Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P < 0.00001). Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

Influence of gestational diabetes on circadian rhythms of children and their association with fetal adiposity.

OBJECTIVE: To analyse the circadian rhythm maturation of temperature, activity and sleep during the first year of life in offspring of diabetic mothers (ODM) and its relationship with obesity markers. METHODS: A prospective analysis of the children of 63 pregnant women (23 controls, 21 gestational diabetes mellitus (GDM) controlled with diet and 19 GDM with insulin). Fetal abdominal circumference was evaluated ecographically during gestation. Skin temperature and rest-activity rhythms were monitored for 3 consecutive days in children at 15 days and 1, 3 and 6 months. Anthropometrical parameters of the children were evaluated during the first year of life. RESULTS: Children from the GDM groups tended to higher fetal abdominal circumference z-score than controls at the beginning of the last trimester (p = 0.077) and at delivery (p = 0.078). Mean skin temperature or activity was not different among the groups. The I < O sleep index pointed to increasing concordance with parental sleeping at 3 and 6 months but no significant GDM-dependent differences. However, some of the parameters that define temperature maturation and also the circadian function index from the temperature-activity variable were significantly lower at 6 months in the GDM + insulin group. Fetal abdominal circumference z-score, as a predictor of fetal adiposity, correlated negatively with parameters related to circadian rhythm maturation as the circadian/ultradian rhythm (P1 /Pult ratio). CONCLUSIONS: Fetal adiposity correlated with a worse circadian rhythm regulation in ODM. In addition, ODM insulin-treated showed a disturbed pattern of the circadian function index of temperature activity at 6 months of age.

Exercise and melatonin in humans: reciprocal benefits.

The aim of this review is to update the reader as to the association between physical exercise and melatonin, and to clarify how the melatonin rhythm may be affected by different types of exercise. Exercise may act as a zeitgeber, although the effects of exercise on the human circadian system are only now being explored. Depending on the time of the day, on the intensity of light, and on the proximity of the exercise to the onset or decline of the circadian production of melatonin, the consequence of exercise on the melatonin rhythm varies. Moreover, especially strenuous exercise per se induces an increased oxidative stress that in turn may affect melatonin levels in the peripheral circulation because indole is rapidly used to combat free radical damage. On the other hand, melatonin also may influence physical performance, and thus, there are mutually interactions between exercise and melatonin production which may be beneficial.

An approximation to the temporal order in endogenous circadian rhythms of genes implicated in human adipose tissue metabolism.

Although it is well established that human adipose tissue (AT) shows circadian rhythmicity, published studies have been discussed as if tissues or systems showed only one or few circadian rhythms at a time. To provide an overall view of the internal temporal order of circadian rhythms in human AT including genes implicated in metabolic processes such as energy intake and expenditure, insulin resistance, adipocyte differentiation, dyslipidemia, and body fat distribution. Visceral and subcutaneous abdominal AT biopsies (n=6) were obtained from morbid obese women (BMI≥40 kg/m(2) ). To investigate rhythmic expression pattern, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h using quantitative real-time PCR. Clock genes, glucocorticoid metabolism-related genes, leptin, adiponectin and their receptors were studied. Significant differences were found both in achrophases and relative-amplitude among genes (P<0.05). Amplitude of most genes rhythms was high (>30%). When interpreting the phase map of gene expression in both depots, data indicated that circadian rhythmicity of the genes studied followed a predictable physiological pattern, particularly for subcutaneous AT. Interesting are the relationships between adiponectin, leptin, and glucocorticoid metabolism-related genes circadian profiles. Their metabolic significance is discussed. Visceral AT behaved in a different way than subcutaneous for most of the genes studied. For every gene, protein mRNA levels fluctuated during the day in synchrony with its receptors. We have provided an overall view of the internal temporal order of circadian rhythms in human adipose tissue.

Chronobiology, genetics and metabolic syndrome.

PURPOSE OF REVIEW: Circadian rhythms are such an innate part of our lives that we rarely pause to speculate why they even exist. Recently, some studies have suggested that the disruption of the circadian system may be causal for the manifestations of metabolic syndrome (MetS). This review summarizes the latest evidence of the existing interaction among chronobiology, genetics and MetS. RECENT FINDINGS: Shift work, sleep deprivation and bright light exposure at night are related to increased adiposity and prevalence of MetS. Animal models have revealed that mice with circadian locomotor output cycles kaput (clock) gene disruption are prone to develop a phenotype resembling MetS. Moreover, studies in humans have shown that clock genes are expressed in adipose tissue, and that both their levels of expression and their genetic variants correlate with different components of the MetS. Current studies are illustrating the particular role of different clock gene variants and their predicted haplotypes in MetS. SUMMARY: The circadian system has an important impact on metabolic disturbances and vice versa. Although the precise mechanism linking the MetS to chronodisruption is not well known, hypotheses point to the internal desynchronization between different circadian rhythms. The novelty of this area of research is contributing to the development of new and intriguing studies, particularly those focused on the association between different clock genes polymorphisms and MetS traits.

Heritability of the timing of food intake.

BACKGROUND & AIMS: While environmental factors are presumed to be primary drivers of food timing, preliminary evidence suggests that genetics may be an additional determinant. The aim was to explore the relative contribution of genetics and environmental factors to variation in the timing of food intake in a Spanish twin population. Because chronotype, bedtime and wake time are related to food timing, covariance with food timing was further assessed. METHODS: In this observational study, 53 pairs of adult (mean (SD) = 52 (6.03) years) female twins (28 monozygotic; 25 dizygotic) were recruited from the Murcia Twin Register. Zygosity was determined by DNA-testing. Timing of the three main meals of the day was assessed via 7-day dietary records, and the midpoint of food intake was computed by calculating the midpoint between breakfast and dinner times. Chronotype, bedtime and wake time were self-reported. Heritability of food timing and related traits were estimated by comparing monozygotic and dizygotic twin correlations and fitting genetic structural equation models to measured variables. RESULTS: We observed genetic influences for food timing, with highest heritability for the midpoint of food intake (64%) in an overweight/obese population (BMI = 26.01 ± 3.77). Genetic factors contributed to a higher degree to the timing of breakfast (56%) than the timing of lunch (38%) or dinner (n.s.). Similarly, heritability estimates were larger in related behavioral traits earlier on in the day (i.e. wake time, (55%)), than those later on in the day (i.e. bedtime, (38%)). Bivariate analyses revealed a significant genetic overlap between food timing and bedtime and chronotype (rG between 0.78 and 0.91). CONCLUSIONS: Genetic influences appear to account for a significant proportion of the variability in food timing, particularly breakfast. Thus, interventions related to food timing may be more effective when targeting afternoon/evening traits, such as lunch or dinner times. Furthermore, our data suggest shared genetic architecture underlying food timing and phenotypically related traits. CLINICAL TRIAL: NCT03059576. https://clinicaltrials.gov/ct2/show/NCT03059576.

Antioxidant dietary fiber isolated from spent coffee (Coffea arabica L.) grounds improves chronotype and circadian locomotor activity in young adults.

Chrononutrition, or the circadian timing of food intake, proposes that nutrients, bioactive compounds, and foods modulate the peripheral clocks with implications on health. We evaluated the effects of biscuits supplemented with the antioxidant dietary fiber isolated from spent coffee grounds as a food ingredient (SCF-B) or a combination of spent coffee grounds and fructooligosaccharides (SC-FOS-B), and a traditional recipe (TB, without added fiber) on the modulation of circadian rhythm in young adults. The repeated intake (21 days/45 g portion) of SCF-B or SC-FOS-B decreased (p < 0.05) the evening chronotypes. SCF-B and SC-FOS-B consumption enhanced the chronodisruption associated with colonic short chain fatty acid production, thus improving the quality and length of sleep. This is the first study on the positive impact of antioxidant dietary fiber obtained from spent coffee grounds on circadian activity improvement in young adults. Further clinical trials and the role of other bioactive compounds as therapeutic candidates for health disturbances related to circadian dysfunction are necessary to confirm the results.

Targeting neurons in the gastrointestinal tract to treat Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. OBJECTIVE: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. METHODS: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. RESULTS: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10-7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. CONCLUSIONS: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

Blue-Enriched Light Enhances Alertness but Impairs Accurate Performance in Evening Chronotypes Driving in the Morning.

Attention maintenance is highly demanding and typically leads to vigilance decrement along time on task. Therefore, performance in tasks involving vigilance maintenance for long periods, such as driving, tends to deteriorate over time. Cognitive performance has been demonstrated to fluctuate over 24 h of the day (known as circadian oscillations), thus showing peaks and troughs depending on the time of day (leading to optimal and suboptimal times of day, respectively). Consequently, vigilance decrements are more pronounced along time on task when it is performed at suboptimal times of day. According to research, light exposure (especially blue-enriched white) enhances alertness. Thus, it has been proposed to prevent the vigilance decrement under such adverse circumstances. We aimed to explore the effects of blue-enriched white light (vs. dim light) on the performance of a simulated driving task at a suboptimal time of day. A group of evening-types was tested at 8 am, as this chronotype had previously shown their largest vigilance decrement at that time. In the dim light condition, vigilance decrements were expected on both subjective (as increments in the Karolinska Sleepiness Scale scores) and behavioral measures [as slower reaction times (RTs) in the auditory Psychomotor Vigilance Task, slower RTs to unexpected events during driving, and deteriorated driving accuracy along time on task]. Physiological activation was expected to decrease (as indexed by an increase of the distal-proximal temperature gradient, DPG). Under blue-enriched white light, all these trends should be attenuated. Results from the control dim light condition replicated the vigilance decrement in all measures. Most important, the blue-enriched white light attenuated this decrement, leading to both lower DPG and faster RTs. However, it impaired accuracy of driving performance, and did not have any effect on subjective sleepiness. We conclude that exposure to blue-enriched light provides an effective countermeasure to enhance vigilance performance at suboptimal times of day, according to measures such as RTs. However, it should be considered that alerting effects of light could impair accuracy in precision tasks as keeping a proper car position. The current findings provide ergonomic implications for safety and fatigue related management systems.

Effect of Single and Combined Monochromatic Light on the Human Pupillary Light Response.

The pupillary light reflex (PLR) is a neurological reflex driven by rods, cones, and melanopsin-containing retinal ganglion cells. Our aim was to achieve a more precise picture of the effects of 5-min duration monochromatic light stimuli, alone or in combination, on the human PLR, to determine its spectral sensitivity and to assess the importance of photon flux. Using pupillometry, the PLR was assessed in 13 participants (6 women) aged 27.2 ± 5.41 years (mean ± SD) during 5-min light stimuli of purple (437 nm), blue (479 nm), red (627 nm), and combinations of red+purple or red+blue light. In addition, nine 5-min, photon-matched light stimuli, ranging in 10 nm increments peaking between 420 and 500 nm were tested in 15 participants (8 women) aged 25.7 ± 8.90 years. Maximum pupil constriction, time to achieve this, constriction velocity, area under the curve (AUC) at short (0-60 s), and longer duration (240-300 s) light exposures, and 6-s post-illumination pupillary response (6-s PIPR) were assessed. Photoreceptor activation was estimated by mathematical modeling. The velocity of constriction was significantly faster with blue monochromatic light than with red or purple light. Within the blue light spectrum (between 420 and 500 nm), the velocity of constriction was significantly faster with the 480 nm light stimulus, while the slowest pupil constriction was observed with 430 nm light. Maximum pupil constriction was achieved with 470 nm light, and the greatest AUC0-60 and AUC240-300 was observed with 490 and 460 nm light, respectively. The 6-s PIPR was maximum after 490 nm light stimulus. Both the transient (AUC0-60) and sustained (AUC240-300) response was significantly correlated with melanopic activation. Higher photon fluxes for both purple and blue light produced greater amplitude sustained pupillary constriction. The findings confirm human PLR dependence on wavelength, monochromatic or bichromatic light and photon flux under 5-min duration light stimuli. Since the most rapid and high amplitude PLR occurred within the 460-490 nm light range (alone or combined), our results suggest that color discrimination should be studied under total or partial substitution of this blue light range (460-490 nm) by shorter wavelengths (~440 nm). Thus for nocturnal lighting, replacement of blue light with purple light might be a plausible solution to preserve color discrimination while minimizing melanopic activation.

Multidimensional Circadian Monitoring by Wearable Biosensors in Parkinson's Disease.

Parkinson's disease (PD) is associated with several non-motor symptoms that may precede the diagnosis and constitute a major source of frailty in this population. The digital era in health care has open up new prospects to move forward from the qualitative and subjective scoring for PD with the use of new wearable biosensors that enable frequent quantitative, reliable, repeatable, and multidimensional measurements to be made with minimal discomfort and inconvenience for patients. A cross-sectional study was conducted to test a wrist-worn device combined with machine-learning processing to detect circadian rhythms of sleep, motor, and autonomic disruption, which can be suitable for the objective and non-invasive evaluation of PD patients. Wrist skin temperature, motor acceleration, time in movement, hand position, light exposure, and sleep rhythms were continuously measured in 12 PD patients and 12 age-matched healthy controls for seven consecutive days using an ambulatory circadian monitoring device (ACM). Our study demonstrates that a multichannel ACM device collects reliable and complementary information from motor (acceleration and time in movement) and common non-motor (sleep and skin temperature rhythms) features frequently disrupted in PD. Acceleration during the daytime (as indicative of motor impairment), time in movement during sleep (representative of fragmented sleep) and their ratio (A/T) are the best indexes to objectively characterize the most common symptoms of PD, allowing for a reliable and easy scoring method to evaluate patients. Chronodisruption score, measured by the integrative algorithm known as the circadian function index is directly linked to a low A/T score. Our work attempts to implement innovative technologies based on wearable, multisensor, objective, and easy-to-use devices, to quantify PD circadian rhythms in huge populations over extended periods of time, while controlling at the same time exposure to exogenous circadian synchronizers.

Blue-Enriched White Light Enhances Physiological Arousal But Not Behavioral Performance during Simulated Driving at Early Night.

Vigilance usually deteriorates over prolonged driving at non-optimal times of day. Exposure to blue-enriched light has shown to enhance arousal, leading to behavioral benefits in some cognitive tasks. However, the cognitive effects of long-wavelength light have been less studied and its effects on driving performance remained to be addressed. We tested the effects of a blue-enriched white light (BWL) and a long-wavelength orange light (OL) vs. a control condition of dim light on subjective, physiological and behavioral measures at 21:45 h. Neurobehavioral tests included the Karolinska Sleepiness Scale and subjective mood scale, recording of distal-proximal temperature gradient (DPG, as index of physiological arousal), accuracy in simulated driving and reaction time in the auditory psychomotor vigilance task. The results showed that BWL decreased the DPG (reflecting enhanced arousal), while it did not improve reaction time or driving performance. Instead, blue light produced larger driving errors than OL, while performance in OL was stable along time on task. These data suggest that physiological arousal induced by light does not necessarily imply cognitive improvement. Indeed, excessive arousal might deteriorate accuracy in complex tasks requiring precision, such as driving.

Fragmentation of daily rhythms associates with obesity and cardiorespiratory fitness in adolescents: The HELENA study.

BACKGROUND & AIMS: Chronobiology studies periodic changes in living organisms and it has been proposed as a promising approach to investigate obesity. We analyze the association of the characteristics of the rest-activity rhythms with obesity, cardiorespiratory fitness and metabolic risk in adolescents from nine European countries. METHODS: 1044 adolescents (12.5-17.5 y) were studied. Circadian health was evaluated by actigraphy with accelerometers (Actigraph GT1M). Characteristics of the daytime activity such as fragmentation (intradaily variability), estimated acrophase, and 10 h mean daytime activity index were obtained. Body composition was assessed using Bioelectrical-Impedance-Analysis, skinfold thickness, air-displacement-plethysmography and Dual-energy-X-ray-Absorptiometry. Cardiorespiratory fitness (VO2max) and metabolic risk were studied. RESULTS: Highly fragmented activity rhythms were associated with obesity and central adiposity (P < 0.05). Obese adolescents had ∼3 times higher odds of having a high fragmentation of daytime activity compared to normal weight adolescents OR (95% CI) = 2.8 (1.170, 6.443). A highly fragmented rhythm was also related to lower cardiorespiratory fitness and higher metabolic risk (P < 0.05) so those adolescents classified as low fitness showed a significantly higher fragmentation of daytime activity than those included in the high fitness group (P < 0.0001). Other characteristics of the rhythms such as smaller 10 h daytime mean activity index and delayed estimated acrophase were also related to obesity and metabolic risk (P < 0.05). CONCLUSIONS: Our results indicate that the daily organization of the rest-activity cycle is more fragmented in obese and less fit adolescents and correlates with higher metabolic risk. This fact reinforces our hypothesis that disturbances in daily rhythms can be considered as sensitive markers of poorer adolescent's health.

Light and temperature cycles as zeitgebers of zebrafish (Danio rerio) circadian activity rhythms.

Light and temperature cycles are the most important synchronizers of biological rhythms in nature. However, the relative importance of each, especially when they are not in phase, has been poorly studied. The aim of this study was to analyze the entrainment of daily locomotor activity to light and/or temperature cycles in zebrafish. Under two constant temperatures (20 degrees C and 26 degrees C) and 12:12 light-dark (LD) cycles, zebrafish were most active during the day (light) time and showed higher total activity at the warmer temperature, while diurnalism was higher at 20 degrees C than at 26 degrees C (87% and 77%, respectively). Under thermocycles (12:12 LD, 26:20 degrees C thermophase:chryophase or TC), zebrafish daily activity synchronized to the light phase, both when the thermophase and light phase were in phase (LD/TC) or in antiphase (LD/CT). Under constant dim light (3 lux), nearly all zebrafish synchronized to thermocycles (tau=24 h), although activity rhythms (60% to 67% of activity occurred during the thermophase) were not as marked as those observed under the LD cycle. Under constant dim light of 3 lux and constant temperature (22.5 degrees C), 4 of 6 groups of zebrafish previously entrained to thermocycles displayed free-running rhythms (tau=22.9 to 23.6 h). These results indicate that temperature cycles alone can also entrain zebrafish locomotor activity.

Menopause status is associated with circadian- and sleep-related alterations.

OBJECTIVE: The aim of the study was to investigate whether postmenopausal women show differences in circadian-related variables and sleep characteristics compared with premenopausal women, and to analyze potential associations between these circadian-related variables and abdominal fat distribution or metabolic syndrome (MetS) components. METHODS: A total of 177 women were studied (127 premenopausal, 50 postmenopausal). Sixty percent of the total population was overweight/obese, with no significant differences between premenopausal (60%) and postmenopausal women (62%) (P = 0.865). Wrist temperature (WT) and rest-activity cycles were measured during 8 consecutive days, and sleep and food diaries collected. MetS characteristics and daily patterns of saliva cortisol were analyzed. Sleep characteristics were assessed with domiciliary polysomnography. RESULTS: Postmenopausal women showed a less robust rhythm in WT with lower amplitude (°C) (0.8 ±â€Š0.4 vs 0.9 ±â€Š0.5) (P < 0.05) and lower mean temperature values at the midpoint of sleep than premenopausal women. Postmenopausal women were also more morning-type than premenopausal women, showing a phase advance of approximately 1 hour in WT and rest-activity rhythms, and more morning-type habits (earlier sleep onset/offset and breakfast intake) (P < 0.05). Postmenopausal women showed higher levels of activity in the morning and lower in the evening compared with premenopausal women (P < 0.05). Daily variability in cortisol was significantly reduced in postmenopausal women compared with premenopausal women (P < 0.05). Postmenopausal women had increased frequency of sleep-related breathing abnormalities (P < 0.0001). In the women studied, abdominal fat and MetS were associated with an increase in circadian alterations (high fragmentation and low amplitude of the rhythm) (P < 0.05). CONCLUSIONS: Postmenopausal women exhibit loss of circadian robustness and an increase in sleep abnormalities compared with premenopausal women.

Circadian system heritability as assessed by wrist temperature: a twin study.

Previous research shows that wrist temperature (WT) is a good marker to assess the circadian system health in different circumstances. However, no studies have been performed in order to know the genetic component of this circadian marker. For this purpose, the aim was to determine, using classical twin models, the relative genetic and environmental influences on WT. The study was performed in 53 pairs of female twins (28 monozygotic (MZ) and 25 dizygotic (DZ)), with a body mass index 25.9 ± 3.78 and mean age 52 ± 6 years. The sample was selected from the Murcia Twin Register. Circadian patterns were studied by analyzing WT during one week every 10 min "Circadianware®". Genetic influences to WT variability were estimated by comparing correlations of MZ and DZ twin pairs and fitting genetic structural equation models to measured variables. MZ twins showed higher intra-pair correlations than DZ twins for most of the parameters. Genetic factors were responsible for between 46% and 70% of variance (broad sense heritability) in parameters such as mean temperature, mesor, acrophase, Rayleigh test, percentage of rhythmicity and five hours of maximum temperature. The pattern of correlations and the genetic models point to moderate to high heritability for most of the WT parameters, suggesting a relevant genetic influence. The presence of these genetic factors points to endogenicity as the main cause of the coincidence of the WT rhythms. However, some WT parameters are still dependent on environment to a relevant extent and, hence, more amenable to change through external interventions.

Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans.

AIMS: The common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75 g) at different times of the day (morning and evening) as compared to a placebo. METHODS: Seventeen normoglycemic women (24 ± 6 years; BMI 23.0 ± 3.3 kg/m(2)) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]). RESULTS: The effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05). CONCLUSIONS: MTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.

Disruption of Circadian Rhythms and Delirium, Sleep Impairment and Sepsis in Critically ill Patients. Potential Therapeutic Implications for Increased Light-Dark Contrast and Melatonin Therapy in an ICU Environment.

The confinement of critically ill patients in intensive care units (ICU) imposes environmental constancy throughout both day and night (continuous light, noise, caring activities medications, etc.), which has a negative impact on human health by inducing a new syndrome known as circadian misalignment, circadian disruption or chronodisruption (CD). This syndrome contributes to poor sleep quality and delirium, and may impair septic states frequently observed in critically ill patients. However, and although the bidirectional crosstalk between CD with sleep impairment, delirium and inflammation in animal models has been known for years and has been suspected in ICU patients, few changes have been introduced in the environment and management of ICU patients to improve their circadian rhythmicity. Delirium, the most serious condition because it has a severe effect on prognosis and increases mortality, as well as sleep impairment and sepsis, all three of them linked to disorganization of the circadian system in critically ill patients, will be revised considering the functional organization of the circadian system, the main input and output signals that synchronize the clock, including a brief description of the molecular circadian clock machinery, the non-visual effects of light, and the ICU light environment. Finally, the potential usefulness of increased light/dark contrast and melatonin treatment in this context will be analyzed, including some practical countermeasures to minimize circadian disruption and improve circadian system chronoenhancement, helping to make these units optimal healing environments for patients.

Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening.

STUDY OBJECTIVES: To study the effect of melatonin administration on glucose metabolism in humans in the morning and evening. DESIGN: Placebo-controlled, single-blind design. SETTING: Laboratory assessments. PARTICIPANTS: 21 healthy women (24 ± 6 y; body mass index: 23.0 ± 3.3 kg/m(2)). INTERVENTIONS: Glucose tolerance was assessed by oral glucose tolerance tests (OGTT; 75 g glucose) on 4 occasions: in the morning (9 AM), and evening (9 PM); each occurring 15 minutes after melatonin (5 mg) and placebo administration on 4 non-consecutive days. MEASUREMENTS AND RESULTS: Melatonin administration impaired glucose tolerance. When administered in the morning, melatonin significantly increased the incremental area under the curve (AUC) and maximum concentration (Cmax) of plasma glucose following OGTT by 186% and 21%, respectively, as compared to placebo; while in the evening, melatonin significantly increased glucose AUC and Cmax by 54% and 27%, respectively. The effect of melatonin on the insulin response to the OGTT depended on the time of day (P < 0.05). In the morning, melatonin decreased glucose tolerance primarily by decreasing insulin release, while in the evening, by decreasing insulin sensitivity. CONCLUSIONS: Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. When administering melatonin, the proximity to meal timing may need to be considered, particularly in those at risk for glucose intolerance.

Period gene expression in the brain of a dual-phasing rodent, the Octodon degus.

Clock gene expression is not only confined to the master circadian clock in the suprachiasmatic nucleus (SCN) but is also found in many other brain regions. The phase relationship between SCN and extra-SCN oscillators may contribute to known differences in chronotypes. The Octodon degus is a diurnal rodent that can shift its activity-phase preference from diurnal to nocturnal when running wheels become available. To understand better the relationship between brain clock gene activity and chronotype, we studied the day-night expression of the Period genes, Per1 and Per2, in the SCN and extra-SCN brain areas in diurnal and nocturnal degus. Since negative masking to light and entrainment to the dark phase are involved in the nocturnalism of this species, we also compare, for the first time, Per expression between entrained (EN) and masked nocturnal (MN) degus. The brains of diurnal, MN, and EN degus housed with wheels were collected during the light (ZT4) and dark (ZT16) phases. Per1 and Per2 mRNA levels were analyzed by in situ hybridization. Within the SCN, signals for Per1 and Per2 were higher at ZT4 irrespective of chronotype. However, outside of the SCN, Per1 expression in the hippocampus of EN degus was out of phase (higher values at ZT16) with SCN values. Although a similar trend was seen in MN animals, this day-night difference in Per1 expression was not significant. Interestingly, daily differences in Per1 expression were not seen in the hippocampus of diurnal degus. For other putative brain areas analyzed (cortices, striatum, arcuate, ventromedial hypothalamus), no differences in Per1 levels were found between chronotypes. Both in diurnal and nocturnal degus, Per2 levels in the hippocampus and in the cingulate and piriform cortices were in phase with their activity rhythms. Thus, diurnal degus showed higher Per2 levels at ZT4, whereas in both types of nocturnal degus, Per2 expression was reversed, peaking at ZT16. Together, the present study supports the hypothesis that the mechanisms underlying activity-phase preference in diurnal and nocturnal mammals reside downstream from the SCN, but our data also indicate that there are fundamental differences between nocturnal masked and entrained degus.