Disrupted circadian rhythms of body temperature,heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus

We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40–69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.     

Circadian and Ultradian Rhythms in Blood Glucose and Plasma Insulin of Healthy Adults

The circadian and ultradian variations of blood glucose and plasma insulin have been characterized individually and as a group phenomenon in five healthy young adults studied while adhering as closely as possible to their usual routine of sleep, activity, meal content and timing. Three complementary methods were used to analyze the data: displaying raw data as a function of time; cosinor method according to Nelson and Halberg; and time series analyses as proposed by De Prins and Malbecq. The subjects were studied in the laboratory and their life routine were controlled, but very close to that of their habitual routine. They had mainly ultradian rhythms of blood glucose (mainly about 6 hr) and circadian rhythms of immunoreactive insulin (I.R.I.). Blood glucose ultradian rhythms seem to be mainly but not exclusively mealtime dependent, while I.R.I, circadian rhythms appear to be primarily endogenous in origin. Therefore, the role played by insulin in the control of blood glucose levels seems to be programmed on a circadian basis rather than by a time independent feedback phenomenon as postulated by the conventional homeostatic hypothesis. The advantage of this chronophysiologic approach is to consider circadian rhythms of both I.R.I. and insulin effectiveness as an adaptive phenomenon able to maintain blood sugar changes in the ultradian domain of rhythms.     

Metabolic cycles are linked to the cardiovascular diurnal rhythm in rats with essential hypertension

Background

The loss of diurnal rhythm in blood pressure (BP) is an important predictor of end-organ damage in hypertensive and diabetic patients. Recent evidence has suggested that two major physiological circadian rhythms, the metabolic and cardiovascular rhythms, are subject to regulation by overlapping molecular pathways, indicating that dysregulation of metabolic cycles could desynchronize the normal diurnal rhythm of BP with the daily light/dark cycle. However, little is known about the impact of changes in metabolic cycles on BP diurnal rhythm.

Methodology/Principal Findings

To test the hypothesis that feeding-fasting cycles could affect the diurnal pattern of BP, we used spontaneously hypertensive rats (SHR) which develop essential hypertension with disrupted diurnal BP rhythms and examined whether abnormal BP rhythms in SHR were caused by alteration in the daily feeding rhythm. We found that SHR exhibit attenuated feeding rhythm which accompanies disrupted rhythms in metabolic gene expression not only in metabolic tissues but also in cardiovascular tissues. More importantly, the correction of abnormal feeding rhythms in SHR restored the daily BP rhythm and was accompanied by changes in the timing of expression of key circadian and metabolic genes in cardiovascular tissues.

Conclusions/Significance

These results indicate that the metabolic cycle is an important determinant of the cardiovascular diurnal rhythm and that disrupted BP rhythms in hypertensive patients can be normalized by manipulating feeding cycles.     

Familial circadian rhythm disorder in the diurnal primate, Macaca mulatta

In view of the inverse temporal relationship of central clock activity to physiological or behavioral outputs in diurnal and nocturnal species, understanding the mechanisms and physiological consequences of circadian disorders in humans would benefit from studies in a diurnal animal model, phylogenetically close to humans. Here we report the discovery of the first intrinsic circadian disorder in a family of diurnal non-human primates, the rhesus monkey. The disorder is characterized by a combination of delayed sleep phase, relative to light-dark cycle, mutual desynchrony of intrinsic rhythms of activity, food intake and cognitive performance, enhanced nighttime feeding or, in the extreme case, intrinsic asynchrony. The phenotype is associated with normal length of intrinsic circadian period and requires an intact central clock, as demonstrated by an SCN lesion. Entrainment to different photoperiods or melatonin administration does not eliminate internal desynchrony, though melatonin can temporarily reinstate intrinsic activity rhythms in the animal with intrinsic asynchrony. Entrainment to restricted feeding is highly effective in animals with intrinsic or SCN lesion-induced asynchrony. The large isolated family of rhesus macaques harboring the disorder provides a powerful new tool for translational research of regulatory circuits underlying circadian disorders and their effective treatment.     

Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling

The circadian pacemaker in the suprachiasmatic nuclei (SCN) controls endogenous near 24-h physiological and behavioral rhythms in metabolism, neuroendocrine function, and locomotor activity. Recently, we showed that vasoactive intestinal polypeptide (VIP) and its receptor, VPAC(2) are critical to the intercellular communication between individual SCN neurons, and appropriate synchronization and phasing of these oscillatory cells. Mice defective in VIP signaling manifest grossly impaired circadian rhythms of SCN neuronal firing activity and are typically unable to maintain rhythmic wheel-running behavior in the absence of external time cues. Here we report that daily rhythms of metabolism and feeding behavior are also overtly altered in these animals. Under diurnal conditions (12:12-h light-dark; LD), metabolic and feeding rhythms are advanced in mice lacking either VIP or VPAC(2) receptor expression, peaking in the late day, rather than early night, as observed in wild-type mice. When placed in constant light (LL), both VIP-deficient and VPAC(2) receptor-knockout mice exhibit dampening of metabolic and feeding rhythms, which deteriorate after a few days. In addition, overall metabolic rate is greatly reduced in VPAC(2)-knockout mice, when compared with wild-type mice, regardless of lighting condition. The advancement of metabolic and feeding rhythms in these mice under LD suggests that these rhythms are less sensitive to masking by light. These results demonstrate that altering SCN function not only affects neuronal and wheel-running activity rhythms but also dramatically impairs temporal regulation of metabolism and feeding.     

The importance of hormonal circadian rhythms in daily feeding patterns: An illustration with simulated pigs

The interaction between hormonal circadian rhythms and feeding behaviour is not well understood. This study aimed to deepen our understanding of mechanisms underlying circadian feeding behaviour in animals, using pigs, Sus scrofa, as a case study. Pigs show an alternans feeding pattern, that is, a small peak of feed intake at the beginning of the day and a larger peak at the end of the day. We simulated the feeding behaviour of pigs over a 24 h period. The simulation model contained mechanisms that regulate feeding behaviour of animals, including: processing of feed in the gastrointestinal tract, fluctuation in energy balance, circadian rhythms of melatonin and cortisol and motivational decision-making. From the interactions between these various processes, feeding patterns (e.g. feed intake, meal frequency, feeding rate) emerge. These feeding patterns, as well as patterns for the underlying mechanisms (e.g. energy expenditure), fitted empirical data well, indicating that our model contains relevant mechanisms. The circadian rhythms of cortisol and melatonin explained the alternans pattern of feeding in pigs. Additionally, the timing and amplitude of cortisol peaks affected the diurnal and nocturnal peaks in feed intake. Furthermore, our results suggest that circadian rhythms of other hormones, such as leptin and ghrelin, are less important in circadian regulation of feeding behaviour than previously thought. These results are relevant to animal species with a metabolic and endocrine system similar to that of pigs, such as humans. Moreover, the modelling approach to understand feeding behaviour can be applied to other animal species.     

Clinical aspects of human circadian rhythms

Circadian rhythmicity can be important in the pathophysiology, diagnosis, and treatment of clinical disease. Due to the difficulties in conducting the necessary experimental work, it remains unknown whether approximately 24-h changes in pathophysiology or symptoms of many diseases are causally linked to endogenous circadian rhythms or to other diurnal factors that change across the day, such as changes in posture, activity, sleep or wake state, or metabolic changes associated with feeding or fasting. Until the physiology is accurately known, appropriate treatment cannot be designed. This review includes an overview of clinical disorders that are caused or affected by circadian or diurnal rhythms. The clinical side effects of disruption of circadian rhythmicity, such as in shiftwork, including the public health implications of the disrupted alertness and performance, are also discussed.     

Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction

Type 2 diabetes mellitus (T2DM) is complex metabolic disease that arises as a consequence of interactions between genetic predisposition and environmental triggers. One recently described environmental trigger associated with development of T2DM is disturbance of circadian rhythms due to shift work, sleep loss, or nocturnal lifestyle. However, the underlying mechanisms behind this association are largely unknown. To address this, the authors examined the metabolic and physiological consequences of experimentally controlled circadian rhythm disruption in wild-type (WT) Sprague Dawley and diabetes-prone human islet amyloid polypeptide transgenic (HIP) rats: a validated model of T2DM. WT and HIP rats at 3 months of age were exposed to 10 weeks of either a normal light regimen (LD: 12:12-h light/dark) or experimental disruption in the light-dark cycle produced by either (1) 6-h advance of the light cycle every 3 days or (2) constant light protocol. Subsequently, blood glucose control, beta-cell function, beta-cell mass, turnover, and insulin sensitivity were examined. In WT rats, 10 weeks of experimental disruption of circadian rhythms failed to significantly alter fasting blood glucose levels, glucose-stimulated insulin secretion, beta-cell mass/turnover, or insulin sensitivity. In contrast, experimental disruption of circadian rhythms in diabetes-prone HIP rats led to accelerated development of diabetes. The mechanism subserving early-onset diabetes was due to accelerated loss of beta-cell function and loss of beta-cell mass attributed to increases in beta-cell apoptosis. Disruption of circadian rhythms may increase the risk of T2DM by accelerating the loss of beta-cell function and mass characteristic in T2DM.     

Vasopressin deficiency provides evidence for separate circadian oscillators of activity and temperature

Vasopressin-containing Long-Evans and vasopressin-deficient Brattleboro rats were maintained in individual cages while telemetered activity (AC) and body temperature (BT) data were collected. Rats were initially exposed to a 12 h/12-h light/dark cycle (photic zeitgeber) and were allowed ad-libitum access to food and water. Daily feeding, care, and handling (nonphotic zeitgebers) occurred at the beginning of the second hour of the dark cycle. After a 14-day habituation period, rats were subjected to continuous light (LL) or dark (DD) and nonphotic cues were presented irregularly. During the habituation period, both strains exhibited clear 24-h circadian rhythms of AC and BT. In LL or DD, photic cues were removed and nonphotic cues were presented irregularly. There was a shift in the rhythm for Long-Evans animals to 26 h for both AC and BT in LL and 24.6 h in DD. Feeding, care, and handling were seen as minor artifact. In Brattleboro rats, although there were robust 26-h and 24.6-h circadian rhythms of AC in the LL and DD, respectively, BT data were inconsistent and showed sporadic fluctuations. In the BT rhythm of Brattleboro animals, strong peaks were associated with feeding, care, and handling times and trough periods were characterized by a dramatic drop in temperature. This experiment demonstrates that AC and BT are controlled by separate oscillators. In addition, the importance of vasopressinergic fibers in the control of circadian rhythms of BT is evidenced by the loss of circadian rhythms in animals lacking these functional fibers when exposed to free-running paradigms where there is no entrainment of photic or nonphotic oscillators.     

Diurnal Regulation of Lipid Metabolism and Applications of Circadian Lipidomics

The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles （e.g., in shift work） results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.     

High‐fat Diet Followed by Fasting Disrupts Circadian Expression of Adiponectin Signaling Pathway in Muscle and Adipose Tissue

The circadian clock controls energy homeostasis by regulating circadian expression of proteins involved in metabolism. Disruption of circadian rhythms leads to obesity and metabolic disorders. Little is known regarding the control of the biological clock over adiponectin signaling pathway in adipose tissue, the adiponectin producer, and muscle, an adiponectin target tissue under fasting, low‐fat (LF), or high‐fat (HF) diet. Mice were fed LF or HF diet for 7 weeks and fasted on the last day. The circadian mRNA expression of clock genes and components of adiponectin metabolic pathway (mAdipoR1, mAdipoR2, mPparα, mPparγ, mAmpk, and mAcc) in the muscle and adipose tissue were tested. Using average daily levels of multiple time points around the circadian cycle, we assessed mRNA levels of the different adiponectin signaling components. In addition, serum glucose, adiponectin, and insulin were measured. Under LF diet, adiponectin signaling pathway components exhibited circadian rhythmicity at the mRNA levels. Fasting and HF diet followed by fasting disrupted this circadian expression causing a phase advance or delay, respectively. Changes were also found in the expression levels of adiponectin receptor, mAmpk, mAcc, mPparα, and mPparγ reflecting a defect in adiponectin signaling. As both peroxisome proliferator‐activated receptor α (PPARα) and mAMPK are linked to the core clock mechanism, they could mediate the disruptions seen in clock gene expression under HF diet. In turn, the circadian clock affects the daily rhythm of these adiponectin signaling components.     

A Preliminary Investigation into Individual Differences in the Orcadian Variation of Meal Tolerance: Effects on Mood and Hunger

A forced desynchrony methodology was used to assess postprandial blood glucose in 9 female volunteers during a 3-h period following a mixed meal presented at four times of day (08:00, 14:00, 20:00, 02:00). The influence of time of day on the postmeal glucose responses was evaluated by calculating the area under the curve, largest increase, time taken to reach peak, and fasting level. Circadian variations in meal tolerance were found for the area under the curve and largest increase, responses were greater (indicating poorer meal tolerance) in the evening than the morning. Fasting blood glucose exhibited diurnal variation although in the opposite direction to meal tolerance; levels were higher in the morning than the evening. Time taken to reach peak levels was not modulated by circadian rhythmicity. Estimates of the timing of poorest meal tolerance and the magnitude of this intolerance were computed for each subject. Individual differences in the magnitude of meal intolerance were found to influence hunger and self-reported calmness. Subjects with good tolerance had rhythms in both calmness and hunger, which were not found in those with poor tolerance. Subjects with good tolerance also tended to rate themselves as feeling more calm. These mood and hunger effects may result from differences in insulin resistance, which is hypothesized to underlie the circadian variations in meal tolerance. (Chronobiology International, 13(6), 435-447, 1996)     

Restricted daytime feeding attenuates reentrainment of the circadian melatonin rhythm after an 8-h phase advance of the light-dark cycle

It is well established that in the absence of photic cues, the circadian rhythms of rodents can be readily phase-shifted and entrained by various nonphotic stimuli that induce increased levels of locomotor activity (i.e., benzodiazepines, a new running wheel, and limited food access). In the presence of an entraining light-dark (LD) cycle, however, the entraining effects of nonphotic stimuli on (parts of) the circadian oscillator are far less clear. Yet, an interesting finding is that appropriately timed exercise after a phase shift can accelerate the entrainment of circadian rhythms to the new LD cycle in both rodents and humans. The present study investigated whether restricted daytime feeding (RF) (1) induces a phase shift of the melatonin rhythm under entrained LD conditions and (2) accelerates resynchronization of circadian rhythms after an 8-h phase advance. Animals were adapted to RF with 2-h food access at the projected time of the new dark onset. Before and at several time points after the 8-h phase advance, nocturnal melatonin profiles were measured in RF animals and animals on ad libitum feeding (AL). In LD-entrained conditions, RF did not cause any significant changes in the nocturnal melatonin profile as compared to AL. Unexpectedly, after the 8-h phase advance, RF animals resynchronized more slowly to the new LD cycle than AL animals. These results indicate that prior entrainment to a nonphotic stimulus such as RF may "phase lock" the circadian oscillator and in that way hinder resynchronization after a phase shift.     

Exogenous melatonin reduces the resynchronization time after phase shifts of a nonphotic zeitgeber in the house sparrow (Passer domesticus)

Continuous melatonin administration via silastic implants accelerates the resynchronization of the circadian locomotor activity rhythm in house sparrows (Passer domesticus) after exposure to phase shifts of a weak light-dark cycle. Constant melatonin might induce this effect either by increasing the sensitivity of the visual system to a light zeitgeber or by reducing the degree of self-sustainment of the circadian pacemaker. To distinguish between these two possible mechanisms, two groups of house sparrows, one carrying melatonin implants and the other empty implants, were kept in constant dim light and subjected to advance and delay shifts of a 12-h feeding phase. The resynchronization times of their circadian feeding rhythm following the phase shifts were significantly shorter when the birds carried melatonin implants than when they carried empty implants. In a second experiment, melatonin-implanted and control birds were released into food ad libitum conditions 2 days after either a delay or an advance phase shift. The number of hours by which the activity rhythms had been shifted on the second day in food ad libitum conditions was assessed. Melatonin-implanted house sparrows had significantly larger phase shifts in their circadian feeding rhythm than control birds. This is in accordance with the first experiment since a larger phase shift at a given time reflects accelerated resynchronization. Additionally, the second experiment also excludes any possible masking effects of the nonphotic zeitgeber. In conclusion, constant melatonin accelerates resynchronization even after phase shifts of a nonphotic zeitgeber, indicating that constant high levels of melatonin can reduce the degree of self-sustainment of the circadian pacemaker independent of any effects on the photoreceptive system.     

The circadian clock, light, and cryptochrome regulate feeding and metabolism in Drosophila

Recent studies in mammals have demonstrated a central role for the circadian clock in maintaining metabolic homeostasis. In spite of these advances, however, little is known about how these complex pathways are coordinated. Here, we show that fundamental aspects of the circadian control of metabolism are conserved in the fruit fly Drosophila. We assay feeding behavior and basic metabolite levels in individual flies and show that, like mammals, Drosophila display a rapid increase in circulating sugar following a meal, which is subsequently stored in the form of glycogen. These daily rhythms in carbohydrate levels are disrupted in clock mutants, demonstrating a critical role for the circadian clock in the postprandial response to feeding. We also show that basic metabolite levels are coordinated in a clock-dependent manner and that clock function is required to maintain lipid homeostasis. By examining feeding behavior, we show that flies feed primarily during the first 4 hours of the day and that light suppresses a late day feeding bout through the cryptochrome photoreceptor. These studies demonstrate that central aspects of feeding and metabolism are dependent on the circadian clock in Drosophila. Our work also uncovers novel roles for light and cryptochrome on both feeding behavior and metabolism.