CHAPTER 6 ENDOCRINE RHYTHMS
Principles and Practice of Endocrinology and Metabolism
CHAPTER 6 ENDOCRINE RHYTHMS
EVE VAN CAUTER
Period Range and Origin
Methodologic Aspects of the Study of Endocrine Rhythms
Rhythms in the Somatotropic Axis
Rhythms in the Pituitary-Adrenal Axis
Rhythms in Prolactin Secretion
Rhythms in the Gonadotropic Axis
Rhythms in the Thyrotropic Axis
Rhythms in Glucose Regulation
Pronounced temporal oscillations ranging in period from a few minutes to a year occur throughout the endocrine system. These oscillations are part of the wide variety of rhythms that exist in all living organisms. Rhythms with a period of ~24 hours have been called circadian, from the Latin circa diem, meaning “around a day.” According to the terminology of circadian biology, 24-hour rhythms should only be referred to as circadian if they are primarily driven by an endogenous clock system. However, it has become increasingly apparent that nearly all 24-hour rhythms partly reflect the influence of an endogenous circadian pacemaker located in the hypothalamus and partly the influence of other events occurring with a 24-hour periodicity, such as the alternation of waking and sleeping, light and dark, food intake, and postural changes. Thus, the use of the term circadian is often extended to all diurnal variations recurring regularly at a time interval of ~24 hours.
Circadian rhythms have been used to separate two further classes of biologic rhythms: ultradian rhythms, with periods shorter than 24 hours, and infradian rhythms, with periods longer than 24 hours. The pulsatile release of pituitary hormones belongs to the ultradian range. The menstrual cycle and the seasonal variations in the reproductive system are infradian rhythms. Reproducible circadian changes occur in the secretory pattern of the vast majority of hormones.
There is virtually neither a tissue nor a function in the human organism that does not exhibit regular changes from day to night. Distinct patterns of secretion recur at 24-hour intervals for essentially all hormones. Much of the temporal variability and organization of endocrine release ultimately results from the activity of two interacting time-keeping mechanisms in the central nervous system: endogenous circadian rhythmicity and sleep-wake homeostasis (Fig. 6-1). In mammals, endogenous circadian rhythmicity is generated by a pacemaker or group of oscillators located in the paired suprachiasmatic nucleus (SCN) of the hypothalamus.1 Sleep-wake homeostasis is an hourglass-like mechanism relating the amount and quality of sleep to the duration of prior wakefulness.2
FIGURE 6-1. Schematic representation of the central mechanisms involved in the control of temporal variations in pituitary hormone secretions over the 24-hour cycle. Sleep-wake homeostasis is in an hourglass-like mechanism, which relates the propensity for deep non-rapid eye movement (non-REM) sleep to the amount of prior wakefulness. Circadian rhythmicity is an endogenous near-24-hour oscillation generated in the suprachiasmatic nuclei (SCN) of the hypothalamus and transmitted via neural as well as humoral mechanisms. (ACTH, adreno-corticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyrotropin-stimulating hormone.)
The endogenous nature of human circadian rhythms has been established by experiments in which subjects were isolated in a soundproof chamber with no time cues available. Under those conditions, the subjects show free-running rhythms with periods, which deviate slightly from 24 hours and vary from one individual to another. In humans, the endogenous “free-running” period is usually slightly longer than 24 hours. In the past few years, enormous progress has been made in elucidating the molecular and genetic mechanisms underlying the generation of circadian rhythms in mammals. After the discovery of the first mammalian circadian clock gene, called Clock,3,4 a number of other mammalian clock genes were rapidly identified and sequenced.5 Intense efforts are now under way to understand how these genes and their protein products interact with each other through a series of activational and inhibitory pathways to produce the precise periodicity of the circadian signal generated in the SCN.
Environmental agents, primarily the light-dark cycle (i.e., photic cues), affect the expression and properties of the circadian signal. Light exposure in the later part of the subjective night and in the early part of the subjective day (e.g., around dawn) generally advances the phase of the circadian oscillation. In contrast, light exposure in the later part of the subjective day and during the early part of the subjective night (e.g., around dusk) delays circadian phase. Light-dark information reaches the SCN via a direct afferent pathway from the retina as well as an indirect projection via the intergeniculate leaflet of the thalamus.1 There also is good evidence to indicate that nonphotic cues are also capable of altering circadian function. Many of the non-photic stimuli that induce phase shifts in the circadian clock appear to do so by either stimulating physical activity or activating the pathways by which information about the activity-rest state of the organism reaches the clock.1 Phase-shifts may occur when activity pathways are stimulated during the normal rest period or, vice-versa, when rest is enforced during the normal active period. As is the case for light, the magnitude and direction of the phase-shifts depend on their timing relative to the internal circadian clock. There is now substantial evidence to indicate that the Raphe nuclei of the brainstem are involved in mediating the effects of activity on the circadian clock.
Sleep-wake homeostasis is thought to involve a putative neural sleep factor (factor “S”) that rises during waking and decays exponentially during sleep,2 and regulates the timing, amount, and intensity of the deeper stages of sleep. These stages of deep sleep correspond to stages III and IV of non– rapid-eye-movement (REM) sleep, usually referred to as slow-wave (SW) sleep because of the appearance of well-defined waves in the frequency range 0.5 to 4.0 Hz in the electroencephalogram. The neuroanatomical and neurochemical basis of sleep-wake homeostasis has not been entirely elucidated but appears to involve the basal forebrain cholinergic region and adenosine, a neuromodulator of which the extracellular concentrations in this region increase during sustained wakefulness and decrease during sleep.6 The mechanisms controlling sleep propensity and maintenance in the human appear to be somewhat different from those occurring in most other mammalian species. Indeed, human sleep is generally consolidated in a single 7-to 9-hour period, whereas fragmentation of the sleep period in several bouts is the rule in most other mammals. Possibly as a result of this consolidation of the sleep period, the wake-sleep and sleep-wake transitions in the human are associated with physiologic changes—and, in particular, endocrine changes—that are more marked than those observed in animals. Humans are also unique in their capacity to maintain wakefulness despite an increased pressure to sleep. While decrements in mood and cognitive function associated with such behaviors have long been recognized, these behaviors have been found to be associated with endocrine and metabolic alterations that may result in long-term adverse health consequences.6a
The pathways by which circadian rhythmicity, sleep-wake homeostasis, and their interactions modulate hormonal release are largely unknown. At the level of the central nervous system (see Fig. 6-1), humoral and/or neural signals originating from the hypothalamic circadian pacemaker and from brain regions involved in sleep regulation affect the activity of the hypothalamic structures responsible for the pulsatile release of neuroendocrine factors (e.g., corticotropin-releasing hormone [CRH], growth hormone–releasing hormone [GHRH], etc.), which stimulate or inhibit intermittent secretion of pituitary hormones. It appears that stimulatory or inhibitory effects of sleep on endocrine release are primarily associated with SW sleep, rather than REM sleep. Theoretically, the modulation of neuroendocrine release by sleep and circadian rhythmicity could be achieved by modulation of pulse amplitude, modulation of pulse frequency, or a combination of both. The data available so far seem to indicate that circadian rhythmicity of pituitary hormonal release is achieved primarily by modulation of pulse amplitude without changes in pulse frequency, whereas sleep-wake and REM/non-REM transitions affect pulse frequency. Pituitary hormones that influence endocrine systems not directly controlled by hypothalamic factors probably mediate, at least partially, the modulatory effects of sleep and circadian rhythmicity on these systems (e.g., counterregulatory effects of growth hormone [GH] and cortisol on glucose regulation).
Figure 6-2 shows examples of 24-hour patterns of plasma cortisol, thyrotropin (thyroid-stimulating hormone [TSH]), prolactin (PRL), and GH levels observed in normal young men in the presence (left) and in the absence (right) of sleep. To eliminate the effects of feeding, fasting, and postural changes, the subjects remained recumbent throughout the study, and the normal meal schedule was replaced by intravenous glucose infusion at a constant rate. These profiles exemplify the high degree of temporal organization provided by circadian rhythms in the endocrine system. As is the case for the majority of hormones, the plasma levels of these four pituitary-dependent hormones follow a pattern that repeats itself day after day. The nocturnal rise of TSH starts in the evening, at a time when cortisol secretion is quiescent, and ends at the beginning of the sleep period, when GH and PRL concentrations surge. The early morning period is associated with low TSH, low PRL, and low GH concentrations but high cortisol levels. Thus, the release of these four hormones follows a highly coordinated temporal program that results from interactions between circadian rhythmicity, sleep, and pulsatile release. It is apparent that the presence or absence of sleep had only modest effects on the wave shape of the cortisol profile but markedly affected the profilers of TSH, PRL, and GH. Thus, the relative contributions of circadian rhythmicity and sleep-wake homeostasis vary from one endocrine axis to the other, but, as will be shown in subsequent sections, inputs from both central nervous system processes can be recognized in the majority of 24-hour hormonal patterns.
FIGURE 6-2. From top to bottom: Temporal profiles of plasma cortisol (COR), thyrotropin (thyroid-stimulating hormone [TSH]), prolactin (PRL), and growth hormone (GH) in a healthy male adult studied over a 24-hour cycle with a normal sleep period (left) or continuously awake (right). The black bars denote the sleep periods; the open bars the periods of nocturnal sleep deprivation.
Among the medical implications of circadian rhythms, those relating to clinical diagnosis are the most obvious. Indeed, because of the wide amplitude of certain rhythms, the estimation of the mean level of a parameter from a single measurement may involve an error exceeding 100%. For example, a plasma cortisol level of 15 µg/dL (i.e., 414 nmol/L) at 8:00 a.m. is perfectly normal, whereas the same value obtained at 8:00 p.m. is suggestive of some form of hypercortisolism. Differentiation between normal and pathologic levels may be greatly improved by adequately selecting the time of sample collection. To illustrate this concept, Figure 6-3 shows the mean of 56 profiles of plasma cortisol from patients with Cushing syndrome as compared with the mean of 60 profiles obtained in normal subjects. Overlap between individual values from the two groups of subjects should be expected at all times except between 10:00 p.m. and 2:00 a.m., when the mean cortisol level allows for the discrimination between healthy controls and patients with hypercortisolism in 114 out of 116 cases. As discussed later in this section, it is also important to find out whether the patient has been recently involved in night work or has just returned from transmeridian travel when interpreting certain hormonal data for diagnostic purposes.
FIGURE 6-3. Mean, across individuals, of the 24-hour profile of plasma cortisol in 60 normal subjects (closed circles) and 56 patients with Cushing syndrome (open circles). The hatched and shaded areas represent one standard error of the mean above and below the mean for normal subjects or patients with Cushing syndrome, respectively.
Another medical implication of circadian rhythms is based on the fact that the response of the organism to many stimuli depends on the time at which that stimuli is applied. This finding forms the theoretical basis of chronopharmacology (i.e., the investigation of drug effects as a function of their time of administration) and of chronotherapy (i.e., the design of better protocols of treatment that take into account the chronobiologic characteristics of the system).7
Abnormal 24-hour regulation of endocrine and other physiologic functions occur in a variety of highly prevalent conditions, including shift work, “jet lag” (see Chap. 10), blindness, major depressive illness (see Chap. 201), and sleep disorders. The health symptoms of shift workers and the general feeling of discomfort experienced after a transmeridian flight are well-known consequences of the desynchronization between internal and external time. Both are associated with a variety of physical and performance deficits. The jet lag syndrome usually includes symptoms of fatigue, subjective discomfort, sleep disturbances, reduced mental and psychomotor performance, and gastrointestinal tract disorders. The malaise partly reflects a state of internal desynchrony, because different physiologic systems adapt to abrupt shifts of environmental time at different rates. The syndrome subsides as adaptation to local time is achieved. Unless the condition of jet lag is repeated at frequent time intervals for prolonged periods of time (as in the case of air transportation professionals), this transient syndrome is not thought to be associated with long-term adverse effects on physical and mental health. In contrast, shift work, which is voluntarily accepted by millions of workers, is a major health hazard, involving an increased risk of cardiovascular illness, gastrointestinal disorders, psychosocial symptoms, sleep disturbances, substance abuse, reduced immune function, and infertility.8,9 and 10 Shift workers are generally in a condition of chronic sleep debt,9 which could in itself result in endocrine and metabolic disturbances. Workers on permanent or rotating night shifts do not fully adapt to these schedules, even after several years,11,12 and live in a chronic state of internal desynchrony of the endocrine system. An example is shown in Figure 6-4, which compares mean 24-hour profiles of plasma cortisol and PRL in permanent night workers as compared with day workers.13,14 and 15 The components of these endocrine rhythms, which are primarily controlled by sleep-wake homeostasis (e.g., sleep-related PRL secretion), partly adapted to the night schedule, whereas components reflecting circadian timing (i.e., onset of the early morning elevation of cortisol secretion) showed little, if any, adaptation. As a result, the night workers had to initiate sleep when cortisol levels were already high and maintain wakefulness despite elevated concentrations of PRL, a hormone thought to be involved in sleep regulation.
FIGURE 6-4. Mean 24-hour profiles of plasma cortisol (left) and prolactin (right), either in healthy subjects who work during the daytime or in healthy subjects who have been working during the night for at least 2 years. The vertical lines at each time point represent the standard error of the mean. The black bars represent the sleep periods. (Data from Weibel L, Follenius M, Spiegel K, et al. Comparative effect of night and daytime sleep on the 24-hour cortisol secretory profile. Sleep 1995; 18:549; Weibel L, Spiegel K, Follenius M, et al. Internal dissociation of the circadian markers of the cortisol rhythm in night workers. Am J Physiol 1996; 270:E608; Spiegel K, Weibel L, Gronfier C, et al. Twenty-four hour prolactin profiles in night workers. Chronobiol Int 1996; 13:283.)
Abnormal synchronization of circadian rhythms, including hormonal rhythms, have also been observed in totally blind subjects. These disturbances are thought to reflect a lack of entrainment to the 24-hour environmental periodicity that is due to the absence of photic synchronization.
In severely depressed subjects, early timing of a number of circadian rhythms, including hormonal rhythms, has been observed. These findings provide the basis for the phase-advance hypothesis for affective illness, which proposes that abnormalities in circadian time-keeping are involved in the pathophysiology of depression.16 Patients experiencing sleep apnea, a condition in which frequent awakenings interrupt sleep, have abnormalities of sleep-related endocrine release. When the condition is untreated, nocturnal PRL and GH levels do not increase to the same extent as in healthy subjects with normal sleep. Studies that have examined the impact of treatment with continuous positive airway pressure have demonstrated that treatment of the sleep disorder partly normalizes the endocrine alteration.17,17a This is illustrated in the profiles shown in Figure 6-5 in the case of GH. After 3 months of treatment, nasal continuous positive airway pressure therapy increases plasma insulin-like growth factor-I levels in men with severe obstructive sleep apnea.18 In children, surgical correction of obstructive sleep apnea may restore GH secretion and a normal growth rate.19
FIGURE 6-5. Mean profiles of plasma growth hormone (GH) in patients with sleep apnea studied before (top) and after (bottom) treatment with continuous positive airway pressure. The vertical line at each time point represents the standard error of the mean. (Data from Saini J, Krieger J, Brandenberger G, et al. Continuous positive airway pressure treatment: effects on growth hormone, insulin and glucose profiles in obstructive sleep apnea patients. Horm Metab Res 1993; 25:375. Reproduced from Van Cauter E, Spiegel K. Circadian and sleep control of hormonal secretions. In: Turek FW, Zee PC, eds. Regulation of sleep and circadian rhythms. New York: Marcel Dekker, Inc., 1999:397.)
Age-related changes in endocrine, metabolic, and behavioral circadian rhythms have been well described.20,21 One of the most prominent changes is a reduction in rhythm amplitude. The overall findings of a study that examined age-related differences in 24-hour endocrine rhythms and sleep in healthy subjects are shown in Figure 6-6. The cortisol and TSH rhythms were dampened in the older group. A decrease by at least 50% in the nocturnal release of both GH and melatonin was observed in the older volunteers, and SW sleep was drastically diminished. Deficits in the maintenance and depth of nocturnal sleep are generally paralleled by decreased alertness during the daytime. Many circadian rhythms are also phase advanced in older subjects such that specific phase points of the rhythms occur earlier than in young subjects.21 The alterations in circadian regulation are closely associated with changes in sleep-wake habits (i.e., earlier bedtimes and waketimes).
FIGURE 6-6. From top to bottom, mean 24-hour profiles of plasma cortisol, thyrotropin (thyroid-stimulating hormone [TSH]), melatonin, prolactin, and growth hormone (GH) levels, and distribution of slow-wave (SW) and rapid-eye-movement (REM) stages in sleep in old and young subjects. The distribution of SW and REM is expressed in minutes of each 15-minute sampling interval spent in the corresponding stage. Vertical lines at each time point represent the standard error of the mean. The black bars correspond to the mean sleep period. (From van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging. Am J Physiol 1991; 260:E651.)
PERIOD RANGE AND ORIGIN
The term ultradian is primarily used to designate rhythmicities with periods ranging from fractions of hours to several hours. In the hourly range, the most prominent ultradian rhythms are the alteration of REM and non-REM stages in sleep and the pulsatility of hormonal secretions. Oscillations in the 80- to 120-minute range also occur at the rate of urine flow and gastric motility. Pulsatile hormonal release is ubiquitous in the endocrine system. Indeed, the plasma levels of most hormones undergo episodic fluctuations of variable duration and magnitude, referred to as secretory “episodes” or “pulses.” These pulses recur at 1- to 4- hour intervals (see Fig. 6-2). Pulsatility has been observed for anterior and posterior pituitary hormones; for hormones directly under their control; and for other endocrine variables, such as insulin, glucagon, and renin. The long-disputed theory that ultradian variations of brain activity—similar to those occurring during sleep—were also present during wake (constituting a basic rest-activity cycle) has received some experimental support. One study demonstrated the existence of an ultradian rhythm of brain electrical activity in the frequency range of 13 to 35 Hz, an index of central alertness, during waking.22 Furthermore, it appeared that pulses of cortisol release were significantly associated with increases in this marker of alertness.
In discussing the origin of ultradian hormonal fluctuations, one must distinguish two general cases: that of the hormones under direct hypothalamic control and that of hormones that are part of more peripheral endocrine systems. In the first case, periodic release ultimately reflects phasic neural activation, whereas in the second case, oscillatory behavior is a property of the dynamics of local regulatory networks. The episodic pulses of anterior pituitary hormones, which are representative of the first case, result from secretion in discrete bursts in response to pulsa-tile stimulation and/or inhibition by hypothalamic factors. The specific hypothalamic mechanism controlling pulsatile release appears to be different for each pituitary axis, but common stimuli may operate in different axes. The state of knowledge is most advanced in the case of the gonadotropins, for which pulsatile release is caused by intermittent discharges of gonadotropin-releasing hormone (GnRH) into the pituitary portal circulation. The GnRH pulses are obtained by synchronous discharges of GnRH-containing neurons in the arcuate of the mediobasal hypothalamus.23 Sharp increases in the frequency of hypothalamic multiunit electrical activity are associated with each pulse of peripheral luteinizing hormone (LH) level.23 The pulsatile behavior is intrinsic to the GnRH neurons, as attested by their coordinate secretion in tissue cultures.24 Intermittent stimulation by pituitary hormones is then in turn responsible for the episodic release of hormones under their control (see Chap. 16).
For hormones other than those controlled by the hypo-thalamo-pituitary axis, the mechanisms causing episodic variations in plasma levels are generally less well understood. Notable exceptions are the ultradian 1- to 2-hour oscillations of insulin secretion that occur after meal ingestion, as well as during constant glucose infusion or continuous enteral nutrition.25,26 Theoretical and experimental evidence suggests that in conditions of normal glucose tolerance, these oscillations arise from the negative feedback interactions linking insulin and glucose.26
The physiologic significance of hormonal pulsatility has been first demonstrated by experiments showing that normal LH and follicle-stimulating hormone (FSH) levels may be restored by pulsatile, but not continuous, administration of exogenous GnRH to primates with lesions in the hypothalamus that had abolished endogenous GnRH production.23 These findings were rapidly applied to the treatment of a variety of disorders of the pituitary-gonadal axis, using either pulsatile GnRH administration to correct a deficient production of endogenous GnRH or long-acting GnRH analogs to induce pituitary desensitization.27 Similar approaches have been investigated for other hypothalamo-pituitary axes.
METHODOLOGIC ASPECTS OF THE STUDY OF ENDOCRINE RHYTHMS
To investigate circadian hormonal rhythms, a group of individuals is usually studied for a minimum of 24 hours each, following the same experimental protocol. The demonstration of circadian rhythmicity is then based on the observation of consistently reproducible characteristics in the set of 24-hour profiles obtained. To validate such an approach, the group of subjects should be as homogeneous as possible, not only in terms of physical parameters, such as age and gender, but also in terms of living habits, such as bedtimes and meal schedules. To maximize interindividual synchronization, the volunteers should comply with a standardized schedule of meals and bedtimes for several days before the investigation. Blood sampling is usually done at regular intervals through a catheter inserted into a forearm vein. During bedtime hours, the catheter is connected to plastic tubing extending to an adjacent room to collect blood samples without disturbing the subject. Because of the major modulatory effects exerted by sleep stages on hormonal release, it is important to obtain polygraphic sleep recordings using standardized methods for recording and scoring. If polygraphic monitoring is not possible, estimates of sleep onset and awakenings should be carefully recorded. Daytime naps should be avoided. To obtain valid estimations of the circadian parameters, it is necessary to sample at intervals not exceeding 1 hour. Indeed, the pulsatile variations may bias the estimation of the characteristics of the circadian rhythm if sampling is less frequent. Procedures to analyze 24-hour hormonal profiles usually involve the fitting of a smooth curve to the data. The times of occurrence of the maximum and the minimum of the best-fit curve are often referred to as, respectively, the acrophase and the nadir. The amplitude of the circadian rhythm may be estimated as 50% of the difference between the maximum and the minimum of the best-fit curve.
The definition of an optimal sampling protocol to study pulsatile hormonal fluctuations depends on the type of phenomenon under study. Presently, sampling at 1-minute intervals represents probably the fastest rate technically achievable with reasonable precision. Sampling every few minutes uncovers high-frequency, low-amplitude variations superimposed on the slower pulsatile release occurring at hourly intervals. These intensified rates of venous sampling may not allow for the estimation of the characteristics of major secretory bursts, because the total duration of sampling compatible with this rate of blood withdrawal limits the observed number of large peaks. Sampling rates of 20 and 30 minutes only detect major pulses lasting >1 hour.
The analysis of pulsatile variations may be considered at two levels. The researcher may wish to define and characterize significant variations in peripheral levels based on estimations on the size of measurement error (i.e., primarily assay error). However, under certain circumstances, it is possible to mathematically derive secretory rates from the peripheral concentrations. This procedure, often referred to as deconvolution, often reveals more pulses of secretion than the analysis of peripheral concentrations. It also more accurately defines the temporal limits of each pulse.
The association between pulsatile GH secretion and sleep stages in a single individual is shown in Figure 6-7.28 The profile shown on the top represents the plasma levels of GH measured at 15-minute intervals. Three pulses were found significant using a pulse detection algorithm (i.e., ULTRA28). The corresponding profile of GH secretory rates calculated by deconvolution is shown in the second profile from the top. A single compartment model for GH disappearance with a half-life of 19 minutes and a volume of distribution of 7% of the body weight was used in this calculation. Pulse analysis of the secretory rates now reveals the occurrence of three additional pulses of GH secretion. The three lower profiles show the percentages of each 15-minute sampling interval spent in stages of wake, SW, and REM, respectively. When the profile of plasma concentrations is compared with the SW profile, it appears that subsequent to its initiation in concomitance with the beginning of the first SW period, the sleep-onset GH pulse spanned the first 3 hours of sleep, without apparent modulation by non-REM and REM stages. However, the profile of secretory rates clearly reveals that GH was preferentially secreted during the SW stage, with interruptions of secretory activity coinciding with the intervening REM or wake stages. Deconvolution demonstrated a closer association between SW stages and active GH secretion than the analysis of plasma levels, because the temporal limits of each pulse were more accurately defined and additional pulses were revealed. The validity of the deconvolution procedure is critically dependent on the knowledge of the clearance kinetics of the hormone under study; extra caution in interpreting the data must be exerted, because this procedure involves an amplification of measurement error, with increased risk of false-positive error.
FIGURE 6-7. 24-hour profile of plasma growth hormone (GH; top) sampled at 15-minute intervals in a normal man. The black bar indicates the sleep period. The second panel from the top shows the profile of GH secretory rates derived by deconvolution from the profile of plasma concentrations. Significant pulses of plasma levels and secretory rates are indicated by arrows. The three lower panels represent the temporal distribution of slow-wave (SW) stages (III + IV), wake, and rapid eye movement (REM) during sleep. Vertical lines indicate the temporal association between pulses of GH secretion and SW stages. (From Van Cauter E. Computer-assisted analysis of endocrine rhythms. In: Rodbard D, Forti G, eds. Computers in endocrinology. New York: Raven Press, 1990:59.)
Whether examining peripheral concentrations or secretory rates, there are two major approaches to analyzing the episodic fluctuations. The first, and most commonly used, is the time domain analysis in which the data are plotted against time and pulses are detected and identified. The second is the analysis in the frequency domain in which amplitude is plotted against frequency or period. These two approaches differ fundamentally both in the mathematical treatment of the data and in the questions they may help to resolve; therefore, they should be viewed as being complementary. The regularity of pulsatile behavior may be quantified by both approaches (i.e., by examining the distribution of interpulse intervals derived from a time domain analysis or by examining the distribution of spectral power in a frequency domain analysis). Additionally, another analytical tool, the approximate entropy, has been introduced to quantify regularity of oscillatory behavior in endocrine and other physiologic time series.29,30
RHYTHMS IN THE SOMATOTROPIC AXIS
In normal subjects, the 24-hour profile of plasma GH consists of stable low levels abruptly interrupted by bursts of secretion (see Fig. 6-2, Fig. 6-5, Fig. 6-6 and Fig. 6-7). The most reproducible secretory pulse occurs shortly after sleep onset, in association with the first phase of SW sleep.31 Other secretory pulses may occur in later sleep and during wakefulness in the absence of any identifiable stimulus. In women, daytime GH pulses are more frequent than in men, and the sleep-associated pulse, although still present, does not generally account for most of the 24-hour GH release. The secretory profile is less regular in women than in men.32 Circulating estradiol concentrations play an important role in determining overall levels of spontaneous GH secretion.33 Sleep onset elicits a pulse in GH secretion whether sleep is advanced, delayed, interrupted, or fragmented. Delta wave electroencephalographic activity consistently precedes the elevation in plasma GH levels. While SW sleep is clearly a major determinant of the 24-hour profile of GH secretion in humans, there is also evidence for the existence of a circadian modulation of the occurrence and height of GH pulses, reflecting decreased somatostatin inhibition in the evening and nocturnal hours.34 Administration of a specific GHRH antagonist results in a near total suppression of sleep-related GH release, indicating an important role for GHRH in the control of nocturnal GH secretion.35
Two studies involving pharmacologic stimulation of SW sleep have provided evidence for a common mechanism in the control of SW sleep and GH secretion and have indicated that compounds, which increase SW sleep, could represent a novel class of GH secretagogues. Indeed, enhancement of SW sleep by oral administration of low g-hydroxybutyrate (a naturally occurring metabolite of g-aminobutyric acid used in the treatment of narcolepsy) or ritanserin (a selective 5HT2 receptor antagonist) results in simultaneous and highly correlated increases of nocturnal GH release.36,37
The total amount and the temporal distribution of GH release are strongly dependent on age.31 A pulsatile pattern of GH release, with increased pulse amplitude during sleep, is present in prepubertal boys and girls. During puberty, the amplitude of the pulses, but not the frequency, is increased, particularly at night. Maximal overall GH concentrations are reached in early puberty in girls and in late puberty in boys. Age-related decreases in GH secretion have been well documented in both men and women and are illustrated in Figure 6-6.
There is a marked suppression of GH levels throughout the 24-hour span in obese subjects. In normal-weight subjects, fasting, even for only 1 day, enhances GH secretion via an increase in both pulse amplitude and pulse frequency.38 Nonobese juvenile or maturity-onset diabetic patients hypersecrete GH during wakefulness as well as during sleep, primarily because of an increase in the amplitude of pulses.39 This abnormality may disappear when blood sugar levels are strictly controlled. In acromegaly, GH is hypersecreted throughout the 24-hour span, with a pulsatile pattern superimposed on elevated basal levels, indicative of the presence of tonic secretion.40,41 After trans-sphenoidal surgery, a normal circadian pattern of GH release can be restored.41 In contrast, bromocriptine therapy lowers the overall GH secretion but does not lead to the resumption of normal 24-hour profiles.
RHYTHMS IN THE PITUITARY-ADRENAL AXIS
Twenty-four-hour profiles of cortisol typical of normal subjects are shown in Figure 6-2, Figure 6-3, Figure 6-4 and Figure 6-6. The patterns of plasma adrenocorticotropic hormone (ACTH) and cortisol variations show an early morning maximum, declining levels throughout daytime, a quiescent period of minimal secretory activity, and an abrupt elevation during late sleep. With a 15-minute sampling rate, ~15 pulses of ACTH and cortisol can be detected in a 24-hour span. The cortisol profiles shown in the upper panels of Figure 6-2 illustrate the remarkable persistence of the wave shape of the rhythm in the absence of sleep and support the notion that the 24-hour periodicity of corticotropic activity is primarily controlled by circadian rhythmicity. Nevertheless, modulatory effects of the sleep or wake condition have been clearly demonstrated. Sleep onset is reliably associated with a short-term inhibition of cortisol secretion,42,43 and 44 although this effect (which appears to be related to slow-wave stages45) may not be detectable when sleep is initiated at the peak of corticotropic activity (i.e., in the morning13). Conversely, awakening at the end of the sleep period is consistently followed by a pulse of cortisol secretion.46,47 During sleep deprivation, these rapid effects of sleep onset and sleep offset on corticotropic activity are obviously absent, and the amplitude of the rhythm is reduced as compared with normal conditions (see Fig. 6-2).
In addition to the immediate modulatory effects of sleep-wake transitions on cortisol levels, nocturnal sleep deprivation—even partial—results in higher-than-normal cortisol concentrations on the following evening.48 Sleep loss, thus, appears to delay the normal return to evening quiescence of the corticotropic axis. This suggests that sleep loss may slow down the rate of recovery of the hypothalamic–pituitary–adrenal axis response after a challenge.
A circadian variation parallel to that of cortisol occurs for the plasma levels of adrenal steroids.49 Figure 6-8 shows the mean 24-hour profiles of cortisol, 11-hydroxyandrostenedione, dehydroepiandrosterone, and androstenedione (AD) for 10 normal young men. The amplitude of the circadian variation in 11-hydroxyandrostenedione levels, a steroid derived from adrenal AD, is essentially similar to that of cortisol, whereas the amplitude of the variations in dehydroepiandrosterone and AD levels, two steroids of partially gonadal origin, is much lower.49 Pulses of the plasma concentrations of adrenal steroids occur in remarkable synchrony with bursts of cortisol secretion, indicating that pulsatile ACTH release is reflected in the temporal organization of all adrenal secretions.
FIGURE 6-8. Mean 24-hour profiles of plasma cortisol, 11-hydroxyan-drostenedione (11-OAD), dehydroepiandrosterone (DHEA), and andro-stenedione (AD) obtained at 15-minute intervals in 10 normal young men. For each subject and each hormone, the data were expressed as a percentage of the individual 24-hour mean before calculating group values. The vertical bars at each time point represent the standard error of the mean. (Data from Lejeune-Lenain C, Van Cauter E, Desir D, et al. Control of circadian and episodic variations of adrenal androgens secretion in man. J Endocrinol Invest 1987; 10:267.)
A distinct circadian rhythm of serum cortisol levels emerges at ~6 months of age. Once this periodicity has been established, it persists throughout adulthood and has been observed through the ninth decade.21 The overall pattern of the rhythm remains unchanged (see Fig. 6-6), but in older subjects, the nadir is advanced by 1 to 2 hours and the amplitude is decreased.21 In women, oral contraceptive therapy results in a large increase of the mean cortisol level and of the amplitude of the rhythm resulting from an estrogen-induced elevation of transcortin-binding capacity. Thus, when hypercortisolism is suspected in a female patient, it is essential to know whether the patient is receiving estrogen treatment.
The 24-hour profile of pituitary-adrenal secretion remains unaltered in a wide variety of pathologic states. Disease states in which alterations of the cortisol rhythm have been observed50 include primarily (a) disorders involving abnormalities in binding and/or metabolism of cortisol, (b) the various forms of Cushing syndrome, and (c) severe depression.
The relative amplitude of the circadian rhythm and of the episodic fluctuations of cortisol is blunted in patients with liver disease and in patients with anorexia nervosa, primarily because of the decreased metabolic clearance of cortisol. In contrast, in hyperthyroidism, for which cortisol production and peripheral metabolism are increased, episodic pulses are enhanced. In hypothyroid patients, there is diminished cortisol clearance, the mean level is markedly elevated, and the relative amplitude of the rhythm is, therefore, dampened. Figure 6-9 illustrates typical 24-hour cortisol patterns of plasma cortisol and cortisol secretory rates in a patient with pituitary Cushing disease and a patient with major endogenous depression as compared with a normal subject. In patients with Cushing syndrome secondary to adrenal adenoma or ectopic ACTH secretion, the circadian variation of plasma cortisol is invariably absent. However, in pituitary-dependent Cushing disease, a low-amplitude circadian variation may persist, suggesting that there is no defect in the neural clock generating the periodicity. Cortisol pulsatility is blunted in ~70% of patients with Cushing disease, suggesting autonomous tonic secretion of ACTH by a pituitary tumor. However, in ~30% of these patients, the magnitude of the pulses is instead enhanced. These “hyperpul-satile” patterns could be caused by enhanced hypothalamic release of CRH or persistent pituitary responsiveness to CRH. Hypercortisolism with persistent circadian rhythmicity and increased pulsatility is found in a majority of acutely depressed patients. In these patients, who do not develop the clinical signs of Cushing syndrome despite the high cortisol levels, the quiescent period often occurs earlier than in normal subjects of comparable age. This phase-advance could reflect an alteration in the regulation of the circadian pacemaker system. When a clinical remission is obtained, the hypercortisolism and the abnormal timing of the quiescent period disappear, indicating that these disturbances are “state” rather than “trait” dependent. Contrasting with the increased cortisol pulsatility that characterizes many patients with major depression, a few studies have suggested that pulsatile variations are of lower amplitude in post-traumatic stress disorder and chronic fatigue syndrome.51,52
FIGURE 6-9. Twenty-four-hour profiles of cortisol secretory rate (top) and plasma cortisol (bottom) in a normal subject (left), a patient with pituitary Cushing disease (middle), and a patient with major endogenous depression of the unipolar subtype (right). Cortisol secretory rates were derived from plasma levels using a two-compartment model for cortisol distribution and metabolism. Note that circadian rhythmicity is markedly attenuated in the subject with Cushing disease, but it is preserved in the depressed patient. Cortisol secretion is entirely intermittent in the normal subject and the depressed patient, but the secretory pattern of the patient with Cushing disease shows evidence of tonic cortisol release.
RHYTHMS IN PROLACTIN SECRETION
Under normal conditions, the 24-hour profile of plasma PRL levels (see Chap. 13) follows a bimodal pattern, with minimal concentrations around noon, an afternoon phase of augmented secretion, and a major nocturnal elevation starting shortly after sleep onset and culminating around midsleep. Episodic pulses occur throughout the 24-hour span. Morning awakening is consistently associated with a brief PRL pulse.53,54 Studies on PRL during daytime naps or after shifts of the sleep period have demonstrated that sleep onset is invariably associated with an increase in PRL secretion. This is well illustrated by the profiles shown in Figure 6-2 in the presence and in the absence of sleep and in Figure 6-4, which compares the profiles of day and night workers. However, a sleep-independent circadian component of PRL secretion may be observed in some individuals, particularly in women.54 An example may be seen in the PRL profiles of night workers (see Fig. 6-4) in whom a nocturnal elevation occurred despite nocturnal activity.15
When sleep structure is characterized by power spectral analysis of the electroencephalogram, a close temporal association between increased PRL secretion and SW activity is clearly apparent.55 Conversely, prolonged awakenings, which interrupt sleep, are consistently associated with decreasing PRL concentrations. Thus, shallow and fragmented sleep is generally associated with lower nocturnal PRL levels. This is indeed what is observed in elderly subjects (see Fig. 6-6),21 who have an increased number of awakenings and markedly decreased amounts of SW sleep, and in whom a dampening of the nocturnal PRL rise is evident. Benzodiazepine hypnotics taken at bedtime often cause an increase in the nocturnal PRL rise, resulting in concentrations in the pathologic range for part of the night.56
Absence or blunting of the nocturnal increase of plasma PRL has been reported in a variety of pathologic states, including uremia, breast cancer in postmenopausal women, and Cushing disease. In subjects with insulin-dependent diabetes, the circadian and sleep modulation of PRL secretion is preserved, but overall levels are markedly diminished.57 In hyperprolactinemia associated with prolactinomas, the nocturnal elevation of PRL is preserved in patients with microadenomas but altered in patients with macroadenomas.58 Selective removal of PRL-secreting microadenomas can result in the normalization of the PRL pattern.
RHYTHMS IN THE GONADOTROPIC AXIS
Rhythms in the gonadotropic axis cover a wide range of frequencies, from episodic release in the ultradian range to diurnal rhythmicity and monthly and seasonal cycles. These various rhythms interact to provide a coordinated temporal program governing the development of the reproductive axis and its operation at every stage of maturation. The following summary is centered on 24-hour rhythms and their interaction with pulsatile release at the various stages of maturation of the human reproductive system. More detailed reviews may be found elsewhere.50,59,60
Before puberty, LH levels are very low. Both LH and FSH appear to be secreted in a pulsatile pattern but with a very low amplitude, which is insufficient to activate the gonad. The onset of puberty is associated with an augmentation of pulsatile activity in a majority of both girls and boys. In pubertal children, the magnitude of the nocturnal pulses of LH and FSH is consistently increased during sleep. As the pubescent child enters adulthood, the daytime pulse amplitude increases as well, eliminating or diminishing the diurnal rhythm. In pubertal girls, there is a diurnal variation of circulating estradiol levels, with higher concentrations during the daytime than during the nighttime. The lack of parallelism between gonadotropin and estradiol levels reflects a 6- to 8-hour delay between gonadotropin stimulation and the subsequent ovarian response. In pubertal boys, the nocturnal rise of testosterone coincides with the elevation of gonadotropins.
Patterns of LH release in adult men exhibit large interindi-vidual variability. The diurnal variation is dampened and may become undetectable. A marked diurnal rhythm in circulating testosterone levels in young adults, with minimal levels in the late evening and maximal levels in the early morning, has been well demonstrated. In young male adults, the amplitude of the circadian variation averages 25% of the 24-hour mean.49 In older men, the amplitude of LH pulses is decreased, and no significant diurnal pattern can be detected. However, the circadian rhythm in testosterone remains apparent, although markedly dampened.
In adult women, the 24-hour variation in plasma LH is modulated by the menstrual cycle. In the early follicular phase, LH pulses are large and infrequent, and a slowing of the frequency of secretory pulses occurs during sleep. In the midfollicular phase, pulse amplitude is decreased, pulse frequency is increased, and frequency modulation of LH pulsatility by sleep is less apparent. Pulse amplitude increases again by the late follicular phase. No modulation by sleep is apparent until the early luteal phase, when nocturnal slowing of pulsatility is again evident. During the luteal-follicular transition, there is a four- to five-fold increase in LH pulse frequency, which accompanies the selective FSH rise necessary for normal folliculogenesis. Toward menopause, gonadotropin levels are elevated but show no consistent circadian pattern.
Abnormal ultradian and/or circadian hormonal profiles have been found in a wide variety of reproductive disorders. The findings pertaining to disorders of female and male reproduction for which an abnormal function of the hypothalamic pulse generator and/or its modulation by diurnal rhythmicity seem to be primarily involved have been reviewed elsewhere.50,59,60
RHYTHMS IN THE THYROTROPIC AXIS
In normal adult men and women, TSH levels are low throughout the daytime and begin to increase in the late afternoon or early evening.61 Maximal levels occur shortly before sleep. During sleep, TSH levels generally decline slowly. A further decrease occurs in the morning hours (see Fig. 6-2 and Fig. 6-6). Studies involving sleep deprivation and shifts of the sleep-wake cycle have consistently indicated that an inhibitory influence is exerted on TSH secretion during sleep. Interestingly, when sleep occurs during daytime hours, TSH secretion is not suppressed significantly below normal daytime levels. When the depth of sleep is increased by prior sleep deprivation, the nocturnal TSH rise is even further blunted. There is a consistent association between descending slopes of TSH concentrations and SW stages.62 The pronounced enhancing effect of sleep deprivation on the nighttime TSH rise is illustrated in Figure 6-2. The timing of the evening rise seems to be controlled by circadian rhythmicity. The temporal pattern of TSH secretion seems to reflect both tonic and pulsatile release, with both the frequency and the amplitude of the pulses increasing during the nighttime. Pulses of TSH secretion persist during somatostatin or dopamine treatment, suggesting that the control of pulsatility is largely thyrotropin-releasing hormone dependent.61
Because triiodothyronine and thyroxine are largely bound to serum protein, the existence of a circadian rhythm independent of postural changes has been difficult to establish. However, under conditions of sleep deprivation, the increased amplitude of the TSH rhythm results in an increased amplitude of the tri-iodothyronine rhythm, which becomes detectable in a majority of subjects.
The fact that the inhibitory effects of sleep on TSH secretion are time dependent may cause, under certain circumstances, elevations of plasma TSH levels, which reflect the misalignment of sleep and circadian timing. Figure 6-10 shows the mean profiles of plasma TSH levels observed in a group of normal young men in the course of adaptation to simulated jet lag.63 After a 24-hour baseline period, the sleep-wake cycle and the dark period were abruptly advanced by 8 hours. In the course of adaptation, TSH levels increased progressively, because daytime sleep failed to inhibit TSH, and nighttime wakefulness was associated with large circadian-dependent TSH elevations. As a result, mean TSH levels after awakening from the second shifted sleep period were more than two-fold higher than during the same time interval after normal nocturnal sleep. This study demonstrates that the subjective discomfort and fatigue associated with jet lag may involve a prolonged elevation of a hormonal concentration in the peripheral circulation.
FIGURE 6-10. Mean (and standard error of the mean) profiles of plasma thyrotropin (thyroid-stimulating hormone [TSH]) from eight normal young men who were subjected to an 8-hour advance of the sleep-wake and dark-light cycles. Black bars indicate bedtime periods. (Data from Hirschfeld U, Moreno-Reyes R, Akseki E, et al. Progressive elevation of plasma thyrotropin during adaptation to simulated jet lag: effects of treatment with bright light or zolpidem. J Clin Endocrinol Metab 1996; 81:3270.)
In older adults, there is an overall decrease of TSH levels (see Fig. 6-6), but the rhythm persists, albeit slightly dampened and with an earlier evening rise than in younger adults.64 Fasting decreases overall TSH levels by decreasing pulse amplitude, resulting in a dampening of the nocturnal surge.65
A decreased or absent nocturnal rise of TSH has been observed in a wide variety of nonthyroidal illnesses, suggesting that hypothalamic dysregulation generally affects the circadian TSH surge. The nocturnal TSH surge is diminished or absent in hyperthyroidism, central hypothyroidism, and in various conditions of hypercortisolism. The lack of normal nocturnal elevation of TSH levels also appears to be a sensitive index of preclinical hyperthyroidism. In poorly controlled diabetic states, whether type 1 or type 2, the surge also disappears.66 Correction of hyperglycemia is associated with a reappearance of the nocturnal elevation.66
RHYTHMS IN GLUCOSE REGULATION
In normal humans, glucose tolerance varies with the time of day.67 Figure 6-11 illustrates circadian variations in glucose tolerance to oral glucose, identical meals, constant glucose infusion, and enteral nutrition in normal subjects. Plasma glucose responses to oral glucose, intravenous glucose, or meals are markedly higher in the evening than in the morning. Overnight studies of subjects sleeping in the laboratory have consistently observed that despite the prolonged fasting condition, glucose levels remain stable or fall only minimally across the night, contrasting with the clear decrease that is associated with daytime fasting. Thus, a number of mechanisms operative during nocturnal sleep must intervene to maintain stable glucose levels during the overnight fast. Experimental protocols using intravenous glucose infusion or enteral nutrition (the two experimental conditions allowing for the study of nighttime glucose tolerance during sleep without awakening the subjects) have shown that glucose tolerance deteriorates further as the evening progresses, reaches a minimum around midsleep, and then improves to return to morning levels (see Fig. 6-11).67 There is evidence to indicate that this diurnal variation in glucose tolerance is partly driven by the wide and highly reproducible 24-hour rhythm of circulating levels of cortisol, an important counterregulatory hormone.68 Diminished insulin sensitivity and decreased insulin secretion in relation to elevated glucose levels are both involved in causing reduced glucose tolerance later in the day. During the first part of the night, decreased glucose tolerance is due to decreased glucose utilization both by peripheral tissues (relaxed muscles and rapid insulin-like effects of sleep-onset GH secretion) and by the brain (imaging studies have demonstrated a reduction in glucose uptake during SW sleep). During the second part of the night, these effects subside, as sleep becomes more shallow and fragmented. Thus, complex interactions of circadian and sleep effects result in a consistent and predictable pattern of changes of the setpoint of glucose regulation over the 24-hour cycle.
FIGURE 6-11. Twenty-four-hour pattern of blood glucose changes in response to oral glucose (top panel; 50 g glucose every 3 hours), identical meals, constant glucose, and continuous enteral nutrition in normal young adults. At each time point, the mean glucose level is shown with the standard error of the mean. (Reproduced from Van Cauter E, Polon-sky KS, Scheen AJ. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev 1997; 18:716.)
Human insulin secretion is a complex oscillatory process including rapid pulses recurring every 10 to 15 minutes superimposed on slower, ultradian oscillations with periods in the 90- to 120-minute range.26 The ultradian oscillations are tightly coupled to glucose, and the periodicity of the insulin secretory oscillations can be entrained to the period of an oscillatory glucose infusion, supporting the concept that these ultradian oscillations are generated by the glucose-insulin feedback mechanism.69 Stimulatory effects of sleep on insulin secretion are mediated by an increase in the amplitude of the oscillation.70 The rapid 10- to 15-minute pulsations seem to have a different origin from that of the ultradian oscillations.26 Indeed, they may appear independently of glucose, because they have been observed in the isolated perfused pancreas and in isolated islets. Thus, the existence of an intrapancreatic pacemaker generating rapid oscillations has been postulated.
In obese and diabetic subjects, the diurnal and ultradian variations in glucose regulation are abnormal. In obesity, the morning versus evening difference in glucose tolerance observed in normal subjects is abolished. In type 1 diabetic patients, the increase in glucose levels and/or insulin requirements, which occurs in a prebreakfast period ranging from 5:00 a.m. to 9:00 a.m., has been called the dawn phenomenon.71 A role for nocturnal GH secretion in the pathogenesis of the dawn phenomenon has been demonstrated in some, but not all, studies. The observation of a dawn phenomenon in type 2 diabetes patients under normal dietary conditions has been less consistent. Prominent diurnal variations in glucose levels and insulin secretion in both normal subjects and diabetic patients become apparent during prolonged fasting.72 Figure 6-12 illustrates these variations in diabetic patients and age-, sex-, and weight-matched controls studied during a 24-hour fast following an overnight fast.72 As expected, glucose levels initially declined as a result of the fasting condition, but started rising again in the late evening to reach a morning maximum. The nocturnal rise of glucose during prolonged fasting could represent a normal diurnal variation in the set-point of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition.
FIGURE 6-12. Individual 24-hour glucose profiles from four subjects with type 2 diabetes who remained fasted throughout the study period. The two upper profiles were obtained from 8 a.m. the first day until 8 a.m. the next day. The two lower profiles were obtained from 2 p.m. the first day until 2 p.m. the next day. Irrespective of the timing of the beginning of the fasting period, glucose concentrations started increasing in the evening and peaked in the morning. The dashed lines represent the best-fit curve. (From Shapiro ET, Polonsky KS, Copinschi G, et al. Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes. J Clin Endocrinol Metab 1991; 72:444.)
The rapid and ultradian oscillations of insulin secretion are perturbed in type 2 diabetes and in impaired glucose tolerance without hyperglycemia. The rapid pulses appear to be less regular and of shorter duration than in normal subjects.73,74 A less regular oscillatory pattern may already be detected in relatives of patients with type 2 diabetes. The ultradian oscillations, which have an exaggerated amplitude in obese subjects without apparent changes in frequency or pattern of recurrence, are irregular and of lower amplitude in subjects with established type 2 diabetes.75,76 and 77 Disturbances in the pattern of entrainment of insulin secretion to oscillatory glucose infusions are evident in type 2 diabetes patients, in nondiabetic subjects with impaired glucose tolerance,77 and in nondiabetic first-degree relatives of subjects with type 2 diabetes.26
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