Ultradian pulsatility of plasma glucose and insulin secretion rate: circadian and sleep modulation

Insulin release is a complex oscillatory process with rapid pulses (10 min) superimposed on slower circhoral oscillations (50-100 min). The exact mechanism of the circhoral oscillations, which are probably in part the consequence of a negative feedback loop linking glucose and insulin secretion rate, remains unclear. Stimulatory effects of sleep on insulin secretion are achieved by an enhancement of the oscillation amplitude which could be partly mediated by GH. The different patterns observed after acute or chronic shift of sleep suggest however an interaction between sleep influence and circadian rhythmicity, as described for numerous pituitary hormones. The intra-sleep awakenings have a modulatory effect on glucose levels but no systematic relationship exists between glucose or insulin secretion rate oscillations and the REM-NREM sleep cycles. Irrespective of the mechanisms involved, sleep or GH stimulatory effects result from a modulation of the oscillation amplitude rather than of their frequency which is probably an important feature of insulin efficacy.     

Circadian and ultradian variations of leptin in normal man under continuous enteral nutrition: relationship to sleep and body temperature

To determine the influence of circadian rhythmicity and sleep on the 24-h leptin diurnal variations, plasma leptin levels were measured at 10-min intervals over 24 h in seven normal subjects, once during nocturnal sleep, and once after an 8-h shift of sleep. The subjects were submitted to constant conditions (continuous enteral nutrition and bed rest in controlled chambers). Body temperature and plasma glucose and insulin levels were measured simultaneously. During nighttime sleep, leptin levels increased to a maximum (109.9 +/- 2.5% of the 24-h mean) and then decreased to reach a nadir in the late afternoon. The mean diurnal variation was 18.0 +/- 3.8% of the 24-h mean. In the daytime sleep condition, leptin levels rose during the night of deprivation to a maximum of 104.7 +/- 2.3% of the 24-h mean, decreased to a minimum around 0700 h, and then rose again during diurnal sleep (108.4 +/- 3.1% of the 24-h mean); the mean diurnal variation was 13.4 +/- 3.6% of the 24-h mean. ANOVA revealed a significant interaction between time of day and sleep effects (P < 0.05). The diurnal and the sleep-related variations of plasma leptin mirrored those of body temperature and roughly paralleled those of plasma glucose and insulin; the amplitudes of the diurnal leptin variations were significantly correlated with the amplitudes of the diurnal body temperature variations (P < 0.05). Plasma leptin levels also displayed irregular pulses of low amplitude (mean duration, 70 min) that were not affected by sleep, but were associated with a significant decrease in glucose and insulin levels (P < 0.01). These results demonstrate that under continuous enteral nutrition, plasma leptin levels are modulated by both a slight circadian component and sleep, which interact under normal conditions, and suggest that leptin is implicated in circadian thermoregulatory adjustments.     

Effect of redox conditions on the DNA-binding efficiency of the retinoic acid receptor zinc-finger

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30-40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.     

Effects of ageing on modulation of hormonal secretions by sleep and circadian rhythmicity

Circadian rhythmicity persists in healthy elderly subjects but a number of 24 hour rhythms are dampened and/or advanced in old age. The tendency for earlier sleep onset, earlier morning awakening and a more fragmented and more shallow sleep period is representative of these alterations. Other overt rhythms which have been shown to be of lower amplitude and/or phase-advanced are those of body temperature and of the peripheral levels of hormones such as cortisol, melatonin, TSH, testosterone, prolactin and GH. Mean hormonal levels are generally decreased, but overall cortisol secretion is increased with ageing. These modifications are likely to be partially due to alterations of the circadian central nervous system processes controlling circadian rhythmicity and sleep.     

Sleep inertia varies with circadian phase and sleep stage in older adults.

The purpose of our analysis was to determine if older adults show sleep inertia effects on performance at scheduled wake time, and whether these effects depend on circadian phase or sleep stage at awakening. Using the Digit Symbol Substitution Test, effects of sleep inertia on performance were assessed over the first 30 min after wake time on baseline days and when sleep was scheduled at different circadian phases. Mixed model analyses revealed that performance improved as time awake increased; that beginning levels of performance were poorest when wake time was scheduled to occur during the biological night; and that effects of sleep inertia on performance during the biological night were greater when awaking from non-REM (NREM) sleep than from REM sleep. Based on our current understanding of sleep inertia effects in young subjects, and previous reports that older subjects awaken at an earlier circadian phase and are more likely to have their final awakening from NREM sleep than younger adults, our findings suggest older adults may be more vulnerable to sleep inertia effects than young adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects

We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.     

Circadian patterns of ischemic events

These is evidence of circadian variations in the occurrence of ischemic events such as: silent myocardial ischemia, stable angina, instable angina, acute myocardial infarction, sustained ventricular tachycardia, cerebral infarction, transient ischemic attack (TIA) and sudden cardiac death. In the general population many cardiovascular disorders occur with the greatest frequency between 6 and 12 a.m. (i.e. after awakening). Blood pressure, too, follows a distinct circadian pattern. Factors affecting circadian variations in cardiovascular disorders include physiological determinants, such as heart rate, catecholamine release, and platelet aggregation-which themselves cyclically vary-, and exogenous factors such as mental stress, anxiety, and physical activity. In chronotherapy, circadian variations in disease states and in the pharmacodynamic properties of drugs are exploited to improve prevention and treatment. Characterization of diseases states with this approach allows more accurate determination of the times when patients are at highest risk and therefore in greatest need of preventive measures; it also provides a mechanism for designing optimal drug regimens. In this review we therefore describe recent findings about the effects of biorhythms on cardiovascular disorders and their implications for optimal drug therapy.     

Effects of two types of clothing on the day-night variation of core temperature and salivary immunoglobulin A

Circadian variations in core temperature, skin temperatures, heart rate, and salivary immunoglobulin A (IgA) were compared in subjects wearing two different types of clothing that covered, or left uncovered, their extremities. The experiments were carried out on six female subjects at an ambient temperature of 24 +/- 0.5 degrees C and relative humidity of 50 +/- 5%. One type of clothing consisted of long-sleeved shirts, full-length trousers, and socks (Type L: 1042 g, 1.048 clo); the other was half-sleeved shirts and knee-length trousers (Type H: 747 g, 0.744 clo). The main results were as follows: (i) The level of rectal temperature during night sleep was significantly lower with Type H than Type L clothing, and cosinor analysis indicated a significantly higher circadian amplitude with Type H clothing. (ii) Skin temperatures in the lower extremities increased significantly more on retiring to sleep with Type H than Type L clothing. (iii) Heart rate was significantly lower with Type H than Type L clothing during the sleep period. (iv) The day-night variation of salivary IgA showed a pattern that was the inverse of that of rectal temperature (i.e., low in the daytime and high in the nighttime), and the concentration of salivary IgA was significantly higher with Type H than Type L clothing at 02:30. (v) Subjectively, the self-assessed sleep quality was better with Type H clothing. These results suggest that clothing that leaves the extremities uncovered might be regarded as favorable at the moderate temperature since it induces good sleep and activates the immune response.     

Evidence for an endogenous clock in the retina of rainbow trout: II. Circadian rhythmicity of serotonin metabolism

The purpose of the present study was to investigate patterns of circadian rhythmicity in the retina of a salmonid fish, the rainbow trout (Oncorhynchus mykiss). Our data present the first demonstration of intraretinal variations of serotonergic substances under light/dark-conditions (LD) and during continuous darkness (DD). All substances examined (serotonin, N-acetyl serotonin, 5-hydroxytryptophol, 5-hydroxyindole acetic acid) were rhythmic in LD. Serotonin, N-acetyl-serotonin, and 5-hydroxyindole acetic acid showed a preservation of specific features of rhythmicity in DD indicating the involvement of an endogenous pacemaker in the regulation of serotonin metabolism in the rainbow trout eye.     

Differential sensitivity of membrane-associated pyrophosphatases to inhibition by diphosphonates and fluoride delineates two classes of enzyme

The participation of GABAergic mechanisms in the regulation of circadian rhythmicity by the suprachiasmatic nuclei (SCN) has been suggested from different lines of evidence. Little is known, however, whether GABA synthesis, release, uptake or content within the SCN may show a circadian pattern. The present results show that the activity of the GABAergic system within the SCN region of the rat exhibits circadian rhythmicity, which is manifested by correlative changes of the GABA content and the glutamic acid decarboxylase activity under the light/dark cycle, and by changes in the GABA content in animals kept under constant darkness.     

Changes in cortisol secretion during shiftwork: implications for tolerance to shiftwork?

The present study was conducted to determine the size of changes and the time point of those changes in biological rhythms during night-shift and whether they are associated with tolerance to shiftwork. The adrenal hormone cortisol has frequently been investigated in the field of shiftwork since it follows a pronounced circadian variation and has been demonstrated to be affected by night-work. However, studies are restricted with respect to sample size, number of measurements or duration of sampling periods. Therefore, a sample of 24 night-shift workers was investigated in a cardiac emergency unit for seven nights. Saliva samples were collected frequently for determination of cortisol. A total of 28 cortisol measurements in each subject were made in order to decide whether the circadian rhythm changed, and if so at which time point. A clear reversal of circadian function could be observed for the total group (mean cortisol concentrations) after the fifth night. However, inspection of individual patterns revealed that six out of 24 subjects did not change in circadian function. These subjects exhibited lower durations of and less consistency in recovery sleep across the following days after night-work. With respect to personality dimensions a pattern associated with neuroticism can be observed in subjects without appropriate changes in cortisol rhythm. However, owing to the small sample size of non-adapters these results are preliminary and should be replicated with larger samples. The overall relationship between neuroticism and low adaptability has been discussed.     

Gastric intramucosal acidosis in mechanically ventilated patients: role of mucosal blood flow

To examine the roles of Arg-vasopressin (AVP)- and vasoactive intestinal peptide (VIP)-containing neurons in the suprachiasmatic nucleus (SCN) in production of circadian rhythmicity of locomotor activity, variations in the contents of AVP and VIP in punched-out SCN tissue and locomotor activity were measured under a light-dark cycle as well as under conditions of constant light for up to 3 weeks. Under the light-dark cycle, contents of AVP and VIP, and locomotor activity showed marked circadian rhythmicity. Under constant light, AVP content showed circadian rhythmicity until 3 weeks, while VIP rhythm disappeared from the first week with decreases in its content. Locomotor activity showed a free-running circadian rhythm for more than 3 weeks under constant light conditions in most cases. These results suggest that AVP but not VIP in the SCN may be involved in the generation of locomotor activity rhythm under conditions of constant light.     

The role of melatonin in the human fetus (review)

Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.     

Melatonin, its receptors, and relationships with biological rhythm disorders

Melatonin is a neurohormone produced during the night by the pineal gland. Its secretion is regulated by circadian and seasonal variations in daylength, transmitted via visual projections to the suprachiasmatic nucleus which functions as a circadian clock in mammals. Melatonin has been proposed to act as an internal synchronizer of circadian rhythms generated at different levels of the organism. The chronobiotic effects of melatonin in humans have been mainly studied in circadian rhythm sleep disorders related to jet lag, shift work, blindness or aging. Alterations of the melatonin profiles have also been reported in other biological rhythm disorders.     

Failure of nocturnal changes in growth hormone to alter carbohydrate tolerance the following morning

To determine whether the increases in growth hormone that occur during sleep alter carbohydrate tolerance the following morning, two groups of volunteers were studied on two occasions. In one group saline alone was injected and infused (i.e. no octreotide) on one occasion and on the other octreotide was injected at 23.00 hours to inhibit endogenous growth hormone secretion followed by saline infusion to create a state of relative nocturnal growth hormone deficiency. In the other group the octreotide injection was followed on one occasion by a constant growth hormone infusion designed to maintain growth hormone concentrations at "basal" levels throughout the night whereas on the other it was followed by a constant infusion plus two supplemental growth hormone infusions given at midnight and 02.30 hours to mimic the normal nocturnal rise in growth hormone. The next morning, subjects were fed a radiolabelled mixed meal. The differences in the nocturnal growth hormone concentrations had no effect on the glucose, insulin, C-peptide and glucagon concentrations following breakfast ingestion nor did they alter postprandial rates of glucose production, disappearance or substrate oxidation. Thus, the normal nocturnal rise in growth hormone does not appear to be an important regulator of carbohydrate tolerance the following morning.     

Identification of two novel diurnal genes by screening of a rat brain cDNA library

While the hypothalamus is fundamental for sleep and circadian regulation, the molecular mechanisms involved are poorly understood. We have used a differential gene expression technique to identify hypothalamic genes which have altered expression in rat sleep periods. Complex cDNA probes from rat hypothalami removed at Zeitgeber times 4 and 15 were hybridised to rat brain cDNA library girds. From 30 differentially expressed clones, six were further analysed and two were confirmed to exhibit increased expression at Zeitgeber time 4. A Northern blot hybridization of brain, heart, kidney, lung, testis and skin mRNA showed that both clones were brain specific. Therefore, we have identified two novel brain specific diurnally expressed hypothalamic genes. Both genes may have roles in sleep or circadian regulation.     

Robust circadian rhythmicity of Drosophila melanogaster requires the presence of lateral neurons: a brain-behavioral study of disconnected mutants

Mutations at the disconnected (disco) locus of Drosophila melanogaster disrupt neural cell patterning in the visual system, leading to the loss of many optic lobe neurons. Drosophila's presumptive circadian pacemaker neurons--the dorsal and ventral lateral neurons--are usually among the missing cells, and most disco flies are behaviorally arrhythmic. In this study, I show that ventral lateral neurons (LNvs) are occasionally present and provoke robust circadian rhythmicity in disco mutants. Of 357 individual disco flies four animals with robust circadian rhythmicity were found. All four retained LNvs together with terminals in the superior protocerebrum. Residual or bi-circadian rhythmicity was found in about 20% of all flies; the remaining flies were completely arrhythmic. One of the flies with residual rhythmicity and two of the arrhythmic flies also had some LNvs stained. However, these flies lacked the LNv fibers in the superior protocerebrum. The results suggest that the presence of single LNvs is sufficient to provoke robust circadian rhythmicity in locomotor activity if the LNv terminals reach the superior protocerebrum. The presence of residual or bi-circadian rhythmicity in 20% of the flies without LNvs indicates that also other cells contribute to the rhythmic control of locomotor activity.     

Influence of polar route schedules on the duty and rest patterns of aircrew

The duty and rest periods of aircrew operating the polar route from London via Anchorage were recorded during five schedules which involved 1-, 2- or 3-day sojourns in Japan. Sleep throughout each schedule was fragmented, with naps before duty and short sleeps after arrival at a new location. Sleep disturbance rather than cumulative sleep loss appeared to be the overriding problem, and the shorter schedules had the most marked disturbances in sleep during the trip and during the immediate recovery period. Electroencephalographic studies are necessary to confirm these observations, and information on circadian rhythmicity is needed to define the circumstances which lead to persistence of sleep disturbance on return to Europe.     

Severe loss of vasopressin-immunoreactive cells in the suprachiasmatic nucleus of aging voles coincides with reduced circadian organization of running wheel activity

Aging leads to a decrease in circadian organization of behavior. Whether this general observation is related to the finding that in older subjects the arginine-vasopressin (AVP) system in the suprachiasmatic nucleus (SCN) has deteriorated is an unsolved question. Here we assessed circadian organization of running wheel behavior and numbers of AVP cells in the SCN of old voles (n=12, 11. 5 months of age) and compared the results with data from young voles (n=16, 4.5 months of age). A third of the young voles, but three-quarter of the old voles lost circadian rhythmicity. Analysis of daily onset to onset periodicity of running wheel activity at the age of 5 and 10 months in individual voles revealed a significant loss of precision of circadian rhythmicity at the higher age. The number of AVP cells in the SCN of old voles decreased substantially, over 78% compared to young voles in general. AVP cell numbers, however, cannot be directly correlated with the state of rhythmicity in old voles; in one of the three circadian rhythmic old voles the SCN contained the least AVP cells. This study does not support the idea of a causal relationship between aging induced reduction in AVP cells in the SCN and the presence of circadian rhythmicity in behavior.     

Endocrine secretions under abnormal light-dark cycles and in the blind

Both endogenous and exogenous factors are involved in regulation of endocrine secretions. Among the exogenous ones, light plays an important role both in animals and in humans. Pineal gland mediates light action on the endocrine system, by means of variations of melatonin (MT) secretion. Here we discuss about the influence of abnormal light-dark cycles and in particular of blindness on pineal and pituitary secretions and on those of correlated glands. MT secretion is usually inhibited by light: thus it reaches the highest levels at night. Exposure to short or long photoperiod causes variations in circadian or infradian MT rhythmicity. Blind patients can show higher daytime levels with a phase-advanced or phase-delayed circadian rhythm. Lack of light stimulus affects cortisol rhythm shifting the zenith of secretion and inducing a free-running rhythm. Blindness can abolish nocturnal growth hormone (GH) peak and impair the GH response to some stimuli; moreover it impairs the growth of affected patients. Light stimulus influences favorably gonadal function both in animals and in man. In animals, sexual activity and gonadal function decline during the seasons with reduced luminosity. A similar finding has been described in women living in a region with a strong seasonal contrast in luminosity. Blindness can impair luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone secretion in prepubertal boys causing pubertal delay or more severe hypogonadism; it can affect pubertal development and fertility in women. Light can influence thyroid function in animals. Lack of light stimulus in blind man seems to cause different effects on thyroid function before and after puberty. Increase of free thyroid hormone levels has been found in prepubertal but not in adult blind patients, probably due to a resetting of the threshold for thyrotropin feedback suppression after puberty in these patients.