Investigations on the role of sleep and circadian rhythmicity in endocrine regulation, glucose metabolism, cardiovascular function, mood and cognitive performance.
Sleep exerts modulatory effects on hormones and metabolism. Hormonal levels during total sleep deprivation are markedly different than those on a normal night of sleep. Recovery sleep following acute total sleep deprivation is generally associated with a full recovery of the hormonal consequences of sleep loss. It has thus been assumed that sleep curtailment is harmless for metabolic and endocrine function. In our laboratory studies however, the subjects submitted to repeated sleep restriction have demonstrated that chronic partial sleep loss, an endemic condition in modern society, is associated with deleterious hormonal alterations that are distinct from those seen during one night of total sleep deprivation. Chronic partial sleep loss results in a profound suppression of TSH levels, in increased evening levels of the stress hormone cortisol and in an abnormal nocturnal profile of growth hormone release. In addition, the neuroendocrine control of appetite is altered, as the levels of the anorexigenic hormone leptin are decreased by sleep loss while the levels of the orexigenic factor ghrelin are increased. These alterations are associated with an increase in hunger and appetite that is probably excessive in relation to the actual caloric requirements of extended wakefulness. Chronic partial sleep loss could therefore represent a risk factor for weight gain and obesity. Chronic sleep curtailment impairs carbohydrate metabolism as well and the magnitude of the deleterious effect on glucose tolerance could be clinically significant for at risk population.
- Spiegel K, Leproult R, Van Cauter E. Impact of a sleep debt on metabolic and endocrine function. The Lancet, 354: 1435-1439, 1999.
- Spiegel K, Sheridan JF, and Van Cauter E. Effect of sleep deprivation on response to immunization. Jama, 288(12): p. 1471-1472, 2002.
- Spiegel K, Tasali E, Penev P, and Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med,141(11):846-850, 2004.
- Van Cauter E. Endocrine Physiology. In: Principles and Practice of Sleep Medicine (M. Kryger, T. Roth and W.C. Dement, eds), 4rd edition, 266-282, Elsevier-Saunders, Philadelphia, 2005.
- Spiegel K., Knutson K., Leproult R., Tasali E., Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J. Appl. Physiol., 99 (5) : 2008-19, 2005
Investigations on the interactive effects of sleep loss and altered circadian rhythmicity in the aging process and its associated health and cognitive deficits.
In healthy elderly subjects, circadian rhythmicity persists but a number of 24-hour rhythms are dampened and/or advanced. Age-related alterations in sleep consist mainly of a marked reduction of slow wave sleep, a decrease in REM sleep and a marked increase in the number and duration of awakenings. Overt rhythms of body temperature and of the peripheral levels of hormones such as cortisol, melatonin, thyroid-stimulating-hormone, testosterone, prolactin and growth hormone are of lower amplitude and/or phase-advanced. In men, age-related changes in sleep occur with different chronologies for SWS and REM, each associated with specific hormonal alterations. Indeed, aging affects SWS and GH release with a similar chronology as the abrupt decrements occur from early adulthood to midlife whereas the impact of age on REM, wake and cortisol profiles appears more gradually.We have investigated sex differences in sleep variables and hormonal profiles in older adults. Normalized delta activity in older women is lower than in older men. This is consistent with sex differences in subjective complaints, in fragility of sleep with environmental disturbances, and in the relationship to growth-hormone release. Lower sleep-onset release of growth hormone in women as compared with men could be related to lower levels of delta activity. Current work includes age and gender differences in adaptation to and recovery from sleep loss.
- Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab, 81:2468-2473, 1996.
- Van Cauter E, Leproult R and Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 284: 861-868, 2000.
- Latta F., Leproult R., Tasali E., L’Hermite-Balériaux M., Copinschi G., Van Cauter E. Sex differences in nocturnal growth hormone and prolactin secretion in healthy older adults: Relationships with sleep EEG variables. Sleep, 28 (12): 1519-1524, 2005.
- Latta F., Leproult R., Tasali E., Van Cauter E. Sex differences in delta and alpha EEG activities in healthy older adults. Sleep, 28 (12): 1525-1534, 2005.
- Penev P, Spiegel K, Marcinkowski T, and Van Cauter E. Impact of carbohydrate-rich meals on plasma epinephrine levels: dysregulation with aging. J Clin Endocrinol Metab, 90(11): 6198-6206, 2005.
Studies on the control of human circadian rhythmicity including mechanisms of adaptation to abrupt time shifts (jet lag, shift work).
Both photic and non-photic stimuli may affect the diurnal pattern of hormonal secretions and may induce either a phase-advance or a phase-delay of the circadian clock, according to the timing of administration. We have studied phase-shifting effects for light and for dark pulses, physical exercise, melatonin and melatonin agonists, and benzodiazepine hypnotics. These results open new perspectives for the treatment of a variety of disorders involving dysregulation of the circadian rhythmicity.
- Copinschi G, Akseki E, Moreno-Reyes R, Leproult R, L’Hermite-Balériaux M, Caufriez A., Vertongen F, Van Cauter E. Effects of bedtime administration of zolpidem on circadian and sleep-related hormonal profiles in normal women. Sleep, 18: 417-424,1995.
- Hirschfeld U, Moreno-Reyes R, Akseki E, L’Hermite-Balériaux M, Leproult R, Copinschi G, Van Cauter E. Progressive elevation of plasma thyrotropin during adaptation to simulated jet lag: Effects of treatment with bright light or zolpidem. J Clin Endocrinol Metab 81: 3270-77, 1996.
- Buxton OM, Frank SA, L’Hermite-Balériaux M, Leproult R, Turek FW, Van Cauter E. Roles of intensity and duration of exercise in causing phase delays of human circadian rhythms. Am J Physiol (Endocrinology and Metabolism),273: E536-E542, 1997.
- Buxton OM, L’Hermite-Balériaux M, Turek FW, Van Cauter E. Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin. Am J Physiol: Regul Integr Comp Physiol, 278: R373-R382, 2000.
- Buxton OM, Copinschi G, Van Onderbergen A, Karrison TG, Van Cauter E. A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an 8-hour delay shift simulating westward jet lag. Sleep 23: 915-927, 2000.
Analysis and modeling of biological rhythms, including development of computer algorithms quantifying the temporal variations of hormones, cardiovascular variables, EEG variables and neurobehavioral variables.
Diurnal hormonal variations generally reflect the modulation of pulsatile release at 1-2 h intervals by signals occurring with nearly 24-hour periods, including the circadian signal, sleep-wake homeostasis and environmental and behavioral factors, including the light-dark cycle, periodic changes in activity levels and meal intake.We are currently developing a software package that analyzes chronobiological time series, in particular 24-hour hormonal profiles. The software package includes a peak detection and quantification program, a best fit curve determination program and a secretory rates calculation program.
- Van Cauter E. Method for the characterization of the 24-hour temporal variation of blood components. Am J Physiol 273:E255-E264, 1979.
- Van Cauter E. Estimating false positive and negative errors in analyses of hormonal pulsatility. Am J Physiol 254:E786-E794, 1988.
- Van Cauter E. Computer-assisted analysis of endocrine rhythms. In: Computers in Endocrinology, V. Guardabasso, D. Rodbard and G. Forti (eds), Serono Symposia Publications, Raven Press, New York, 59-70,1990.
- Burgess HJ, Penev PD, Schneider R, Van Cauter E. Estimating cardiac autonomic activity during sleep: impedance cardiography, spectral analysis, and Poincaré plots. Clin Neurophysiol; 115(1):19-28, 2004