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Plasma norepinephrine (NE) and epinephrine (E) levels are indicators of peripheral sympathetic and adrenomedullary activities, respectively. The sympathoadrenomedullary system is involved in the metabolic response to carbohydrate intake and is affected by aging; however, the relationship between glucose metabolism and adrenomedullary activity in older adults remains poorly defined.The objective of this study was to examine the changes in the impact of carbohydrate-rich meals on circulating catecholamines with aging.After iv glucose tolerance testing and 1 d of habituation, blood samples were collected every 10-30 min for 24 h. Daytime hours were spent at bed rest. Sleep was scheduled between 2300 and 0700 h with polygraphic monitoring.The study was performed at a general clinical research center.Nine young (age, 20-28 yr) and eight older (age, 50-69 yr) healthy men participated in this study.Identical mixed meals (62% carbohydrate) were given at 0900, 1400, and 1900 h.The main outcome measures were 24-h plasma E and NE measurements.The profiles of E and NE were characterized by clear day-night differences, which were preserved in the older group. Young subjects showed a clear dissociation between postprandial adrenomedullary and sympathetic activities characterized by a rapid decline in plasma E and increased NE levels. There was an overall increase in NE levels and markedly dampened postprandial variation in plasma E in the older men.In young adults, postprandial E levels follow a biphasic pattern that is inversely related to that of glucose and insulin. Aging is associated with a dysregulation of this response.

Sleep plays an important role in energy homeostasis. The present study tests the hypothesis that circulating levels of leptin, a hormone that signals energy balance to the brain, are influenced by sleep duration. We also analyzed associations between leptin and sympathovagal balance, cortisol, TSH, glucose, and insulin under different bedtime conditions. Twenty-four-hour hormonal and glucose profiles were sampled at frequent intervals, and sympathovagal balance was estimated from heart rate variability in 11 subjects studied after 6 d of 4-h bedtimes (mean +/- sem of sleep duration during last 2 d: 3 h and 49 +/- 2 min) and after 6 d of 12-h bedtimes (sleep: 9 h and 03 +/- 15 min). A study with 8-h bedtimes was performed 1 yr later (sleep: 6 h and 52 +/- 10 min). Caloric intake and activity levels were carefully controlled in all studies. Mean levels, maximal levels, and rhythm amplitude of leptin were decreased (-19%, -26%, and -20%, respectively) during sleep restriction compared with sleep extension. The decrease in leptin levels was concomitant with an elevation of sympathovagal balance. The effects of sleep duration on leptin were quantitatively associated with alterations of the cortisol and TSH profiles and were accompanied by an elevation of postbreakfast homeostasis model assessment values. Measures of perceived stress were not increased during sleep restriction. During the study with 8-h bedtimes, hormonal and metabolic parameters were intermediate between those observed with 4-h and 12-h bedtimes. In conclusion, sleep modulates a major component of the neuroendocrine control of appetite., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Objective: To compare noninvasive measures of cardiac autonomic activity during sleep. Methods: The absolute and normalized (n.u.) high and low frequency peaks from the spectral analysis of R-R intervals (HF, LF, HFn.u., LFn.u.), LF/HF ratio, pre-ejection period (PEP) from impedance cardiography, and the autocorrelation coefficient (rRR) as illustrated in Poincareplots were measured during night-time sleep in 9 young healthy subjects. Heart rate and blood pressure were also recorded. Results: Heart rate was significantly associated with cardiac sympathetic activity (PEP, average r ¼ 20:46), but not with cardiac parasympathetic activity (HF, average r ¼ 20:17). rRR was significantly associated with heart rate (average r ¼ 0:41), and LF/HF (average r ¼ 0:69), but not with PEP or HF. From NREM to REM sleep, heart rate, LFn.u., LF and rRR significantly increased, HFn.u. significantly decreased, LF/HF showed an increasing trend (P ¼ 0:07) and PEP showed a decreasing trend (P ¼ 0:06). Blood pressure and HF were highly variable without significant changes from NREM to REM sleep. Conclusions: Cardiac parasympathetic activity (HF) does not vary greatly between sleep stages. Cardiac sympathetic activity (PEP) decreases linearly during sleep. rRR and LF/HF can track sympathovagal changes during sleep, but cannot differentiate between changes in cardiac parasympathetic and sympathetic activity. The relative advantages and disadvantages of the different measures are discussed. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The fact that the secretion of growth hormone (GH) is markedly stimulated during sleep has been recognized for more than three decades. Early studies using the first available radioimmunoassays for GH demonstrated that the peripheral levels of this hormone increased rapidly following sleep onset (1–5). In normal adult subjects, the 24-h profile of plasma GH levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible pulse occurs shortly after sleep onset (3,4). This relationship between sleep onset and GH secretion appears to be most consistent in the human species, because it is more difficult to evidence in other mammals, although elevated blood GH levels have been observed during sleep in baboons, rhesus monkeys, dogs, lambs, and both immature and adult rats (6–12). Species differences could be related to the fact that human sleep is consolidated in a single 7 to 9-h period, whereas multiple sleep bouts are the rule in other mammals. Thus, the sleep-wake transition in the human is generally associated with more pronounced variations in endocrine, metabolic, and other parameters than in other species.

Human behavioral and physiological processes are under the dual control of circadian rhythmicity and sleep-wake homeostasis. In mammalian species, the underlying mechanism for the generation of most circadian rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Sleep-wake homeostasis is an hourglass-like mechanism relating sleep propensity and intensity to the duration of prior wakefulness. Studies under “constant routine conditions” have facilitated the detection of circadian and sleep regulation and have delineated the temporal variations over the 24-hr day of subjective alertness (or its antonym, subjective sleepiness), cognitive performance (i.e. objective alertness), and mood, as well as endocrine, metabolic, and cardiovascular function. Subjective and objective alertness vary in parallel, with detectable decreases starting around the usual bedtime until a minimum is reached in the early morning hours, and then increase during the daytime hours. Decreased sleep quality and sleep loss due to voluntary behavioral alterations or to pathological conditions are associated with disturbances of a variety of neurobehavioral, physiological parameters, as well as of subjective alertness, mood, and cognitive performance. Aging is commonly associated with pronounced alterations of both the homeostatic process and the circadian pacemaker. Strategies to improve sleep quality may have beneficial effects on mental and physical well-being. Keywords: aging; circadian rhythms; endocrine rhythms; REM sleep; sleep deprivation; slow-wave sleep; vigilance

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20–30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (±SD) 42 ± 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed ( P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 ± 15 min (SE) compared with the phase delays observed in the no-exercise group (−25 ± 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.

This study examines the individual reproducibility of alterations of subjective, objective, and EEG measures of alertness during 27 h of continuous wakefulness and analyzes their interrelationships. Eight subjects were studied twice under similar constant-routine conditions. Scales and performance tasks were administered at hourly intervals to define temporal changes in subjective and objective alertness. The wake EEG was recorded every 2 h, 2 min with eyes open and 2 min with eyes closed. Plasma glucose and melatonin levels were measured to estimate brain glucose utilization and individual circadian phase, respectively. Decrements of subjective alertness and performance deficits were found to be highly reproducible for a given individual. Remarkably, there was no relationship between the impairments of subjective and objective alertness. With increased duration of wakefulness, EEG activity with eyes closed increased in the delta range and decreased in the alpha range, but the magnitudes of these changes were also unrelated. These findings indicate that sleep deprivation has highly reproducible, but independent, effects on brain mechanisms controlling subjective and objective alertness.

To investigate the adaptation of plasma cortisol profiles to an abrupt phase advance of the rest-activity cycle, eight normal young subjects were submitted in a sleep laboratory to an 8-h advance shift of their sleep-wake and dark-light cycles. The shift was achieved by advancing bedtimes from 2300–0700 to 1500–2300. Blood samples were obtained at 20-min intervals for 68 consecutive hours. The shift resulted within 6–9 h in a 3- to 4-h advance of timings of the nadir of the cortisol profile and of the end of the quiescent period but had no immediate effect on the timing of cortisol acrophase. The quiescent period of cortisol secretion was shortened and fragmented. Thus a major advance shift achieved without enforcing sleep deprivation results in a rapid partial adaptation of the temporal profiles of cortisol but also in a marked disruption of the cortisol quiescent period. Sleep onset was consistently followed by a decrease in cortisol concentrations. Conversely, both sleep-wake and dark-light transitions were consistently associated with cortisol secretory pulses.

Vineet M. Arora, MD, MAPP1,5, Kevin L. Chang, BS2, Arshiya Fazal3, Paul G. Staisiunas, BA1, Phyllis C. Zee, MD, PhD4, Kristen L. Knutson, PhD1,5, David O. Meltzer, MD, PhD2, and Eve Van Cauter, PhD1,5 1Department of Medicine, University of Chicago 2Pritzker School of Medicine, University of Chicago 3The College, University of Chicago 4Department of Neurology, Northwestern University 5Sleep, Metabolism and Health Center, University of Chicago

In the human, sleep and hormonal secretions are under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness. The circadian clock plays a major role in the timings of sleep onset and offset, sleep consolidation, and the distributions of rapid eye movement (REM) sleep. The temporal organization of the secretions of a number of hormones such as melatonin and the hormones of the hypothalamo–pituitary–adrenal axis are also primarily controlled by the circadian pacemaker. On the other hand, the temporal profile of non-REM sleep, in particular slow-wave sleep, and a number of hormones such as prolactin and growth hormone are primarily controlled by the homeostatic process. Normal aging is commonly associated with profound alterations of both the homeostatic process and the circadian pacemaker, which are, however, chronologically dissociated. Alterations of the homeostatic process, as assessed by exponential decreases in slow-wave sleep and in nocturnal growth hormone secretion, are essentially complete by midlife. In contrast, alterations of the circadian pacemaker, as assessed in particular by modifications of REM sleep and of the glucocorticoid secretory profiles, occur essentially from 50 years onward. Strategies for preventing or limiting such alterations should take into account this dissociated chronology of aging. Pharmacological approaches to restore normal sleep could represent an indirect form of hormonal therapy with possible beneficial health effects. © 2001 Academic Press.

A high degree of temporal organization exists in the endocrine system and is reflected by distinct 24-hour temporal patterns of secretory activity for each endocrine axis. One hormone may be actively secreted in a complex, pulsatile pattern while another may be in a quiescent period. Much of the temporal variability and organization of endocrine activity results from modulatory effects of circadian rhythmicity, a near-24-hour endogenous oscillation originating in the suprachiasmatic nucleus of the hypothalamus and from the effects of sleep/wake homeostasis controlled by diverse and diffuse neural centers, as depicted in Figure 1.. These rhythmic patterns of hormonal secretion are thought to provide internal temporal organization through the coordination of physiologic processes in the time domain, and to also provide an adaptive synchronization of the organism relative to predictable variations of the external environment.

ContextIn young adults, sleep affects the regulation of growth hormone (GH) and cortisol. The relationship between decreased sleep quality in older adults and age-related changes in the regulation of GH and cortisol is unknown.ObjectiveTo determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.Design and SettingData combined from a series of studies conducted between 1985 and 1999 at 4 laboratories.SubjectsA total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.Main Outcome MeasuresTwenty-four–hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings.ResultsThe mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep. The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (−24 minutes per decade; P

Chronic sleep debt is becoming increasingly common and affects millions of people in more-developed countries. Sleep debt is currently believed to have no adverse effect on health. We investigated the effect of sleep debt on metabolic and endocrine functions.We assessed carbohydrate metabolism, thyrotropic function, activity of the hypothalamo-pituitary-adrenal axis, and sympathovagal balance in 11 young men after time in bed had been restricted to 4 h per night for 6 nights. We compared the sleep-debt condition with measurements taken at the end of a sleep-recovery period when participants were allowed 12 h in bed per night for 6 nights.Glucose tolerance was lower in the sleep-debt condition than in the fully rested condition (p0.02), as were thyrotropin concentrations (p0.01). Evening cortisol concentrations were raised (p=0.0001) and activity of the sympathetic nervous system was increased in the sleep-debt condition (p0.02).Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.

To investigate the adaptation of melatonin secretion to an abrupt time shift and the effects of sleep facilitation with a hypnotic, eight subjects were submitted to an 8-h advance shift achieved by advancing bedtimes from 2300–0700 to 1500–2300. Each subject participated in two studies (i.e., placebo and zolpidem). Each study included a baseline period with dim light during waking hours and 2300–0700 bedtimes in total darkness. Blood samples for determination of plasma melatonin were obtained at 20-min intervals for 68 h. Advanced exposure to sleep and darkness resulted in a nearly 2-h advance of melatonin onset, which appeared within 6 h after lights-out during the first shifted night, and an almost 1-h advance of the melatonin offset. No further adaptation occurred during the second shifted sleep period. Zolpidem had no beneficial effects on the adaptation of the melatonin profile. There was no relationship between sleep parameters and the magnitude of the melatonin shifts. Thus the overall advance of melatonin profiles was primarily achieved during the initial exposure to an 8-h period of darkness. The present data suggest that exposure to dark affects human circadian phase.

A complex interrelationship exists between sleep and somatotropic activity. In humans, intravenous injections of growth hormone-releasing hormone (GHRH) given during sleep consistently stimulate slow-wave (SW) sleep, particularly when given in the latter part of the night. In the present study, the possible somnogenic effects induced under similar conditions by GH-releasing peptide (GHRP) were investigated in seven young healthy men. Bolus intravenous injections of GHRP-2 (1 μg/kg body wt) or saline, in randomized order, were given after 60 s of the third rapid-eye-movement period. All GHRP injections were immediately followed by transient prolactin elevations and by GH pulses of a magnitude within or around the upper limit of the physiological range. Except for a nonsignificant tendency to increased amounts of wakefulness during the 1st h after the injection, no effects of GHRP-2 administration on sleep were detected. There was in particular no enhancement of SW sleep. Thus, in contrast to GHRH, late-night single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep. The present data provide evidence against the involvement of the GHRP axis in human SW sleep regulation.

Sleep curtailment constitutes an increasingly common condition in industrialized societies and is thought to affect mood and performance rather than physiological functions. There is no evidence for prolonged or delayed effects of sleep loss on the hypothalamo-pituitary-adrenal (HPA) axis. We evaluated the effects of acute partial or total sleep deprivation on the nighttime and daytime profile of cortisol levels. Plasma cortisol profiles were determined during a 32-hour period (from 1800 hours on day 1 until 0200 hours on day 3) in normal young men submitted to three different protocols: normal sleep schedule (2300-0700 hours), partial sleep deprivation (0400-0800 hours), and total sleep deprivation. Alterations in cortisol levels could only be demonstrated in the evening following the night of sleep deprivation. After normal sleep, plasma cortisol levels over the 1800-2300-hour period were similar on days 1 and 2. After partial and total sleep deprivation, plasma cortisol levels over the 1800-2300-hour period were higher on day 2 than on day 1 (37 and 45% increases, p = 0.03 and 0.003, respectively), and the onset of the quiescent period of cortisol secretion was delayed by at least 1 hour. We conclude that even partial acute sleep loss delays the recovery of the HPA from early morning circadian stimulation and is thus likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess.

To define the physiological relationships between cardiovascular function, glucose regulation, and insulin secretion, we submitted nine young normotensive subjects to ambulatory blood pressure monitoring and blood sampling at 20-minute intervals for 24 hours to measure glucose, insulin, C peptide, cortisol, and growth hormone. Subjects ingested three identical carbohydrate-rich meals in the morning (8:30 am ), early afternoon (2 pm ), and evening (8 pm ). On the following day, they underwent an intravenous glucose tolerance test for quantification of insulin sensitivity. Significant postmeal increases in systolic pressure averaging 18±10 mm Hg in the morning, 18±8 mm Hg in the early afternoon, and 26±19 mm Hg in the evening were observed. Postprandial variations in diastolic pressure and heart rate were significant only for the morning meal. The magnitude of the postprandial increases in systolic pressure was correlated with the amount of insulin secreted in the morning but not later in the day. Pulses of growth hormone consistently occurred 3 to 4 hours after the morning and midday meals, as well as after the onset of sleep. Our findings indicate that under normal conditions, there is a quantitative relationship between postprandial insulin secretion and blood pressure.

The temporal relation between the first few hours of sleep and the secretion of growth hormone (GH), which is present in normal persons of both sexes from early childhood until late adulthood, is reviewed. In adults the most reproducible pulse of GH secretion occurs shortly after the onset of sleep in association with the first phase of slow-wave sleep (SWS) (stages III and IV). In men approximately 70% of the GH pulses during sleep coincide with SWS, and the amount of GH secreted during these pulses correlates with the concurrent amount of SWS. Sleep-related secretion of GH appears to be primarily dependent on the release of growth hormone-releasing-hormone. Rodent and human studies have shown that growth hormone-releasing hormone injections decrease wakefulness and increase SWS. During the fourth decade of life (ages 30 to 40 years) the total amount of GH secreted over a 24-hour span decreases by two- to threefold. Similarly, the amount of SWS decreases dramatically over the same narrow age range. Because the sleep-onset GH pulse is often the major secretory output in adults, age-related decrements in sleep-related GH secretion likely play a major role in the hyposomatotropism of senescence.

We present a detailed numerical investigation of the phase-locking regions in a forced model of slow oscillations in human insulin secretion and blood glucose concentration. The bifurcation structures of period 2pi and 4pi tongues are mapped out and found to be qualitatively identical to those of several other periodically forced self-oscillating systems operating across a Hopf-bifurcation point. The numerical analyses are supplemented by clinical experiments. (c) 1995 American Institute of Physics.

Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown.To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance.Randomized, 2-period, 2-condition, crossover clinical study.University of Chicago Clinical Resource Center.Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m(2) (SD, 1.6).Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity.Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt-tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test.The insulin concentration for the half-maximal pAkt-tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt-tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.This was a single-center study with a small sample size.Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues.National Institutes of Health.

Objective: To characterize sleep and the 24-hour profiles of cortisol, prolactin (PRL), and growth hormone (GH) secretion in mania. Methods: Blood was sampled at 15-minute intervals, and sleep was polygraphically recorded in eight unmedicated male patients with pure mania and the results compared with those from a group of 14 healthy age-matched controls. The circadian, sleep-related, and pulsatile hormonal variations were quantitatively characterized using specially designed computer algorithms. Results: The manic state was associated with alterations of corticotropic activity and circadian rhythmicity partially overlapping those previously observed in acute endogenous depression, consisting of an elevation of nocturnal cortisol levels and an early timing of the nadir of the circadian variation. Sleep onset was delayed and the sleep period was reduced. A trend for short rapid eye movement latencies was apparent in the adult patients. Both the amount and the temporal organization of PRL and GH secretion were normal. Conclusion: The manic state seems to be characterized by similar but less severe neuroendocrine and circadian abnormalities, compared with major depression.

Publisher Summary This chapter discusses the modulatory influences of experimental conditions, hormonal clearance kinetics, and diurnal changes using simple computer simulations. Modulatory effects on pulsatility may occur at various levels. The characteristic of a stable limit cycle is its attracting behavior, that is, that the system will respond to an external perturbation by settling back into oscillatory behavior with the same period and amplitude as before the perturbation. Circadian modulation could be achieved by the modulation of pulse frequency with more pulses occurring around the time of the daily maximum and fewer pulses occurring around the time of the daily minimum. The slow oscillations in insulin secretion appear to be regulated closely by the glucose concentration in normal man. Thus, during a constant intravenous administration of glucose, concomitant oscillations occur in glucose and insulin secretion with an approximate 2-hr periodicity.

To the Editor: Chronic sleep curtailment is endemic in modern societies. The majority of the daily testosterone release in men occurs during sleep.1 Sleep fragmentation and obstructive sleep apnea are associated with reduced testosterone levels.2 In older men, morning testosterone levels are partly predicted by total sleep time.3 Testosterone is critical in male sexual behavior and reproduction, but also has important beneficial effects on muscle mass and strength, adiposity, bone density, and vigor and well-being.4 We investigated the effect of 1 week of sleep restriction on testosterone levels in young healthy men.

Insulin secretion rates can be accurately estimated from plasma C-peptide levels with a two-compartment model for C-peptide distribution and degradation. In previous studies, the kinetic parameters of C-peptide clearance were derived in each subject from the decay curve observed after bolus intravenous injection of biosynthetic human C-peptide. To determine whether standard parameters for C-peptide clearance could be defined and used to calculate insulin secretion without obtaining a decay curve in each subject, we analyzed 200 decay curves of biosynthetic human C-peptide obtained in normal, obese, and non-insulindependent diabetes mellitus subjects studied in ourlaboratory. This analysis showed that the volume of distribution and kinetic parameters of C-peptide distribution and metabolism vary by

In animals, the major environmental signal responsible for the entrainment of circadian rhythmicity to external time is the light-dark cycle. While for many years, it was thought that light did not play an important role in synchronizing human rhythms, and that social cues were the primary entraining agent, extensive evidence obtained during the past decade using light of greater intensity than in earlier studies has indicated that the light-dark cycle is also a major zeitgeber for human circadian rhythmicity. The evolution of concepts regarding zeitgebers for non-human mammalian rhythms ran in many ways opposite to that occurring in the field of human rhythms. Indeed, social and/or behavioral cues were long thought to be ineffective as zeitgebers in rodents and other mammals, but evidence has accumulated over the past few years to indicate that behavioral changes are indeed capable of inducing shifts in circadian rhythms. Specifically, stimuli which cause an alteration of the rest activity cycle, either by eliciting activity (i.e. locomotor activity in rodent studies) during the normal rest period or by preventing activity during the normal active period, result in phase shifts of circadian rhythms. These findings implied that physical activity during the usual rest period (i.e. nighttime) as well as sleep occurring during the normal active period (i.e. daytime) could alter the phase of human rhythms.

Slow oscillations of human insulin secretion have been observed during the last couple of decades. They may be explained either by an unstable insulin/glucose feedback mechanism or in terms of an intrapancreatic pacemaker. In the present paper, a simulation model of the insulin/glucose feedback system is presented which exhibits self-sustained oscillations for realistic parameter combinations when a constant glucose infusion is simulated. Entrainment of the oscillations occurs when an oscillatory rather than a constant glucose infusion is simulated, which suggests that the presence of the oscillations can be explained by the insulin/glucose feedback mechanism. The design and results of clinical experiments performed in non-diabetic humans are described which verity the simulation results, in that entrainment is also experimentally achieved. Finally, additional simulation results are presented which show that the system can have coexisting solutions, and potential clinical implications hereof are discussed.

Since the introduction of glyburide in 1984, many studies have evaluated the effects of this oral hypoglycemic agent on beta cell function in patients with non-insulin-dependent diabetes mellitus. The early studies, which were performed in patients receiving concomitant insulin therapy, may have underestimated the true effect of glyburide on insulin secretion. The more recent studies demonstrate that both short- and long-term glyburide therapy increaes C-peotide levels in diabetic as well as nondiabetic subjects and that the effects of glyburide are comparable to those of the other second-generation sulfonylurea, glipizide. The effects of glyburide on insulin secretory rates calculated from plasma C-peptide levels were recently evaluated using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Glyburide did not influence fasting insulin secretion (196 ± 34 versus 216 ± 23 pmol/min) but did cause an increase in the total amount of insulin secreted over a 24-hour period (447 ± 58 versus 561 ± 55 nmol). This increase in the production of insulin was generated by an increase in amplitude of secretory pulses occurring after lunch and dinner rather than by a greater number of pulses. The full effect of glyburide on the beta cell became evident when glucose concentrations were clamped at the hyperglycemic level of 300 mg/dL both befor and during treatment for a 3-hour period. During that time, insulin secretion rates increased by 221 percent in response to glyburide. Glyburide did not, however, completely reverse the beta cell secretory defect characteristic of non-insulin-dependent diabetes mellitus. In the patients receiving glyburide, the sluggish insulin secretory response to breakfast persisted, and the insulin secretory response during the hyperglycemic clamping was less than the response normally seen in nondiabetic subjects. These experiments suggest that the primary effect of glyburide on the beta cell is to increase its responsiveness to glucose. Although the precise mechanism of action of glyburide at the cellular level is unclear, in vitro studies suggest that its effect is mediated through binding with specific receptors on the beta cell membrane, which in turn leads to alterations in the cellular efflux of potassium ions and influx of calcium ions

Background Evidence from laboratory and epidemiologic studies suggests that decreased sleep duration or quality may increase diabetes risk. We examined whether short or poor sleep is associated with glycemic control in African Americans with type 2 diabetes mellitus. Methods We conducted a cross-sectional study of volunteers with type 2 diabetes interviewed at the University of Chicago Hospitals, Chicago, Ill. The final analysis included 161 participants. Glycemic control was assessed by hemoglobin A 1c (HbA 1c ) level obtained from medical charts. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Perceived sleep debt was calculated as the difference between preferred and actual weekday sleep duration. Results The mean ± SD sleep duration was 6.0 ± 1.6 hours, and 71% of the participants were classified as having poor quality sleep (PSQI score >5). We excluded patients with sleep frequently disrupted by pain (n = 39). In patients without diabetic complications, glycemic control was associated with perceived sleep debt but not PSQI score. The predicted increase in HbA 1c level for a perceived sleep debt of 3 hours per night was 1.1% above the median. In patients with at least 1 complication, HbA 1c level was associated with PSQI score but not perceived sleep debt. The predicted increase in HbA 1c level for a 5-point increase in PSQI was 1.9% above the median. Conclusions In our sample, sleep duration and quality were significant predictors of HbA 1c , a key marker of glycemic control. Combined with existing evidence linking sleep loss to increased diabetes risk, these data suggest that optimizing sleep duration and quality should be tested as an intervention to improve glucose control in patients with type 2 diabetes.

Total sleep deprivation in rodents and in humans has been associated with hyperphagia. Over the past 40 years, self-reported sleep duration in the United States has decreased by almost 2 hours.To determine whether partial sleep curtailment, an increasingly prevalent behavior, alters appetite regulation.Randomized, 2-period, 2-condition crossover clinical study.Clinical Research Center, University of Chicago, Chicago, Illinois.12 healthy men (mean age [+/-SD], 22 +/- 2 years; mean body mass index [+/-SD], 23.6 +/- 2.0 kg/m2).Daytime profiles of plasma leptin and ghrelin levels and subjective ratings of hunger and appetite.2 days of sleep restriction and 2 days of sleep extension under controlled conditions of caloric intake and physical activity.Sleep restriction was associated with average reductions in the anorexigenic hormone leptin (decrease, 18%; P = 0.04), elevations in the orexigenic factor ghrelin (increase, 28%; P0.04), and increased hunger (increase, 24%; P0.01) and appetite (increase, 23%; P = 0.01), especially for calorie-dense foods with high carbohydrate content (increase, 33% to 45%; P = 0.02).The study included only 12 young men and did not measure energy expenditure.Short sleep duration in young, healthy men is associated with decreased leptin levels, increased ghrelin levels, and increased hunger and appetite.

Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.

Studies comparing glucose tolerance in the morning vs. that in the evening have suggested that time of day may influence glucose regulation. To examine the variation in glucose tolerance throughout the 24-h span, normal subjects were given an iv glucose infusion at a constant rate of either 5 or 8 g/kg.24 h during 30 h, and plasma levels of insulin and glucose were measured at 15-min intervals for the last 24 h of the infusion. The timing of initiation of the infusion was varied to differentiate effects of time of day from effects of duration of the infusion. A nocturnal elevation of glucose levels, culminating around midsleep and corresponding to an increase of about 15% above daytime levels, was observed in all subjects. The timing of this nocturnal maximum was not dependent on the rate of the infusion or on the time elapsed since the beginning of the infusion. Insulin levels did not show a consistent diurnal pattern. Both insulin and glucose exhibited large ultradian oscillations recurring at 100- to 150-min intervals. The amplitude of these oscillations increased with the rate of glucose infusion. These ultradian oscillations of glucose and insulin levels were temporally correlated, with a tendency for glucose pulses to lead insulin pulses by 15-30 min. These results demonstrate in normal subjects the existence of a diurnal variation in glucose tolerance distinct from the dawn phenomenon observed in diabetic subjects and indicate that spontaneous 100- to 150-min oscillations in peripheral glucose and insulin levels characterize stimulated pancreatic function, with the amplitude of the oscillations being dependent on the size of the stimulus.

Plasma ACTH, cortisol, and GH concentrations were measured at 15-min intervals for 24 h in 11 men suffering from major depressive illness during an acute episode of depression and during clinical remission following antidepressant treatment with either electroconvulsive therapy or amitriptyline. Seven age-matched normal men also were studied. During the acute phase of the illness, the patients had abnormally short rapid eye movement sleep latencies, hypercortisolism, early timing of the nadirs of the ACTH-cortisol rhythms, and shorter nocturnal periods of quiescent cortisol secretion. GH was hypersecreted during wakefulness, and a major pulse occurred before, rather than after, sleep onset. After treatment, rapid eye movement sleep latencies were lengthened, and cortisol levels returned to normal due to a decrease in the magnitude of episodic pulses. Moreover, the timing of the circadian rhythms of ACTH and cortisol as well as the duration of the quiescent period of cortisol secretion were normalized. The amount of GH secreted during wakefulness decreased to normal values, with fewer significant GH pulses. The major elevation of GH secretion in the early part of the night occurred later than that during the depressive episode. These results demonstrate that a disorder of circadian rhythmicity characterizes acute episodes of major depressive illness and that this chronobiological abnormality as well as the hypersecretion of ACTH, cortisol, and GH are state rather than trait dependent.