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs. Both successful and failed adaptation to dynamic environmental stimuli has been postulated to occur due to changes in the transcriptional and epigenetic regulation of pathways associated with islet secretory function and survival. Therefore, in this review we examined and evaluated the current evidence elucidating the key epigenetic mechanisms and transcriptional programs underlying the islet’s coordinated response to the interaction between the timing and the composition of dietary nutrients common to modern lifestyles. With the explosion of next generation sequencing, along with the development of novel informatic and –omic approaches, future work will continue to unravel the environmental-epigenetic relationship in islet biology with the goal of identifying transcriptional and epigenetic targets associated with islet perturbations in T2DM.
... We previously observed a similar reduction in insulin secretion in participants on an LFD who had RCD combined with sleep restriction for 2-3 weeks [26], an outcome which we attributed to inadequate insulin secretion. However, the RCD (LFD) participants in the current study did not exhibit increases in glucose despite the reduction in insulin secretion, raising an alternative possibility that this reflects some degree of internal desynchrony resulting from the history of chronic circadian disruption, which may lead to the uncoupling of the insulin response from normal glucose control [24], a hypothesis that has received some recent support [70]. ...
Article
Background: Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity, diabetes, and other cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods. Methods: We investigated the effects of recurrent circadian disruption (RCD) on glucose metabolism in C57BL/6 mice and in human subjects exposed to non-24-h light-dark (LD) schedules vs. those on standard 24-h LD schedules. These LD schedules were designed to cause circadian misalignment between behaviors including rest/activity and fasting/feeding with the output of the near-24-h circadian system, while minimizing sleep loss, and were maintained for 12 weeks in mice and 3 weeks in humans. We examined interactions of these circadian-disrupted schedules compared to control 24-h schedules with a lower-fat diet (LFD, 13% in mouse and 25-27% in humans) and high-fat diet (HFD, 45% in mouse and 45-50% in humans). We also used young vs. old mice to determine whether they would respond differently to RCD. Results: When combined with a HFD, we found that RCD caused significant weight gain in mice and significantly impaired glucose tolerance and insulin sensitivity in both mice and humans, but this did not occur when RCD was combined with a LFD. This effect was similar in both young and older mice. Conclusion: These results suggest that reducing dietary fat may protect against the metabolic consequences of a lifestyle (such as shift work) that involves chronic circadian disruption.
Article
The mammalian circadian clocks are entrained by environmental time cues, such as the light-dark cycle and the feeding-fasting cycle. In modern society, circadian misalignment is increasingly more common under the guise of shift work. Shift workers, accounting for roughly 20% of the workforce population, are more susceptible to metabolic disease. Exposure to artificial light at night and eating at inappropriate times of the day uncouples the central and peripheral circadian clocks. This internal circadian desynchrony is believed to be one of the culprits leading to metabolic disease. In this review, we discuss how alterations in the rhythm of gut microbiota and their metabolites during chronodisruption send conflicting signals to the host, which may ultimately contribute to disturbed metabolic processes. We propose two behavioural interventions to improve health in shift workers. Firstly, by carefully timing the moments of exposure to blue light, and hence shifting the melatonin peak, to improve sleep quality of daytime sleeping episodes. Secondly, by timing the daily time window of caloric intake to the biological morning, to properly align the feeding-fasting cycle with the light-dark cycle and to reduce the risk of metabolic disease. These interventions can be a first step in reducing the worldwide burden of health problems associated with shift work.
Article
Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6‐h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin‐releasing hormone‐antagonist degarelix. We demonstrate that CD has sex‐specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG‐rich lipoproteins in both sexes, coinciding with reduced TG‐derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex‐dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.
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Background: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. Content: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. Conclusion: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.
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Over the course of mammalian evolution, the ability to store energy likely conferred a survival advantage when food became scarce. A long-term increase in energy storage results from an imbalance between energy intake and energy expenditure, two tightly regulated parameters that generally balance out to maintain a fairly stable body weight. Understanding the molecular determinants of this feat likely holds the key to new therapeutic development to manage obesity and associated metabolic dysfunctions. Time-restricted feeding (TRF), a dietary intervention that limits feeding to the active phase, can prevent and treat obesity and metabolic dysfunction in rodents fed a high-fat diet, likely by exerting effects on energetic balance. Even when body weight is lower in mice on active-phase TRF, food intake is generally isocaloric as compared with ad libitum fed controls. This discrepancy between body weight and energy intake led to the hypothesis that energy expenditure is increased during TRF. However, at present, there is no consensus in the literature as to how TRF affects energy expenditure and energy balance as a whole, and the mechanisms behind metabolic adaptation under TRF are unknown. This review examines our current understanding of energy balance on TRF in rodents and provides a framework for future studies to evaluate the energetics of TRF and its molecular determinants.
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A network of cellular timers ensures the maintenance of homeostasis by temporal modulation of physiological processes across the day. These so-called circadian clocks are synchronized to geophysical time by external time cues (or zeitgeber s). In modern societies, natural environmental cycles are disrupted by artificial lighting, around-the-clock availability of food or shiftwork. Such contradictory zeitgeber input promotes chronodisruption, i.e. , the perturbation of internal circadian rhythms, resulting in adverse health outcomes. While this phenomenon is well described, it is still poorly understood at which level of organization perturbed rhythms impact on health and wellbeing. In this review, we discuss different levels of chronodisruption and what is known about their health effects. We summarize the results of disrupted phase coherence between external and internal time vs. misalignment of tissue clocks amongst each other, i.e., internal desynchrony. Last, phase incoherence can also occur at the tissue level itself. Here, alterations in phase coordination can emerge between cellular clocks of the same tissue or between different clock genes within the single cell. A better understanding of the mechanisms of circadian misalignment and its effects on physiology will help to find effective tools to prevent or treat disorders arising from modern-day chronodisruptive environments.
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Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is a progressive chronic metabolic disease that has increasingly spread worldwide, enhancing the mortality rate, particularly from cardiovascular diseases (CVD). Lifestyle improvement through diet and physical activity is, together with drug treatment, the cornerstone of T2DM management. The Mediterranean diet (MD), which favors a prevalence of unprocessed vegetable foods and a reduction in red meats and industrial foods, without excluding any food category, is usually recommended. Recently, scientific societies have promoted a very low-calorie ketogenic diet (VLCKD), a multiphasic protocol that limits carbohydrates and then gradually re-introduces them, with a favorable outcome on body weight and metabolic parameters. Indeed, gut microbiota (GM) modifications have been linked to overweight/obesity and metabolic alterations typical of T2DM. Diet is known to affect GM largely, but only a few studies have investigated the effects of VLCKD on GM, especially in T2DM. In this study, we have compared anthropometric, biochemical, lifestyle parameters, the quality of life, and the GM of eleven patients with recently diagnosed T2DM and overweight or obesity, randomly assigned to two groups of six and five patients who followed the VLCKD (KETO) or hypocaloric MD (MEDI) respectively; parameters were recorded at baseline (T0) and after two (T2) and three months (T3). The results showed that VLCKD had more significant beneficial effects than MD on anthropometric parameters, while biochemical improvements did not statistically differ. As for the GM, despite the lack of significant results regarding the alpha and beta diversity, and the Firmicutes/Bacteroidota ratio between the two groups, in the KETO group, a significant increase in beneficial microbial taxa such as Verrucomicrobiota phylum with its members Verrucomicrobiae, Verrucomicrobiales, Akkermansiaceae, and Akkermansia, Christensenellaceae family, Eubacterium spp., and a reduction in microbial taxa previously associated with obesity (Firmicutes and Actinobacteriota) or other diseases (Alistipes) was observed both at T2 and T3. With regards to the MEDI group, variations were limited to a significant increase in Actinobacteroidota phylum at T2 and T3 and Firmicutes phylum at T3. Moreover, a metagenomic alteration linked to some metabolic pathways was found exclusively in the KETO group. In conclusion, both dietary approaches allowed patients to improve their state of health, but VLCKD has shown better results on body composition as well as on GM profile.
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Chronotype reflects body clock timing. Intuitively, late chronotypes should be less impacted than early chronotypes when working a night shift. However, a series of laboratory studies found early and late chronotypes had similar sleep, cognitive performance, hunger, and snack consumption before and during a single night shift.
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Late eating has been linked to obesity risk. It is unclear whether this is caused by changes in hunger and appetite, energy expenditure, or both, and whether molecular pathways in adipose tissues are involved. Therefore, we conducted a randomized, controlled, crossover trial (ClinicalTrials.gov NCT02298790) to determine the effects of late versus early eating while rigorously controlling for nutrient intake, physical activity, sleep, and light exposure. Late eating increased hunger (p < 0.0001) and altered appetite-regulating hormones, increasing waketime and 24-h ghrelin:leptin ratio (p < 0.0001 and p = 0.006, respectively). Furthermore, late eating decreased waketime energy expenditure (p = 0.002) and 24-h core body temperature (p = 0.019). Adipose tissue gene expression analyses showed that late eating altered pathways involved in lipid metabolism, e.g., p38 MAPK signaling, TGF-b signaling, modulation of receptor tyrosine kinases, and autophagy, in a direction consistent with decreased lipolysis/increased adipogenesis. These findings show converging mechanisms by which late eating may result in positive energy balance and increased obesity risk.
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Circadian rhythm, an innate 24-h biological clock, regulates several mammalian physiological activities anticipating daily environmental variations and optimizing available energetic resources. The circadian machinery is a complex neuronal and endocrinological network primarily organized into a central clock, suprachiasmatic nucleus (SCN), and peripheral clocks. Several small molecules generate daily circadian fluctuations ensuring inter-organ communication and coordination between external stimuli, i.e., light, food, and exercise, and body metabolism. As an orchestra, this complex network can be out of tone. Circadian disruption is often associated with obesity development and, above all, with diabetes and cardiovascular disease onset. Moreover, accumulating data highlight a bidirectional relationship between circadian misalignment and cardiometabolic disease severity. Food intake abnormalities, especially timing and composition of meal, are crucial cause of circadian disruption, but evidence from preclinical and clinical studies has shown that food could represent a unique therapeutic approach to promote circadian resynchronization. In this review, we briefly summarize the structure of circadian system and discuss the role playing by different molecules [from leptin to ghrelin, incretins, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF15)] to guarantee circadian homeostasis. Based on the recent data, we discuss the innovative nutritional interventions aimed at circadian re-synchronization and, consequently, improvement of cardiometabolic health.
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Background Emerging research suggests that food intake timing, eating behavior and food preference are associated with aspects of the circadian system function but the role that the circadian system may play in binge eating (BE) behavior in humans remains unclear. Objective To systematically evaluate the evidence for circadian system involvement in BE behavior. Methods Systematic searches of PubMed, EMBASE, and Scopus were performed for reports published from inception until May 2020 (PROSPERO Registration CRD42020186325). Searches were conducted by combining Medical Subject Headings related to the circadian system, BE behavior, and/or interventions. Observational and interventional studies in humans with BE behavior published in peer-review journals in the English language were included. Studies were assessed using quality and risk of bias tools (AXIS, ROB 2.0, or ROBINS). Results The search produced 660 articles, 51 of which were included in this review. Of these articles, 46 were observational studies and 5 were interventional trials. Evidence from these studies suggests that individuals with BE behavior tend to have more food intake, more binge cravings, and more BE episodes later in the day. Hormonal and day/night locomotor activity rhythm disturbances may be associated with BE behavior. Furthermore, late diurnal preference (“eveningness”) was associated with BE behavior and chronobiological interventions that shift the circadian clock earlier (e.g., morning bright light therapy) were found to possibly decrease BE behavior. Substantive clinical overlap exists between BE and night eating behavior. However, there is a significant knowledge gap regarding their potential relationship with the circadian system. Limitations include the lack of studies that use best-established techniques to assess the chronobiology of BE behavior, heterogeneity of participants, diagnostic criteria, and study design, which preclude a meta-analytic approach. Conclusion Current evidence, although limited, suggests that the circadian system may play a role in the etiology of BE behavior. Further mechanistic studies are needed to fully characterize a potential role of the circadian system in BE behavior. A chronobiological approach to studying BE behavior may lead to identification of its neurobiological components and development of novel therapeutic interventions. Systematic review registration [ https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020186325 ], identifier [CRD42020186325].
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Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we: i) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; ii) discuss the interaction between circadian molecular metabolism and TRE; iii) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; iv) summarize other time-related dietary interventions that have been studied in people; and v) identify current gaps in knowledge and provide a framework for future research directions.
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The daily rhythm of plasma melatonin concentrations is typically unimodal, with one broad peak during the circadian night and near‐undetectable levels during the circadian day. Light at night acutely suppresses melatonin secretion and phase shifts its endogenous circadian rhythm. In contrast, exposure to darkness during the circadian day has not generally been reported to increase circulating melatonin concentrations acutely. Here, in a highly‐controlled simulated night shift protocol with 12‐h inverted behavioral/environmental cycles, we unexpectedly found that circulating melatonin levels were significantly increased during daytime sleep (P < 0.0001). This resulted in a secondary melatonin peak during the circadian day in addition to the primary peak during the circadian night, when sleep occurred during the circadian day following an overnight shift. This distinctive diurnal melatonin rhythm with antiphasic peaks could not be readily anticipated from the behavioral/environmental factors in the protocol (e.g., light exposure, posture, diet, activity) or from current mathematical model simulations of circadian pacemaker output. The observation therefore challenges our current understanding of underlying physiological mechanisms that regulate melatonin secretion. Interestingly, the increase in melatonin concentration observed during daytime sleep was positively correlated with the change in timing of melatonin nighttime peak (P = 0.0015), but not with the degree of light‐induced melatonin suppression during nighttime wakefulness (P = 0.92). Both the increase in daytime melatonin concentrations and the change in the timing of the nighttime peak became larger after repeated exposure to simulated night shifts (P = 0.009 and P = 0.0001, respectively). Furthermore, we found that melatonin secretion during daytime sleep was positively associated with an increase in 24‐h glucose and insulin levels during the night shift protocol (P = 0.014 and P = 0.027, respectively). Future studies are needed to elucidate the key factor(s) driving the unexpected daytime melatonin secretion and the melatonin rhythm with antiphasic peaks during shifted sleep/wake schedules, the underlying mechanisms of their relationship with glucose metabolism, and the relevance for diabetes risk among shift workers. This article is protected by copyright. All rights reserved.
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Globally, gestational diabetes (GDM) is increasing at an alarming rate. This increase is linked to the rise in obesity rates among women of reproductive age. GDM poses a major global health problem due to the related micro-and macro-vascular complications of subsequent Type 2 diabetes and the impact on the future health of generations through the long-term impact of GDM on both mothers and their infants. Therefore, correctly identifying subjects as having GDM is of utmost importance. The oral glucose tolerance test (OGTT) has been the mainstay for diagnosing gestational diabetes for decades. However, this test is deeply flawed. In this review, we explore a history of the OGTT, its reproducibility and the many factors that can impact its results with an emphasis on pregnancy.
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Objectives This discussion paper aims to provide scientifically based recommendations on night shift schedules, including consecutive shifts, shift intervals and duration of shifts, which may reduce health and safety risks. Short-term physiological effects in terms of circadian disruption, inadequate sleep duration and quality, and fatigue were considered as possible links between night shift work and selected health and safety risks, namely, cancer, cardio-metabolic disease, injuries, and pregnancy-related outcomes. Method In early 2020, 15 experienced shift work researchers participated in a workshop where they identified relevant scientific literature within their main research area. Results Knowledge gaps and possible recommendations were discussed based on the current evidence. The consensus was that schedules which reduce circadian disruption may reduce cancer risk, particularly for breast cancer, and schedules that optimize sleep and reduce fatigue may reduce the occurrence of injuries. This is generally achieved with fewer consecutive night shifts, sufficient shift intervals, and shorter night shift duration. Conclusions Based on the limited, existing literature, we recommend that in order to reduce the risk of injuries and possibly breast cancer, night shift schedules have: (i) ≤3 consecutive night shifts; (ii) shift intervals of ≥11 hours; and (iii) ≤9 hours shift duration. In special cases - eg, oil rigs and other isolated workplaces with better possibilities to adapt to daytime sleep - additional or other recommendations may apply. Finally, to reduce risk of miscarriage, pregnant women should not work more than one night shift in a week.
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The proliferation in the rate of diagnosis of obesity and type 2 diabetes mellitus continues unabated, with current recommendations for primary lifestyle changes (i.e. modification to dietary patterns) having a limited impact in reducing the incidence of these metabolic diseases. Part of the reason for the failure to alter nutritional practices is that current dietary recommendations may be unrealistic for the majority of adults. Indeed, round-the-clock access to energy-dense, nutrient-poor food makes long-term changes to dietary habits challenging. Hence, there is urgent need for innovations in the delivery of evidence-based diet interventions to rescue some of the deleterious effects on circadian biology induced by our modern-day lifestyle. With the growing appreciation that the duration over which food is consumed during a day has profound effects on numerous physiological and metabolic processes, we discuss dietary protocols that modify the timing of food intake to deliberately alter the feeding–fasting cycle. Such chrono-nutrition functions to optimise metabolism by timing nutrient intake to the acrophases of metabolic rhythms to improve whole-body insulin sensitivity and glycaemic control, and thereby positively impact metabolic health. Graphical abstract
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Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBα and β in adult mouse hepatocytes disrupted diurnal rhythms of a subset of liver genes and altered the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by non-hepatocytic cells, and the loss of hepatocyte REV-ERBs remodeled the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrated the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. Together, these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.
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Recent studies indicate that the timing of food intake can significantly affect metabolism and weight management. Workers operating at atypical times of the 24-h day are at risk of disturbed feeding patterns. Given the increased risk of weight gain, obesity and metabolic syndrome in shift working populations, further research is required to understand whether their eating behavior could contribute to these increased metabolic risks. The objective of this study was to characterize the dietary patterns of police officers across different types of shifts in their natural environments. Thirty-one police officers (six women; aged 32.1 ± 5.4 years, mean ± SD) from the province of Quebec, Canada, participated in a 28- to 35-day study, comprising 9- to 12-h morning, evening, and night shifts alternating with rest days. Sleep and work patterns were recorded with actigraphy and diaries. For at least 24 h during each type of work day and rest day, participants logged nutrient intake by timestamped photographs on smartphones. Macronutrient composition and caloric content were estimated by registered dieticians using the Nutrition Data System for Research database. Data were analyzed with linear mixed effects models and circular ANOVA. More calories were consumed relative to individual metabolic requirements on rest days than both evening- and night-shift days (p = 0.001), largely sourced from increased fat (p = 0.004) and carbohydrate (trend, p = 0.064) intake. Regardless, the proportions of calories from carbohydrates, fat, and protein did not differ significantly between days. More calories were consumed during the night, between 2300 h and 0600 h, on night-shift days than any other days (p < 0.001). Caloric intake occurred significantly later for night-shift days (2308 h ± 0114 h, circular mean ± SD) than for rest days (1525 h ± 0029 h; p < 0.01) and was dispersed across a longer eating window (13.9 h ± 3.1 h vs. 11.3 h ± 1.8 h, mean ± SD). As macronutrient proportions were similar and caloric intake was lower, the finding of later meals times on night-shift days versus rest days is consistent with emerging hypotheses that implicate the biological timing of food intake—rather than its quantity or composition—as the differentiating dietary factor in shift worker health.
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In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body. Feeding-associated hormones insulin and IGF-1 entrain circadian rhythms throughout the body by induction of PERIOD clock proteins.
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Objectives To prospectively evaluate the joint association of duration of rotating night shift work and lifestyle factors with risk of type 2 diabetes risk, and to quantitatively decompose this joint association to rotating night shift work only, to lifestyle only, and to their interaction. Design Prospective cohort study. Setting Nurses’ Health Study (1988-2012) and Nurses’ Health Study II (1991-2013). Participants 143 410 women without type 2 diabetes, cardiovascular disease, or cancer at baseline. Exposures Rotating night shift work was defined as at least three night shifts per month in addition to day and evening shifts in that month. Unhealthy lifestyles included current smoking, physical activity levels below 30 minutes per day at moderate to vigorous intensity, diet in the bottom three fifths of the Alternate Healthy Eating Index score, and body mass index of 25 or above. Main outcome measures Incident cases of type 2 diabetes were identified through self report and validated by a supplementary questionnaire. Results During 22-24 years of follow-up, 10 915 cases of incident type 2 diabetes occurred. The multivariable adjusted hazard ratios for type 2 diabetes were 1.31 (95% confidence interval 1.19 to 1.44) per five year increment of duration of rotating night shift work and 2.30 (1.88 to 2.83) per unhealthy lifestyle factor (ever smoking, low diet quality, low physical activity, and overweight or obesity). For the joint association of per five year increment rotating night shift work and per unhealthy lifestyle factor with type 2 diabetes, the hazard ratio was 2.83 (2.15 to 3.73) with a significant additive interaction (P for interaction <0.001). The proportions of the joint association were 17.1% (14.0% to 20.8%) for rotating night shift work alone, 71.2% (66.9% to 75.8%) for unhealthy lifestyle alone, and 11.3% (7.3% to 17.3%) for their additive interaction. Conclusions Among female nurses, both rotating night shift work and unhealthy lifestyle were associated with a higher risk of type 2 diabetes. The excess risk of rotating night shift work combined with unhealthy lifestyle was higher than the addition of risk associated with each individual factor. These findings suggest that most cases of type 2 diabetes could be prevented by adhering to a healthy lifestyle, and the benefits could be greater in rotating night shift workers.
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Significance Shift workers, whose schedules are misaligned relative to their suprachiasmatic nuclei (SCN) circadian pacemaker, are at elevated risk of metabolic disorders. In a study of simulated day- versus night-shift work followed by a constant routine, we separated plasma-circulating metabolites according to whether their 24-h rhythms aligned with the central SCN pacemaker or instead reflected externally imposed behavioral schedules. We found that rhythms in many metabolites implicated in food metabolism dissociated from the SCN pacemaker rhythm, with the vast majority aligning with the preceding sleep/wake and feeding/fasting cycles. Our metabolomics study yields insight into the link between prolonged exposure to shift work and the spectrum of associated metabolic disorders by providing a window into peripheral oscillators and the biobehavioral factors that orchestrate them.
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Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants’ circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.
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The circadian system plays a role in regulating metabolism. Night-shift work, a form of circadian misalignment, is associated with increased type 2 diabetes risk. This study aimed to determine if night-shift workers with type 2 diabetes experience poorer glycaemic control than non-shift workers. Patients with type 2 diabetes (104 unemployed, 85 day workers and 60 night-shift workers) participated. Sleep duration, sleep quality, morningness-eveningness preference, depressive symptoms and dietary intake were assessed using standardized questionnaires. Haemoglobin A1c levels were measured. Night-shift workers had significantly higher haemoglobin A1c levels compared with others, while there were no differences between day workers and unemployed participants (median 7.86% versus 7.24% versus 7.09%, respectively). Additionally, night-shift workers were younger, had a higher body mass index, and consumed more daily calories than others. Among night-shift workers, there were no significant differences in haemoglobin A1c levels between those performing rotating versus non-rotating shifts (P = 0.856), or those with clockwise versus counterclockwise shift rotation (P = 0.833). After adjusting for age, body mass index, insulin use, sleep duration, morningness-eveningness preference and percentage of daily intake from carbohydrates, night-shift work, compared with day work, was associated with significantly higher haemoglobin A1c (B = 0.059, P = 0.044), while there were no differences between unemployed participants and day workers (B = 0.016, P = 0.572). In summary, night-shift work is associated with poorer glycaemic control in patients with type 2 diabetes.
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Context: Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (i.e., misalignment between the central circadian pacemaker and 24-h environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown. Objective: Test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects. Design: Randomized, crossover study with two 3-day laboratory visits. Setting: Center for Clinical Investigation. Patients: Healthy chronic shift workers. Intervention: Simulated night work including 12-h inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment). Main outcome measures: Postprandial glucose and insulin responses to identical meals given at 8AM and 8PM in both protocols. Results: Postprandial glucose was 6% higher at 8PM than 8AM (circadian phase effect), independent of behavioral effects (P=0.0042). Circadian misalignment increased postprandial glucose by 6%, independent of behavioral and circadian effects (P=0.0041). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early- and late-phase insulin; both P≤0.011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late-phase insulin; P=0.015) without change in early-phase insulin (P=0.38). Conclusions: Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.
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Coordinated daily rhythms are evident in most aspects of our physiology, driven by internal timing systems known as circadian clocks. Our understanding of how biological clocks are built and function has grown exponentially over the past 20 years. With this has come an appreciation that disruption of the clock contributes to the pathophysiology of numerous diseases, from metabolic disease to neurological disorders to cancer. However, it remains to be determined whether it is the disruption of our rhythmic physiology per se (loss of timing itself), or altered functioning of individual clock components that drive pathology. Here, we review the importance of circadian rhythms in terms of how we (and other organisms) relate to the external environment, but also in relation to how internal physiological processes are coordinated and synchronized. These issues are of increasing importance as many aspects of modern life put us in conflict with our internal clockwork. © 2015 The Authors. Bioessays published by WILEY Periodicals, Inc.
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Significance It is established that glucose tolerance decreases from the morning to the evening, and that shift work is a risk factor for diabetes. However, the relative importance of the endogenous circadian system, the behavioral cycle (including the sleep/wake and fasting/feeding cycles), and circadian misalignment on glucose tolerance is unclear. We show that the magnitude of the effect of the endogenous circadian system on glucose tolerance and on pancreatic β-cell function was much larger than that of the behavioral cycle in causing the decrease in glucose tolerance from morning to evening. Also, independent from circadian phase and the behavioral cycle, circadian misalignment resulting from simulated night work lowered glucose tolerance—without diminishing effects upon repeated exposure—with direct relevance for shift workers.
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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.
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Circadian rhythms and cellular metabolism are intimately linked. Here, we reveal that a high-fat diet (HFD) generates a profound reorganization of specific metabolic pathways, leading to widespread remodeling of the liver clock. Strikingly, in addition to disrupting the normal circadian cycle, HFD causes an unexpectedly large-scale genesis of de novo oscillating transcripts, resulting in reorganization of the coordinated oscillations between coherent transcripts and metabolites. The mechanisms underlying this reprogramming involve both the impairment of CLOCK:BMAL1 chromatin recruitment and a pronounced cyclic activation of surrogate pathways through the transcriptional regulator PPARγ. Finally, we demonstrate that it is specifically the nutritional challenge, and not the development of obesity, that causes the reprogramming of the clock and that the effects of the diet on the clock are reversible.
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Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.
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The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. The interplay between the central neural and peripheral tissue clocks is not fully understood and remains a major challenge in determining how neurological and metabolic homeostasis is achieved across the sleep-wake cycle. Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system.
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Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.
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Compared to individuals who work during the day, shift workers are at higher risk of a range of metabolic disorders and diseases (eg, obesity, cardiovascular disease, peptic ulcers, gastrointestinal problems, failure to control blood sugar levels, and metabolic syndrome). At least some of these complaints may be linked to the quality of the diet and irregular timing of eating, however other factors that affect metabolism are likely to play a part, including psychosocial stress, disrupted circadian rhythms, sleep debt, physical inactivity, and insufficient time for rest and revitalization. In this overview, we examine studies on food and nutrition among shift workers [ie, dietary assessment (designs, methods, variables) and the factors that might influence eating habits and metabolic parameters]. The discussion focuses on the quality of existing dietary assessment data, nutritional status parameters (particularly in obesity), the effect of circadian disruptions, and the possible implications for performance at work. We conclude with some dietary guidelines as a basis for managing the nutrition of shift workers.
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Shift work or night work is associated with hypertension, metabolic syndrome, cancer, and other diseases. The cause for these pathologies is proposed to be the dissociation between the temporal signals from the biological clock and the sleep/activity schedule of the night worker. We investigated the mechanisms promoting metabolic desynchrony in a model for night work in rats, based on daily 8-h activity schedules during the resting phase. We demonstrate that the major alterations leading to internal desynchrony induced by this working protocol, flattened glucose and locomotor rhythms and the development of abdominal obesity, were caused by food intake during the rest phase. Shifting food intake to the normal activity phase prevented body weight increase and reverted metabolic and rhythmic disturbances of the shift work animals to control ranges. These observations demonstrate that feeding habits may prevent or induce internal desynchrony and obesity.
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Food-anticipatory activity (FAA) and especially the food-entrained oscillator (FEO) have driven many scientists to seek their mechanisms and locations. Starting our research on FAA we, possibly like many other scientists, were convinced that clock genes held the key to the location and the underlying mechanisms for FAA. In this review, which is aimed especially at discussing the contribution of the peripheral oscillators, we have put together the accumulating evidence that the clock gene machinery as we know it today is not sufficient to explain food entrainment. We discuss the contribution of three types of oscillating processes: (i) within the suprachiasmatic nucleus (SCN), neurons capable of maintaining a 24-h oscillation in electrical activity driven by a set of clock genes; (ii) oscillations in metabolic genes and clock genes in other parts of the brain and in peripheral organs driven by the SCN or by food, which damp out after a few cycles; (iii) an FEO which, we propose, is a system built up of different oscillatory processes and consisting of an as-yet-unidentified network of central and peripheral structures. In view of the evidence that clock genes and metabolic oscillations are not essential for the persistence of FAA we propose that food entrainment is initiated by a repeated metabolic state of scarcity that drives an oscillating network of brain nuclei in interaction with peripheral oscillators. This complex may constitute the proposed FEO and is distributed in our peripheral organs as well as within the central nervous system.
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Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian clock at the molecular, physiological, and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high-fat diet only during the 12-h light phase gain significantly more weight than mice fed only during the 12-h dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today.
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There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h "day." Subjects ate 4 isocaloric meals each 28-h "day." For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling approximately 1,000 assays/subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept approximately 12 h out of phase from their habitual times, systematically decreased leptin (-17%, P < 0.001), increased glucose (+6%, P < 0.001) despite increased insulin (+22%, P = 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (+3%, P = 0.001), and reduced sleep efficiency (-20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work.
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In mammals, circadian oscillators exist not only in the suprachiasmatic nucleus, which harbors the central pacemaker, but also in most peripheral tissues. It is believed that the SCN clock entrains the phase of peripheral clocks via chemical cues, such as rhythmically secreted hormones. Here we show that temporal feeding restriction under light-dark or dark-dark conditions can change the phase of circadian gene expression in peripheral cell types by up to 12 h while leaving the phase of cyclic gene expression in the SCN unaffected. Hence, changes in metabolism can lead to an uncoupling of peripheral oscillators from the central pacemaker. Sudden large changes in feeding time, similar to abrupt changes in the photoperiod, reset the phase of rhythmic gene expression gradually and are thus likely to act through a clock-dependent mechanism. Food-induced phase resetting proceeds faster in liver than in kidney, heart, or pancreas, but after 1 wk of daytime feeding, the phases of circadian gene expression are similar in all examined peripheral tissues.
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Chronic sleep loss as a consequence of voluntary bedtime restriction is an endemic condition in modern society. Although sleep exerts marked modulatory effects on glucose metabolism, and molecular mechanisms for the interaction between sleeping and feeding have been documented, the potential impact of recurrent sleep curtailment on the risk for diabetes and obesity has only recently been investigated. In laboratory studies of healthy young adults submitted to recurrent partial sleep restriction, marked alterations in glucose metabolism including decreased glucose tolerance and insulin sensitivity have been demonstrated. The neuroendocrine regulation of appetite was also affected as the levels of the anorexigenic hormone leptin were decreased, whereas the levels of the orexigenic factor ghrelin were increased. Importantly, these neuroendocrine abnormalities were correlated with increased hunger and appetite, which may lead to overeating and weight gain. Consistent with these laboratory findings, a growing body of epidemiological evidence supports an association between short sleep duration and the risk for obesity and diabetes. Chronic sleep loss may also be the consequence of pathological conditions such as sleep-disordered breathing. In this increasingly prevalent syndrome, a feedforward cascade of negative events generated by sleep loss, sleep fragmentation, and hypoxia are likely to exacerbate the severity of metabolic disturbances. In conclusion, chronic sleep loss, behavioral or sleep disorder related, may represent a novel risk factor for weight gain, insulin resistance, and Type 2 diabetes.
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To study the adaptation and readaptation processes to 1 week of night work (6:30 PM to 6:30 AM) followed by 1 week of day work (6:30 AM to 6:30 PM). Part of a randomized, placebo-controlled, crossover field study. Here, data from the placebo arm are presented. Oil rig in the North Sea. Work schedule: 2 weeks on a 12-hour shift, with the first week on the night shift and the second week on the day shift. Subjects complaining about problems with adjusting to shift work. Seventeen workers completed the study. N/A. Subjective and objective measures of sleepiness (Karolinska Sleepiness Scale and simple serial reaction time test) and sleep (diary and actigraphy). Both subjective and objective measures improved gradually during night work. The return to day work after 1 week on the night shift led to a clear increase in subjective sleepiness and worsening of sleep parameters. During the week on the day shift, sleepiness and sleep gradually improved, similar to the improvement seen during night work. The workers indicated that the day shift was worse than the night shift on some of the measures, e.g., sleep length was significantly longer during the night-shift period. This is one of few studies showing how shift workers in a real-life setting adjust to night work. Both subjective and objective sleepiness and subjective sleep improved across days. The effects were especially pronounced for the subjective data.
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The authors prospectively investigated associations between potentially stressful work characteristics and type 2 diabetes incidence in 62,574 young and middle-aged women, aged 29–46 years at baseline in 1993, from the Nurses' Health Study II; 365 cases of type 2 diabetes accrued over 6 years of follow-up. Cox proportional hazards regression was used to simultaneously evaluate associations of hours per week in paid employment, years of rotating night-shift work, and job strain with incidence of type 2 diabetes. In multivariate-adjusted analyses, women working less than 20 hours per week had a lower risk of diabetes (relative risk = 0.80, 95% confidence interval: 0.50, 1.30), and those working overtime (≥41 hours/week) had an elevated risk of diabetes (relative risk = 1.23, 95% confidence interval: 0.98, 1.55) compared with women working 21–40 hours/week (referent) in paid employment (ptrend = 0.03). In subsequent analysis, the elevated association appeared stronger in unmarried women (pinteraction = 0.02). A positive association between years in rotating night-shift work and diabetes was mediated entirely by body weight. Job strain was unrelated to risk of type 2 diabetes. In conclusion, working overtime predicted a slightly elevated risk of type 2 diabetes in young and middle-aged female nurses.
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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. • aging • sleep quality • sleep disordered breathing • delta waves • insulin resistance
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Aim: The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole-body insulin resistance or a normal adjustment to potentially increased hepatic insulin action is unknown. Methods: We examined the effects of 36 versus 12 h fasting on insulin secretion and whole-body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action was studied using stable isotopes, whereas whole-body insulin action and insulin secretion was studied using an intravenous glucose tolerance test (IVGTT) and minimal modelling. Insulin, glucose and lipid profiles were subsequently measured during a refeeding meal-test. Results: Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action contrasting an increase in whole-body insulin resistance. Accordingly, prolonged fasting was associated with opposite directed effects on hepatic versus whole-body insulin secretion disposition indices. Thirty-six compared with 12 h fasting was associated with increased plasma insulin levels during the refeeding meal test. Conclusion: In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ specific insulin action into account may lead to erroneous conclusions.
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A recent study shows that a history of rotating night-shift work and an unhealthy lifestyle are associated with increased risk of type 2 diabetes mellitus (T2DM), both independently and synergistically. This is the first large-scale, prospective study to quantify how a healthy lifestyle might partially offset T2DM risk in shift workers.
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Glucose tolerance is lower at night and higher in the morning. Shift workers, who often eat at night and experience circadian misalignment (i.e., misalignment between the central circadian pacemaker and the environmental/behavioral cycle), have an increased risk of type 2 diabetes. To determine the separate and relative impacts of the circadian system, behavioral/environmental cycles, and their interaction (i.e., circadian misalignment) on insulin sensitivity and β‐cell function, we used the oral minimal model to quantitatively assess the major determinants of glucose control in 14 healthy adults, using a randomized, cross‐over design with two 8‐day laboratory protocols. Both protocols involved 3 baseline inpatient days with habitual sleep/wake cycle, followed by 4 inpatient days with same nocturnal bedtime (circadian alignment) or with 12‐h inverted behavioral/environmental cycles (circadian misalignment). Our data showed that circadian phase and circadian misalignment affect glucose tolerance through different mechanisms. While the circadian system reduces glucose tolerance in the biological evening compared to the biological morning mainly by decreasing both dynamic and static β‐cell responsivity, circadian misalignment reduced glucose tolerance mainly by lowering insulin sensitivity, not by affecting β‐cell function. This article is protected by copyright. All rights reserved.
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Objective: To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds. Research design and methods: In the UK Biobank, we examined associations of current (N= 272,214) and lifetime (N= 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes. Results: Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05-1.26]; some nights: OR 1.18 [95% CI 1.05-1.32]; and usual nights: OR 1.44 [95% CI 1.19-1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93-1.27]). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (<3/month: OR 1.24 [95% CI 0.90-1.68]; 3-8/month: OR 1.11 [95% CI 0.90-1.37]; and >8/month: OR 1.36 [95% CI 1.14-1.62];Ptrend= 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure. Conclusions: Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication.
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Eating during the night may increase the risk for obesity and type 2 diabetes in shift workers. This study examined the impact of either eating or not eating a meal at night on glucose metabolism. Participants underwent four nights of simulated night work (SW1–4, 16:00–10:00 h, <50 lux) with a daytime sleep opportunity each day (10:00–16:00 h, <3 lux). Healthy males were assigned to an eating at night (NE; n = 4, meals; 07:00, 19:00 and 01:30 h) or not eating at night (NEN; n = 7, meals; 07:00 h, 09:30, 16:10 and 19:00 h) condition. Meal tolerance tests were conducted post breakfast on pre-night shift (PRE), SW4 and following return to day shift (RTDS), and glucose and insulin area under the curve (AUC) were calculated. Mixed-effects ANOVAs were used with fixed effects of condition and day, and their interactions, and a random effect of subject identifier on the intercept. Fasting glucose and insulin were not altered by day or condition. There were significant effects of day and condition × day (both p < 0.001) for glucose AUC, with increased glucose AUC observed solely in the NE condition from PRE to SW4 (p = 0.05) and PRE to RTDS (p < 0.001). There was also a significant effect of day (p = 0.007) but not condition × day (p = 0.825) for insulin AUC, with increased insulin from PRE to RTDS in both eating at night (p = 0.040) and not eating at night (p = 0.006) conditions. Results in this small, healthy sample suggest that not eating at night may limit the metabolic consequences of simulated night work. Further study is needed to explore whether matching food intake to the biological clock could reduce the burden of type 2 diabetes in shift workers.
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Background & aims: Late-night dinner eating is associated with increased risk for type-2 diabetes. The underlying mechanism is unclear. One explanatory hypothesis is that the concurrence of elevated circulating melatonin and high glucose concentrations (characterizing late eating) leads to impaired glucose tolerance. However, to date no study has tested the influence of physiological melatonin concentrations on glucose-tolerance. The discovery of melatonin receptor MTNR1B as a diabetes risk gene provides evidence for a role of physiological levels of melatonin in glucose control. The aim of our study was to test the hypothesis that elevated endogenous melatonin concentrations worsen glucose control when eating late. Registered under ClinicalTrials.gov Identifier no. NCT03003936. Methods: We performed a randomized, cross-over trial to compare glucose tolerance in the presence (late dinner) or absence (early dinner) of elevated physiological melatonin concentrations and we compared the results between homozygous carriers and non-carriers of the MTNR1B risk allele. Results: The concurrence of meal timing with elevated endogenous melatonin concentrations resulted in impaired glucose tolerance. This effect was stronger in MTNR1B risk-carriers than in non-carriers. Furthermore, eating late significantly impaired glucose tolerance only in risk-carriers and not in the non-risk carriers. Conclusions: The interaction of dinner timing with MTNR1B supports a causal role of endogenous melatonin in the impairment of glucose tolerance. These results suggest that moving the dinner to an earlier time may result in better glucose tolerance specially in MTNR1B carriers. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03003936.
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The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee (https://doi.org/10.2337/dc20-SPPC), a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Defective control of endogenous glucose production is an important factor responsible for hyperglycemia in the diabetic individual. In the past decade, more and more evidence has appeared indicating a strong and potentially causal relationship between disturbances of the circadian system and defects of metabolic regulation, including glucose metabolism. The detrimental effects of disturbed circadian rhythms may have their origin in disturbances of the molecular clock mechanisms in peripheral organs, such as pancreas and liver, or in the central brain clock in the hypothalamic suprachiasmatic nuclei (SCN). To assess the role of SCN output per se on glucose metabolism, we investigated 1) the effect of several SCN neurotransmitters on endogenous glucose production and 2) the effect of SCN neuronal activity on hepatic and systemic insulin sensitivity. We show that silencing of SCN neuronal activity results in decreased hepatic insulin sensitivity and increased peripheral insulin sensitivity. Furthermore, both the oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) and the orexin neurons in the lateral hypothalamus may be important targets for the SCN control of glucose metabolism. These data further stress the role of the central clock in the pathophysiology of insulin resistance. This article is protected by copyright. All rights reserved.
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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.
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To examine whether a mismatch between chronotype (i.e., preferred sleep timing) and work schedule is associated with type 2 diabetes risk. In the Nurses' Health Study 2, we followed 64,615 women from 2005 to 2011. Newly developed type 2 diabetes was the outcome measure (n = 1,452). A question on diurnal preference ascertained chronotype in 2009; rotating night shift work exposure was assessed regularly since 1989. Compared with intermediate chronotypes, early chronotypes had a slightly decreased diabetes risk after multivariable adjustment (odds ratio 0.87 [95% CI 0.77-0.98]), whereas no significant association was observed for late chronotypes (1.04 [0.89-1.21]). Among early chronotypes, risk of type 2 diabetes was modestly reduced when working daytime schedules (0.81 [0.63-1.04]) and remained similarly reduced in women working <10 years of rotating night shifts (0.84 [0.72-0.98]). After ≥10 years of shift work exposure, early chronotypes had a nonsignificant elevated diabetes risk (1.15 [0.81-1.63], Ptrend = 0.014). By contrast, among late chronotypes, the significantly increased diabetes risk observed among day workers (1.51 [1.13-2.02]) appeared largely attenuated if their work schedules included night shifts (<10 years: 0.93 [0.76-1.13]; ≥10 years: 0.87 [0.56-1.34]; Ptrend = 0.14). The interaction between chronotype and shift work exposure was significant (Pinteraction = 0.0004). Analyses restricting to incident cases revealed similar patterns. In early chronotypes, type 2 diabetes risk increased with increasing duration of shift work exposure, whereas late types had the highest diabetes risk working daytime schedules. These data add to the growing body of evidence that workers could benefit from shift schedules minimizing interference with chronotype-dependent sleep timing. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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The circadian clock, a highly specialized, hierarchical network of biological pacemakers, directs and maintains proper rhythms in endocrine and metabolic pathways required for organism homeostasis. The clock adapts to environmental changes, specifically daily light-dark cycles, as well as rhythmic food intake. Nutritional challenges reprogram the clock, while time-specific food intake has been shown to have profound consequences on physiology. Importantly, a critical role in the clock-nutrition interplay appears to be played by the microbiota. The circadian clock appears to operate as a critical interface between nutrition and homeostasis, calling for more attention on the beneficial effects of chrono-nutrition. Copyright © 2015 Elsevier Inc. All rights reserved.
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While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.
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Presents new and up-dated material on both the underlying theory and the practical methodology of directional statistics, helping the reader to utilise and develop the techniques appropriate to their work. The book is divided into three parts. The first part concentrates on statistics on the circle. Topics covered include tests of uniformity, tests of good-of-fit, inference on von Mises distributions and non-parametric methods. The second part considers statistics on spheres of arbitrary dimension, and includes a detailed account of inference on the main distributions on spheres. Recent material on correlation, regression time series, robust techniques, bootstrap methods, density estimation and curve fitting is presented. The third part considers statistics on more general sample spaces, in particular rotation groups, Stiefel manifolds, Grassmann manifolds and complex projective spaces. Shape analysis is considered from the perspective of directional statistics. Written by leading authors in the field, this text will be invaluable not only to researchers in probability and statistics interested in the latest developments in directional statistics, but also to practitioners and researchers in many scientific fields, including astronomy, biology, computer vision, earth sciences and image analysis.
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In this review we first present the anatomical pathways used by the suprachiasmatic nuclei to enforce its rhythmicity onto the body, especially its energy homeostatic system. The experimental data show that by activating the orexin system at the start of the active phase, the biological clock not only ensures that we wake up on time, but also that our glucose metabolism and cardiovascular system are prepared for increased activity. The drawback of such a highly integrated system, however, becomes visible when our daily lives are not fully synchronized with the environment. Thus, in addition to increased physical activity and decreased intake of high-energy food, also a well-lighted and fully resonating biological clock may help to withstand the increasing "diabetogenic" pressure of today's 24/7 society.
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The global increase in the prevalence of obesity and metabolic disorders coincides with the increase of exposure to light at night (LAN) and shift work. Circadian regulation of energy homeostasis is controlled by an endogenous biological clock that is synchronized by light information. To promote optimal adaptive functioning, the circadian clock prepares individuals for predictable events such as food availability and sleep, and disruption of clock function causes circadian and metabolic disturbances. To determine whether a causal relationship exists between nighttime light exposure and obesity, we examined the effects of LAN on body mass in male mice. Mice housed in either bright (LL) or dim (DM) LAN have significantly increased body mass and reduced glucose tolerance compared with mice in a standard (LD) light/dark cycle, despite equivalent levels of caloric intake and total daily activity output. Furthermore, the timing of food consumption by DM and LL mice differs from that in LD mice. Nocturnal rodents typically eat substantially more food at night; however, DM mice consume 55.5% of their food during the light phase, as compared with 36.5% in LD mice. Restricting food consumption to the active phase in DM mice prevents body mass gain. These results suggest that low levels of light at night disrupt the timing of food intake and other metabolic signals, leading to excess weight gain. These data are relevant to the coincidence between increasing use of light at night and obesity in humans.
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The stress hormone cortisol shows a pronounced endogenous diurnal rhythm, which is affected by the sleep/wake cycle, meals and activity. Shift work and especially night work disrupts the sleep/wake cycle and causes a desynchronization of the natural biological rhythms. Therefore, different shift schedules may have different impact on performance at work and health. The purpose was to study if health, reaction time, and the cortisol rhythm were negatively affected when a group of shift workers changed their work schedule from ordinary day-night shift (fixed shift) to "swing shift". METHODS AND SETTINGS: 19 healthy workers on a Norwegian oil rig participated in the study. They worked 2 weeks offshore followed by 4 weeks off work. The ordinary schedule consisted of 12-h day shift and 12-h night shift every other work period (14 days or nights=fixed shift). "Swing shift" involved 1 week of night shift, followed by 1 week of day shift during the work period. All participants worked ordinary day-night shift when baseline data were collected (questionnaires, saliva cortisol, and reaction time during work). After collection of baseline data the workers changed their work schedule to "swing shift", for every working period, and 9 months later the same data were collected. "Swing shift" did not give any negative health effects or any negative changes in reaction time during the day they shifted from night work to day work. Personnel adapted to night shift within a week regardless of schedule, but recovery from night shift took longer time. During swing shift the cortisol rhythm went back towards a normal rhythm in the second week, but it was not returned completely to normal values when they returned home for the 4 weeks off period. However, the cortisol rhythms were readapted to normal values after 1 week at home. For personnel returning home directly from 14 consecutive night shifts, cortisol adaptation was not complete after 1 week at home. We found no increase in health complaints from swing shift or reaction time in the shift from night to day work. Recovery from night shift takes longer time.
Article
The aim of this study was to establish the experimental paradigm of fasting, followed by refeeding, to investigate individual differences in nutrient partitioning. Eight nonobese men were fed a normal meal (25% of daily energy requirements) on two occasions, after an overnight (13-h) fast and after a prolonged (72-h) fast. During the entire fasting period, subjects were resident in a whole room indirect calorimeter, and blood samples were drawn periodically. Because no other food was consumed over the 12 h after either meal, negative energy balance was observed after the overnight and prolonged fast. Postprandial carbohydrate oxidation was significantly reduced after the 72- vs. 13-h fast (P < 0.0001), whereas fat oxidation was significantly increased (P < 0.0001). Interestingly, carbohydrate balance was positive after the prolonged fast but negative after the overnight fast (24 +/- 17 vs. -57 +/- 16 g/12 h, respectively; P < 0.001), whereas fat balance was negative under both conditions (-78 +/- 7 vs. -47 +/- 8 g/12 h, respectively; P < 0.002). With 72 h of fasting, the glucose and insulin excursions in response to the mixed meal were significantly greater compared with the 13-h fast (P < 0.001). In conclusion, prolonged fasting resulted in a significant decrease in carbohydrate oxidation and an increase in fat oxidation, after a normal mixed meal, in healthy men. This was associated with a significant decrease in glucose tolerance. Because circulating free fatty acids were greatly elevated at all times after the prolonged fast, these may be mediating some of the changes in postprandial metabolism.
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Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials.
Article
The circadian rhythm of core body temperature (CBT) is a well-documented physiological phenomenon. Already in 1842, Gierse [6] had shown that his own oral temperature revealed a maximum temperature in the early evening and a minimum in the early morning hours with a maximum-minimum range of 0.9 °C. It had been assumed for a long time that muscular activity (exercise) and digestive processes were the most important factors for generation of the CBT rhythm [8]. Aschoff and his colleagues systematically explored the causes of this rhythm [1, 2]. He showed that the circadian rhythm of CBT is determined both by changes in heat production and changes in heat loss, and concluded that heat production undergoes a circadian rhythm which is phase advanced by 1.2h with respect to the circadian rhythm of heat loss, i. e. when heat production surpasses heat loss, CBT increases – transport of heat needs time. Therefore, when we want to explain changes in CBT we need to know the relationship between heat production and heat loss. Under resting conditions, heat production depends mainly on the metabolic activity of inner organs such as liver, intestines, kidneys, heart in the abdominal/thoracic cavity, and the brain, together producing ca. 70 % of the entire resting metabolic rate of the human body [3]. However, this “core” heat is generated in only 8 % of the body mass with a surrounding skin surface of only about 0.3m 2 (surface to volume = 0.1) [3].
Article
Individuals engaged in shift- or night-work show disturbed diurnal rhythms, out of phase with temporal signals associated to the light/dark (LD) cycle, resulting in internal desynchronization. The mechanisms underlying internal desynchrony have been mainly investigated in experimental animals with protocols that induce phase shifts of the LD cycle and thus modify the activity of the suprachiasmatic nucleus (SCN). In this study we developed an animal model of night-work in which the light-day cycle remained stable and rats were required to be active in a rotating wheel for 8 h daily during their sleeping phase (W-SP). This group was compared with rats that were working in the wheel during their activity phase (W-AP) and with undisturbed rats (C). We provide evidence that forced activity during the sleeping phase (W-SP group) alters not only activity, but also the temporal pattern of food intake. In consequence W-SP rats showed a loss of glucose rhythmicity and a reversed rhythm of triacylglycerols. In contrast W-AP rats did not show such changes and exhibited metabolic rhythms similar to those of the controls. The three groups exhibited the nocturnal corticosterone increase, in addition the W-SP and W-AP groups showed increase of plasma corticosterone associated with the start of the working session. Forced activity during the sleep phase did not modify SCN activity characterized by the temporal patterns of PER1 and PER2 proteins, which remained in phase with the LD cycle. These observations indicate that a working regimen during the sleeping period elicits internal desynchronization in which activity combined with feeding uncouples metabolic functions from the biological clock which remains fixed to the LD cycle. The present data suggest that in the night worker the combination of work and eating during working hours may be the cause of internal desynchronization.