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Department of Medicine, University of Chicago, Chicago, Illinois 60637; and Division of Diabetes, Nutrition and Metabolic Disorders, University of Liège, Liège, Belgium B-4000
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Abstract |
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 Top Abstract I. IntroductionII. Characteristics and Causal...III. Alterations of 24-h...IV. Diurnal Variations of...V. Alterations of 24-h...VI. Alterations of 24-h...VII. ConclusionsReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Characteristics and Causal...III. Alterations of 24-h...IV. Diurnal Variations of...V. Alterations of 24-h...VI. Alterations of 24-h...VII. ConclusionsReferences |
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Human sleep is generally consolidated in a single 7- to 9-h period, whereas fragmentation of the sleep period in several bouts is the rule in other mammals. An important metabolic consequence of this organization of sleep and wake states is that an extended period of total fast must be maintained on a daily basis, generally during the overnight period. The consolidation of the sleep period is probably responsible for the fact that the wake-sleep and sleep-wake transitions in man are associated with physiological changes that are usually more marked than those observed in animals. Man is also unique in his capacity to ignore circadian signals and to maintain wakefulness despite an increased pressure to go to sleep. Voluntary sleep curtailment, rapid travel across time zones (i.e., "jet lag"), and shift work rotations are highly prevalent conditions in modern society, and their hormonal and metabolic implications have only begun to be recognized (3).
While the roles of sleep and circadian rhythmicity in the modulation of endocrine function have been most investigated for hormonal secretions that are directly dependent on the hypothalamo-pituitary axes, it is also well established that the characteristics of normal glucose regulation vary across the 24-h cycle (4). Abnormalities in the diurnal variation of glucose tolerance have been recently demonstrated in aging, obesity, and diabetes. These findings, which form the topic of the present review, may have significant clinical implications regarding the importance of time of day for the diagnosis and management of conditions of impaired glucose tolerance. Indeed, a detailed understanding of the chronobiology of glucose regulation may provide strategies to improve dietary schedules and optimize the effects of hypoglycemic agents and insulin.
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II. Characteristics and Causal Mechanisms of 24-h Rhythms of Glucose Regulation in Normal Young Subjects |
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TopAbstractI. IntroductionII. Characteristics and Causal...III. Alterations of 24-h...IV. Diurnal Variations of...V. Alterations of 24-h...VI. Alterations of 24-h...VII. ConclusionsReferences |
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illustrates the results of a study involving the administration of
eight consecutive 50-g glucose loads presented at 3-h intervals during
the same 24-h cycle to normal volunteers. To control for the sequence
effect, each subject received the first load at a different time point.
The subjects remained seated in a comfortable armchair throughout the
study and were allowed to sleep during the period 2300 h to
0700 h. Glucose levels in response to these repeated stimuli were
clearly higher in the evening and during the first half of the night
than in the morning and early afternoon.
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b. In response to identical meals.
A morning to evening
variation in glucose responses to identical mixed meals, consistent
with the diurnal variation in responses to oral glucose, has also been
demonstrated in several studies (15, 16, 17, 18, 19). The presence and magnitude of
a morning to evening difference seemed to be dependent on meal size and
composition (16, 17, 18). Indeed, the magnitude of the morning to evening
increase in postmeal glucose responses increases with the size and
carbohydrate content of the meal (17). A number of studies have
indicated that effects of time of day may be more prominent in women
than in men (16, 18, 20). In all early studies (15, 16, 17, 18), the
"evening" meal was actually given in the late afternoon, between
1630 and 1800 h. Even larger and more consistent effects of time
of day were subsequently observed when the evening meal was consumed
later, around 2000 h (19, 21). An example is shown in Fig. 1
, which shows the glucose responses in response to the same meal (which
included 43% of carbohydrates) given at 0800, 1400, and 2000 h.
The area under the curve is more than 2-fold larger in the evening than
in the morning. Measurements of serum insulin and of insulin secretion
rates (ISR; derived from plasma C-peptide levels using a mathematical
model for C-peptide distribution and clearance) indicate that postmeal
serum insulin levels and ISR responses also increase when the day
progresses, but to a lesser degree than glucose responses. Thus, in the
study illustrated in Fig. 1, peak levels of ISR were similar in the
morning and in the evening, but the area under the curve was
approximately 50% larger in the evening. The temporal patterns of
plasma glucose and ISR have also been examined in subjects who received
continuous enteral nutrition (22, 23). As exemplified in the mean
profile shown in Fig. 1, despite the fact that the caloric intake was
maintained constant, plasma glucose levels increased slowly from early
afternoon until bedtime.
c. In response to intravenous glucose.
Variations in the
glucose and insulin responses to glucose stimulation across the daytime
are more pronounced when the stimulus is given intravenously, rather
than orally (4, 10, 24). Gastrointestinal factors are thus not the
primary cause of the morning to evening decrease in glucose tolerance.
The progressive decrease in glucose tolerance in the evening and early
part of the night has also been clearly documented in studies in which
the subjects were given a low dose iv infusion of glucose at a constant
rate (e.g., 5 g/kg/24 h) for prolonged periods of time
(24–30 h) and maintained at bed rest (2, 25). Irrespective of the
timing of the initiation of the infusion, glucose concentrations begin
to increase in the late afternoon or early evening. A mean profile of
plasma glucose levels in recumbent fasted subjects studied during
constant glucose infusion is shown in Fig. 1. Because the increase in
glucose levels begins well before sleep time, and is observed in the
absence of changes in activity state, it is likely to reflect an effect
of circadian rhythmicity.
2. Nighttime variations in glucose tolerance
a. During overnight fast: the controversial "dawn
phenomenon."
The consolidation of human sleep in a single
7- to 9-h period implies that an extended period of fast must be
maintained overnight. A large number of studies have sampled levels of
glucose and insulin in subjects sleeping in the laboratory and have
observed that, despite the prolonged fasting condition, glucose levels
remain stable or fall only minimally during the night (26, 27, 28, 29, 30, 31, 32). In
contrast, during the daytime period, if subjects are fasting in a
recumbent position, in the absence of any physical activity, glucose
levels fall by an average of 0.5–1.0 mmol/liter (± 10–20 mg/dl) over
a 12-h period (upper panel of Fig. 2). Thus, a number of mechanisms
operative during nocturnal sleep (reviewed below) must intervene to
maintain stable glucose levels during the overnight fast,
substantiating the French popular proverb "Qui dort, dine"
(i.e., "sleeping is dining"). A pronounced nocturnal
elevation of leptin levels has been recently reported in lean normal
subjects studied during an overnight fast, and its role in the
suppression of appetite during the sleep period has been hypothesized
(33).
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b. During constant glucose infusion or enteral nutrition.
Experimental protocols allowing for the study of nighttime glucose
tolerance during sleep without awakening the subjects include constant
intravenous glucose infusion and continuous enteral nutrition.
Confounding effects of food ingestion and prolonged fasting are avoided
by replacing the normal caloric intake by a constant input, thereby
creating a steady-state condition with levels of glucose and insulin
secretion within the physiological range. Sleep has been
polygraphically recorded under both conditions, and normal sleep
parameters are observed after a period of habituation to the laboratory
procedures. Thus, both constant glucose infusion and continuous enteral
nutrition offer the possibility of examining glucose tolerance during
the sleep state, although under conditions that are clearly artificial.
In particular, prolonged glucose infusion results in a marked
inhibition of endogenous glucose production (37, 38, 39). Both experimental
conditions have been used in extended studies in normal subjects (22, 23, 25) and results have demonstrated a marked decrease in glucose
tolerance during nocturnal sleep (illustrated in the lower
panels of Fig. 1). Despite the differences in the mode and nature
of caloric intake, the glucose profiles observed in both conditions are
remarkably similar and showed that glucose tolerance is markedly
decreased during nocturnal sleep. Indeed, when individual profiles were
analyzed, the overall increase in plasma glucose ranged from 20 to
30%, despite the maintenance of rigorously constant rates of caloric
intake. Maximum levels occur around the middle of the sleep period,
well before dawn. During the later part of the night, i.e.,
at the time of the so-called "dawn phenomenon," glucose tolerance
begins to improve and glucose levels progressively decrease toward
morning values.
3. Studies delineating the respective roles of sleep and time of
day.
Studies involving intravenous glucose infusion or continuous
enteral nutrition at a constant rate for 24–30 h showed that glucose
tolerance begins to decrease well before bedtime and continues to
deteriorate until approximately the middle of the night (23, 25),
suggesting that both sleep-independent effects and sleep-dependent
effects could be involved in producing the overall 24-h pattern. To
define the respective roles of circadian rhythmicity (intrinsic effects
of time of day independent of the sleep or wake condition) and sleep
(intrinsic effects of sleep per se irrespective of the time
of day) in the 24-h variation of glucose tolerance, experimental
protocols that take advantage of the fact that circadian rhythms
require several days to adapt to a change of sleep-wake and light-dark
cycles have been used (23, 40). These protocols involve an abrupt delay
of the sleep period by 8–12 h, and therefore allow for the effects of
time of day to be observed in the absence of sleep, and the effects of
sleep to be observed at an abnormal circadian time, i.e., a
time when sleep does not normally occur. During wakefulness, the level
of physical activity is kept minimal and essentially constant. Sleep
quality is polygraphically monitored. Figure 3 shows the mean profiles of plasma
glucose and ISR observed in a study involving a 12-h shift of the
sleep-wake cycle in normal young subjects receiving a constant glucose
infusion (40). The findings are consistent with the concept that both
circadian rhythmicity and sleep modulate glucose regulation. Indeed,
during sleep deprivation, glucose concentrations and ISR increase to
reach a nocturnal maximum at approximately the same time as during
normal sleep and then return to daytime levels. After daytime sleep
onset, a sharp rise in glucose levels and ISR was again observed. The
quantitative analysis of the size of the elevations seen in the absence
of sleep and during daytime sleep suggests that, in normal conditions
of nocturnal sleep, the effects of circadian rhythmicity and sleep are
superimposed. Similar findings regarding the role of sleep in
modulating glucose regulation were obtained in a study involving an 8-h
shift of the sleep-wake cycle in subjects receiving continuous enteral
nutrition (23).
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a. Factors intrinsic to glucose regulation.
There is evidence
to indicate that glucose utilization by insulin-dependent as well as
non-insulin-dependent tissues decreases as the day progresses. A more
than 2-fold reduction in glucose utilization in the later part of the
day has indeed been directly demonstrated in a study combining
[3H]glucose infusion with hepatic and femoral venous
catheterization (39). In contrast, splanchnic glucose uptake was
slightly higher in the afternoon than in the morning (39). Evidence
consistent with a reduction in insulin-independent glucose utilization
has been obtained in a study involving a frequently sampled intravenous
glucose tolerance test (IVGTT) at 0800 h and 1800 h and its
analysis using the minimal model approach (41). Indeed, a modest
15–20% decrease of the insulin-independent glucose utilization
parameter SG (i.e., "glucose effectiveness")
of the minimal model analysis was observed (41). In a more recent study
(42), a larger decrease in SG was reported, perhaps because
the evening test was performed later, at 2000 h. Indirect evidence
for a reduction in glucose utilization has also been obtained in
studies demonstrating the existence of diurnal variations in glucose
tolerance in subjects receiving intravenous glucose infusions at a
constant rate for prolonged periods of time (2, 25, 40). Indeed, under
these conditions of mild hyperglycemia and hyperinsulinemia, endogenous
glucose production is markedly inhibited in normal subjects (37, 38, 39),
and therefore temporal variations in plasma glucose levels mainly
reflect changes in glucose utilization. Whether there is also a
variation in basal hepatic glucose output across the daytime has not
been determined. Indeed, experimental conditions under which glucose
fluxes were directly or indirectly evaluated all involved a near total
suppression of glucose production and therefore could not evaluate
possible variations in basal glucose output.
Conflicting evidence for reduced insulin sensitivity in the afternoon and evening as compared with the morning was obtained in studies performed in the early 1970s. Indeed, Gibson and Jarrett (43) reported that the blood glucose fall after intravenous injection of 0.1 U/kg of insulin was 15% smaller at 1700 h than at 0900 h. This finding was confirmed in a later study (44), which included the performance of an insulin tolerance test at six different clock times spanning the 24-h cycle. Chronobiological analysis of the data indicated that the rate of glucose disappearance was largest at 0800 h and lowest during the evening and nighttime. In contrast, Carroll and Nestel (10), using the same dosage of intravenous insulin, did not observe a significant morning (0700 h) to evening (1900 h) difference in glucose response. The weight of the evidence tends, however, to be on the side of the reduced insulin sensitivity in the evening. Indeed, a study using a glucose-controlled insulin infusion system (Biostator; 45 has shown that the insulin-glucose ratio over a 24-h period of constant low dose glucose infusion undergoes a consistent diurnal variation, with relatively stable daytime levels followed by a pronounced nocturnal elevation, suggesting the existence of a marked decrease in insulin sensitivity during the nighttime. However, the studies were initiated in the morning, and thus the evening and nighttime periods corresponded to more than 12 h of insulin infusion using the Biostator device, a condition that has been shown in later studies to be associated with an aggregation and partial inactivation of the infused insulin (46). Therefore, the magnitude of the 24-h variation in insulin sensitivity was probably overestimated in this study. The finding in subjects receiving a constant glucose infusion of lower levels of leg glucose uptake at 1800 h, as compared with 0800 h in the face of similar levels of serum insulin, is also indicative of a degree of insulin resistance in the later part of the day (39). The most recent studies on variations of insulin sensitivity (SI) across the daytime used the minimal model analysis of the frequently sampled IVGTT. In one study, a 30% reduction in SI at 1800 h, as compared with 0800 h, was observed (41), whereas in another study, no significant morning to evening change was detected (42).
There is also evidence to support a role for inappropriately low insulin secretion in causing decreased glucose tolerance in the later part of the day. After an intravenous injection of tolbutamide, two separate studies have found that the insulin response is larger in the morning than in the afternoon (10, 47). The role of insulin secretion in morning to evening variations of glucose tolerance was also investigated by examining responses to intravenous infusions of glucose and glucagon or glucagon only (48). Levels of insulin were lower in the afternoon than in the morning after both types of stimuli, thus suggesting decreased ß-cell responsiveness in the later part of the day. Analysis of glucose and insulin responses to a frequently sampled IVGTT indicated the existence of a nearly 25% reduction in first phase insulin secretion in the evening as compared with the morning (41). In the same study, a nearly 50% decrease in the slope of glucose potentiation relating acute insulin rise to intravenous arginine was also observed at 1800 h when compared with 0800 h (41). In a recent study using graded glucose infusions (rates 2, 4, 6, and 8 mg/kg/min), ISRs were found to be higher in the morning than in the evening at all infusion rates, and the slope of the linear regression line relating glucose to ISR was 40% lower in the evening than in the morning, consistent again with a marked decrease in ß-cell responsiveness in the evening (42). Comparison of the insulin-secretory responses to identical meals presented at 0800 h and 2000 h also provided evidence for variations of ß-cell responsiveness across the daytime because the 25–50% increase in ISR from morning to evening was not commensurate with the approximate 100% increase in glucose response (19). Contrasting with the overall consensus regarding decreased insulin secretion during the later part of the day, a recent report (49), describing patterns of insulin secretion during euglycemic and hyperglycemic clamps, claimed that a circadian rhythm of insulin secretion with maximum levels in the afternoon and early evening and minimal levels during the nighttime and early morning (i.e., in the direction opposite to that found in all previous studies) could be evidenced at high glucose levels. Whether this discrepant finding reflects an alteration in regulation of insulin secretion at supraphysiological levels or other methodological differences remains to be determined.
In summary, there is good evidence to indicate that reduced glucose utilization, decreased insulin sensitivity, and inappropriately low insulin secretion are involved in causing decreased glucose tolerance in the later part of the day. There are no data to support a role for variations in glucose production. There appears to be no consistent variations in insulin clearance across the daytime portion of the 24-h cycle (10).
b. Factors related to neuroendocrine control of glucose
regulation.
The demonstration, under a variety of experimental
conditions, of the existence of a consistent morning to evening
variation of glucose tolerance in response to the same stimulus, and
unrelated to changes of activity levels or environmental parameters,
suggests that this temporal variation must be, at least partially,
controlled by signals originating from a robust pacemaker generating a
24-h, i.e., circadian, signal. In mammals, the mechanism
responsible for circadian rhythmicity is located in a single central
pacemaker in the suprachiasmatic nuclei of the hypothalamus (50). So
far, hormonal signaling appears to be the primary pathway for the
transmission of centrally generated circadian oscillations to
peripheral organs. Modulatory effects of circadian rhythmicity on
glucose control could be mediated by counterregulatory hormones,
including catecholamines, glucagon, GH, and cortisol.
Among these, epinephrine is weakly modulated by circadian rhythmicity but only during the nighttime period (51, 52). In normal adult subjects, peripheral levels of norepinephrine, GH, and glucagon concentrations do not undergo consistent variations across the daytime period (52, 53, 54, 55).
In contrast to the relative stability of the peripheral concentrations of other counterregulatory hormones across the waking portion of the 24-h cycle, plasma cortisol levels are highly dependent on time of day, with a morning maximum, decreasing concentrations throughout the afternoon and evening, and a quiescent phase centered around midnight, followed by a rapid rise toward morning levels (56). While numerous studies have addressed the complex interactions between cortisol levels and glucose regulation, little is known about the possible metabolic effects of short-term, pulsatile, low-amplitude cortisol elevations occurring at different phases of the circadian cycle in humans. Although, in subjects receiving constant glucose infusions, there is an inverse temporal relationship between the 24-h glucose and insulin patterns, on the one hand, and that of plasma cortisol, on the other hand, and the relative amplitudes of both rhythms are significantly correlated (40), the possibility that the 24-h cortisol rhythm could play a role in causing the normal diurnal variation in glucose tolerance has been repeatedly discarded (41, 57). Indeed, the coincidence of increased insulin sensitivity with high cortisol levels in the morning and of decreased insulin sensitivity with low cortisol levels in the evening is in apparent contradiction to the well known adverse effects of glucocorticoids on insulin sensitivity. However, this interpretation is based on the assumption that alterations of insulin resistance are an immediate consequence of changes in cortisol concentrations. A recent study (58) using intravenous injections of CRH or oral administration of hydrocortisone to amplify the morning elevation of plasma cortisol demonstrated that the nature and time course of the resulting responses of insulin secretion and glucose levels are entirely consistent with the inverse relationship between the cortisol rhythm and the 24-h profiles of blood glucose and insulin secretion occurring under physiological conditions. Indeed, the immediate effect of an increase in plasma cortisol level, even of very small amplitude, was an abrupt inhibition of insulin secretion without change in glucose concentration, consistent with previous in vitro (59, 60, 61, 62, 63) and in vivo (57, 64, 65) studies that have shown that glucocorticoids may have a direct immediate inhibitory action on insulin secretion. Larger cortisol elevations, of magnitude approximating or exceeding the normal daily excursion of peripheral concentrations, were additionally associated with a reduction in insulin sensitivity that does not manifest itself until 4–6 h after the cortisol elevation and may persist for more than 16 h (58). Thus, under physiological conditions, the circadian variation of cortisol concentrations is likely to be a causal mechanism for optimal glucose tolerance with minimal insulin-secretory responses in the morning and diminished insulin sensitivity without appropriate increases in insulin secretion 6–15 h later, i.e., in the afternoon and evening.
2. Mechanisms underlying nighttime variations in glucose
tolerance
a. Factors intrinsic to glucose regulation.
Two studies that
have measured overnight glucose turnover in fasted subjects maintained
at bed rest have shown that the stability of glucose levels during an
overnight fast is achieved by precisely matched changes in glucose
utilization and glucose production that fall in parallel during the
first part of the night and then increase concomitantly in the predawn
hours (29, 34). Examples of the overnight profiles of glucose
production and glucose utilization are shown in Fig. 2. Unfortunately,
neither study included polygraphic recordings of sleep, and therefore
the effects of sleep quality on the overnight glucose profile could not
be defined. The absence of a consistent pulse of GH secretion during
the first half of the sleep period in the mean GH profiles illustrated
in these reports (29, 34) suggests a significant impairment of sleep
quality, as, under normal conditions, the first few hours of sleep are
invariably associated with increased GH release (66). However, when the
subjects were kept actively awake throughout the night, both the fall
in glucose production and the fall in glucose utilization were dampened
and of shorter duration than during sleep (29). The sleep-associated
fall in hepatic glucose output is accompanied by a reduction in plasma
glycerol and FFA, suggesting that, during sleep, hepatic glucose output
may be partially regulated by peripheral signals derived from
lipolysis. Support for this hypothesis has been obtained in a study
examining overnight hepatic glucose output after a 72-h fast, when
hepatic glucose output primarily represents gluconeogenesis (67). Under
these conditions, the sleep-associated fall in hepatic glucose
output was obliterated, and the declines in plasma FFA and glycerol
were similarly absent, suggesting that these lipolytic products play a
role in the regulation of hepatic glucose output during late nocturnal
sleep (67).
Studies that have examined glucose regulation during
polygraphically recorded sleep have further delineated the factors
implicated in the decrease in glucose utilization during the early part
of the night. Figure 4 illustrates mean
profiles of plasma glucose, ISR, plasma GH, and sleep stages in a group
of normal subjects who initiated nocturnal sleep (left
panels) after 8–10 h of constant glucose infusion at a rate of 5
g/kg/24 h or who were kept awake throughout the night (right
panels). The condition of intravenous low-dose constant glucose
infusion for a prolonged period of time results in a marked inhibition
of endogenous glucose production (38, 39), and thus temporal variations
in plasma glucose levels mainly reflect changes in glucose utilization.
Sleep onset and the first half of the sleep period are accompanied by a
robust increase in plasma glucose, which is followed 10 min later by a
more than 50% increase in ISR. The increase in plasma glucose appears
to partially reflect the predominance of non-rapid eye movement (REM)
stages in early sleep. A recent study has also reported an association
between pulsatile increases in insulin and glucagon secretion during
sleep with non-REM stages (32). Positron emission tomography studies
have indeed demonstrated that brain glucose metabolism is reduced by
30–40% during stages III and IV (68, 69). One study (70), comparing
brain glucose utilization with systemic glucose turnover, estimated
that brain glucose utilization falls during non-REM stages only and
contributes to about two-thirds of the fall in systemic glucose
utilization during sleep. The last third would then reflect decreased
peripheral utilization. Diminished muscle tone during deep sleep
probably contributes to decreased peripheral glucose uptake.
Furthermore, in a study involving the estimation of the clearance of
endogenously secreted insulin (as the ratio of the area under the ISR
curve and the area under the simultaneously measured serum insulin
concentrations) during various time intervals across the 24-h cycle, an
approximate 40% acceleration of the disposal of secreted insulin
during the first half of nocturnal sleep was observed (40). Thus, an
increase in insulin clearance could also contribute to the reduction in
glucose utilization during the early part of the night. Finally, as
will be discussed below, GH secretion during early sleep is also likely
to play a role in decreasing peripheral glucose utilization.
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reduction of plasma glucose levels during the late part of the sleep is
likely to partially result from the increase in wake and REM stages, as
glucose utilization during these stages is higher than during non-REM
stages (68, 69, 70, 71, 72). Other factors that may have also contributed to the
decline of glucose levels during late sleep include the hypoglycemic
activity of previously secreted insulin during early sleep, the
increased insulin-independent glucose disposal due to transient mild
hyperglycemia, and the increase in body movements associated with the
higher frequency of awakenings. A role for temporal variations in
cortisol concentrations is also likely, as will be indicated below.
Markedly different profiles of plasma glucose and ISR are observed
during sleep deprivation (right panels of Fig. 4). During
the first part of the night, the persistence of the waking condition
prevents the decrease in brain glucose utilization, and GH secretion is
absent. Thus, glucose levels increase only marginally. During the
second half of the night, despite the persistence of bed rest and
constant glucose infusion, glucose levels and ISR decrease
significantly. The timing of this late night decrease in glucose levels
and ISR coincides with the well documented abrupt decrements of
alertness and performance that occur in sleep-deprived subjects 6–8 h
after their usual bedtime (73, 74).
b. Role of hormonal rhythmicity.
Major differences in the
circulating levels of GH, cortisol, and epinephrine, important
counterregulatory hormones, characterize the first and second half of a
normal night of sleep in young adults (56). During the first half of
the night, GH secretion is markedly stimulated, cortisol levels are
suppressed, and epinephrine concentrations decrease. During the second
half of the night, GH secretion is generally quiescent, cortisol
concentrations are rapidly increasing, and epinephrine levels begin to
return to daytime values. While there has been no study examining the
impact of the nocturnal variations in plasma epinephrine on glucose
regulation during sleep, temporal variations in both GH and cortisol
appear to influence parameters of nighttime glucose tolerance.
There is evidence to suggest that the major pulse of GH secretion that occurs in association with sleep onset plays a role in modulating glucose regulation during the first half of the night. Indeed, the more recent studies that have used bolus administrations of low-dose exogenous GH, to mimic physiological pulsatile release, and examined their short-term metabolic consequences have shown that a primary effect is a rapid decrease in muscular glucose uptake (75, 76). Thus, during early sleep, increased GH secretion may facilitate the maintenance of stable glucose levels despite the fasting condition by inhibiting muscular glucose uptake. In subjects receiving constant glucose infusion, there is a positive correlation between the magnitude of the sleep-associated elevation in glucose levels and the amount of concomitant GH secretion (56). When nocturnal GH secretion is amplified by bedtime intravenous injection of a low dose of GH-releasing hormone (GHRH), a near 50% increase in the postsleep elevation of glucose levels is observed (77), suggesting that sleep-onset GH secretion indeed inhibits glucose utilization during early sleep.
The putative role of the large temporal variation of cortisol levels in modulating parameters of glucose tolerance during sleep remains to be elucidated. A recent study has suggested that the low cortisol concentrations that prevail in the late evening and early part of the night may have a delayed effect on insulin sensitivity in the later part of the night and in the early morning (58). Thus, increased glucose utilization during the second half of the night could reflect a transient enhancement of insulin sensitivity related to the circadian trough of cortisol concentrations occurring 4–6 h earlier. Further studies are necessary to discriminate between the rapid inhibitory effects of cortisol on insulin secretion (57, 59, 60, 61, 62, 63, 64, 65) and its delayed effects on insulin action (78, 79) in the control of physiological variations in glucose tolerance during wake and during sleep.
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III. Alterations of 24-h Rhythms of Glucose Regulation in Normal Aging |
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TopAbstractI. IntroductionII. Characteristics and Causal...III. Alterations of 24-h...IV. Diurnal Variations of...V. Alterations of 24-h...VI. Alterations of 24-h...VII. ConclusionsReferences |
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A. Daytime variations in glucose tolerance
Early studies examining the effect of time of day on oral glucose
tolerance indicated that the morning to afternoon increase in glucose
responses was also present in older adults (age > 45 yr; Refs. 8,
9, and 14) and that the magnitude of this effect may be larger in older
adults than in younger subjects (14). This apparent increased amplitude
of the morning to afternoon variation could reflect an advance of the
overall rhythm of glucose tolerance, consistent with the advance of
circadian rhythmicity and sleep-wake habits that accompany old age.
Indeed, in young subjects, glucose tolerance worsens further from
afternoon to evening. In older adults, it is conceivable that
"evening" levels of glucose tolerance are already attained in the
afternoon. In one study in older subjects receiving a constant glucose
infusion (93), the progressive morning to evening increase in glucose
levels usually seen in normal nonobese young adults was still present,
and only minimally dampened, in the older volunteers. Peak glucose and
ISR levels were achieved earlier in the older than in the young
volunteers, consistent with an advance of circadian timing. Relative
increases in ISR over the same time period were, however, smaller than
in young lean men, suggesting an age-related failure of the ß-cell to
respond appropriately to glucose elevations. The effects of aging on
variations in glucose responses to meals across the daytime remain to
be determined. It is also not known whether the insulin resistance of
the elderly is stable or undergoes a consistent morning to evening
variation.
B. Nighttime variations in glucose tolerance
Studies that have examined glucose and insulin levels during an
overnight fast in older adults have generally observed stable or
slightly declining levels from late evening to morning (83, 94). The
rates of glucose production (Ra) and glucose utilization
(Rd) fell in parallel during the early part of the night
and then remained stable (94). This is in contrast to the profiles of
Ra and Rd seen in young adults, where both
parameters increase concomitantly during the second part of the night
(29, 34). Sleep has not been controlled in any of these overnight
studies.
Two studies (95, 96) have been specifically designed to determine whether the dawn phenomenon occurs in normal elderly subjects and could thus explain the frequent finding of mildly elevated fasting glucose levels in this population. Meneilly et al. (95) performed a euglycemic insulin clamp involving physiological hyperinsulinemia in the morning (0930–1200 h) as compared with the dawn period (0530–0800 h) in five healthy older adults and measured insulin levels, insulin clearance, insulin-mediated glucose disposal, and hepatic glucose production. Sleep-wake conditions were not controlled. There were no differences in any of the parameters measured between the two time periods, except for a nearly 20% increase in insulin clearance in the dawn period, as compared with the morning. The authors conclude that the dawn phenomenon does not occur in normal older adults (95). A similar conclusion was reached by Rosenthal and Argoud (96), who measured glucose production and plasma glucose and insulin levels in healthy young and elderly subjects during the time period 0500–0800 h. A minimal (i.e., averaging 3 mg/dl), but significant, elevation of plasma glucose and glucose production occurred over this time period in young, but not in older, subjects. Both studies (95, 96) speculated that the reduced levels of nocturnal GH secretion in older adults may underlie the absence of the dawn phenomenon. This interpretation is questionable since a majority of studies in young adults have failed to detect a dawn phenomenon during a normal overnight fast.
C. Respective roles of sleep and time of day
To further define the roles of time of day, sleep, and GH
secretion in modulating glucose tolerance and insulin secretion in
older adults, the temporal profiles of plasma glucose, ISR, and GH
levels were obtained in healthy, modestly overweight, older subjects,
young weight-matched controls, and young lean subjects during a 53-h
period of constant glucose infusion (i.e., 5 g/kg/24 h)
including 8 h of nocturnal sleep, 28 h of continuous
wakefulness, and 8 h of daytime sleep (Fig. 5 and 93 . The sleep-associated
glucose increase was dampened in the older subjects as compared with
young adults, but this appeared to reflect primarily an effect of
increased body weight, rather than age. Decreases in insulin-induced
glucose uptake are expected to be smaller in older, slightly
overweight, adults due to reduced muscle mass and absence of
significant GH secretion (86, 97). Decreases in cerebral glucose uptake
could also be of lesser magnitude than in young adults due to the
marked reduction in slow wave stages (i.e., stages III and
IV) in the elderly (91, 98). As clearly apparent in the mean profiles
illustrated in Fig. 5, ISR largely failed to increase in response to
the sleep-associated glucose rise in the older adults, demonstrating
the existence of a clear reduction in ß-cell responsiveness to
glucose in aging.
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IV. Diurnal Variations of Glucose Regulation in Obesity |
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Interestingly, early studies examining the response to a standardized oral glucose load administered once in the morning and once in the afternoon have shown an inverse relationship between the decrease in glucose tolerance from morning to afternoon and the degree of obesity (8, 14). Similar observations have been obtained in obese children who underwent an oral glucose tolerance test at 0900 and 1500 h (100). In the control children, there was a significant drop in the insulin-glucose ratio in the afternoon, whereas in the obese group this ratio remained high, with no significant change across the day. The existence of an abnormality in the daytime variation of components of glucose tolerance in obesity has been recently confirmed and extended in a study using the frequently-sampled IVGTT performed either at 0800 or 1800 h (41). In contrast to lean controls, obese adult subjects showed no morning to evening variation in glucose tolerance, no decline in insulin sensitivity in the afternoon, and only a marginally significant decline in ß-cell responsiveness to glucose in the later part of the day.
Abnormalities in the daytime profile of glucose tolerance and insulin secretion in obesity were further demonstrated in subjects receiving a continuous intravenous glucose infusion (101). In contrast to lean subjects who showed a marked decline in glucose tolerance toward the end of the day, plasma glucose levels in the obese subjects remained stable from morning to evening despite a steady decrease in ISR, indicating an improvement (rather than a deterioration) of glucose tolerance as the day progresses.
B. Nighttime variations in glucose tolerance
A few reports have indicated that, similar to what is observed in
normal lean subjects, plasma glucose levels, insulin concentrations,
and ISR decline progressively across the night in obese subjects who
have had a normal meal schedule during the previous day (27, 31, 99).
In contrast, one study showed that, when the overnight fast follows an
entire day of fasting, a progressive rise in plasma glucose, serum
insulin, and ISR occurs across the nighttime period, with the evening
to morning increase in plasma glucose during the overnight fast
averaging approximately 0.5 mmol/liter (102). Serum insulin and ISR
increased, respectively, by 10–15 pmol/liter and 20–30 pmol/min. It
was hypothesized that the prolonged fasting condition, which,
consistent with previous observations (103, 104), resulted in a
stimulation of evening cortisol secretion and nocturnal GH release, was
responsible for the abnormal overnight profile of glucose tolerance. A
nocturnal rise in circulating leptin levels, similar in timing and
relative magnitude to that occurring in lean adults but set around much
higher levels, has been found in markedly obese subjects (33). Sleep
was not recorded in any of these previous overnight studies in obese
subjects.
Continuous intravenous glucose infusion throughout the night with simultaneous polygraphic sleep recordings allowed for an evaluation of the role of sleep in the nocturnal changes in glucose tolerance in obese subjects (101). Despite the fact that sleep parameters were normal, obesity appeared associated with well defined alterations in nocturnal metabolic profiles, with specific defects characterizing the early and later portions of the sleep period. After sleep onset, the normal elevations in glucose and ISR were markedly reduced in the obese subjects, when compared with lean controls, probably because of the concomitant dampening of GH release. During the later part of the sleep period, obese subjects failed to significantly suppress ISR in contrast to control subjects in whom the second part of the sleep was accompanied by markedly declining glucose and insulin concentrations, which returned to presleep levels before awakening. The absence of a significant decline in ISR before awakening in obese subjects may reflect a prolongation of the secretory response to sleep onset due to insulin resistance. In addition, in overweight subjects, changes in ISR during the second half of sleep appeared to be less markedly and less consistently influenced by changes in cortisol levels, suggesting that in obesity there may be a relative insensitivity of the ß-cell to circadian cortisol changes (58, 101). It is likely that these dual defects in the nighttime control of the glucose-insulin regulation are involved in the reversal of the daytime variation of glucose tolerance in obesity.
C. Significance and clinical implications
The roles of sleep and circadian rhythmicity in glucose regulation
may be particularly important in obese individuals. On the one hand,
and interestingly, the behavioral rhythms of carbohydrate preference in
obese subjects parallel the diurnal variation of glucose tolerance, as
carbohydrate intake is generally lower in the morning and higher in the
evening (105). Further studies are needed to elucidate the
physiological significance and clinical implications of the
chronobiological abnormalities in glucose tolerance and eating patterns
in the initiation and maintenance of obesity. On the other hand, in
view of the relationships between sleep quality and glucose regulation
in normal man (106), the role of sleep disturbances on glucose
tolerance should be better evaluated in the obese subject. Indeed,
alterations in carbohydrate metabolism and insulin sensitivity may be
aggravated in the presence of sleep apnea syndrome, a prevalent
condition in the obese population. A positive relationship between the
degree of insulin resistance and the severity of sleep apnea syndrome
has been reported (107). Furthermore, an independent association
between the incidence of sleep apnea and the levels of fasting insulin
has been recently demonstrated (108). A few studies have examined
nocturnal hormonal release in patients with obstructive apnea (109, 110) and showed a marked decrease in nocturnal GH release, which may be
partially reversed by treatment with continuous positive airway
pressure. While the restoration of GH secretion in early sleep was not
associated with significant changes in overnight glucose and insulin
levels, the possibility of an improvement in daytime insulin
sensitivity remains to be investigated. These findings certainly
deserve further investigations as insulin resistance and
hyperinsulinemia are now considered as major risk factors for
atherosclerotic cardiovascular disease.
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V. Alterations of 24-h Rhythmicity of Glucose Regulation in Non Insulin-Dependent Diabetes Mellitus (NIDDM) |
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B. Alterations in nighttime variations in glucose levels during
fasting
The existence of a paradoxical elevation in blood glucose at the
end of the sleep period in fasted diabetic subjects was first reported
by Hatlehol (112) in 1924, and similar findings were described in a
series of studies conducted over the next three decades (113, 114, 115, 116). In
1967, Faiman and Moorhouse (117) sampled blood at 4-h intervals across
a 72-h fast in diabetic subjects and observed, superimposed on the
expected decline associated with the starvation condition, a
reproducible 24-h variation of glucose concentrations, with more
rapidly declining levels across the daytime period and increasing
levels during the nighttime. Peak levels occurred near 0800 h and
the amplitude of the cycle was proportional to the overall blood
glucose level, i.e, the more hyperglycemic patients had the
largest glucose excursion over the 24-h cycle. In their discussion of
their findings, the authors reviewed previous studies (112, 113, 114, 115, 116) and
remarked that "the diurnal cycle does not appear to be related to
food or activity" (117). These pioneering studies, which were limited
by the techniques available at the time (i.e., infrequent
blood sampling and lack of estimation of the components of glucose
tolerance), were generally supportive of the existence of an elevation
of blood glucose levels around dawn.
1. The dawn phenomenon.
Using a closed-loop
(feedback-controlled) intravenous insulin infusion (i.e.,
the Biostator), one study has described the existence of a clear-cut
dawn phenomenon in both non-insulin-treated and insulin-treated NIDDM
patients (118). The magnitude of the early morning increase in insulin
requirements was similar to that observed in patients with
insulin-dependent diabetes (Table 1). For
instance, intravenous insulin requirements were shown to increase at
least 100% between 0600 and 0900 h in about 75% of patients with
NIDDM (118). However, the prevalence and the magnitude of the dawn
phenomenon may have been overestimated because of a technical
limitation of the Biostator, which, after extended utilization
(e.g., 10–12 h), causes insulin aggregation and degradation
(46). In a study (119) where albumin was added into the insulin
solution to prevent the waning of the biological activity of infused
insulin over time (120), insulin requirements were found to increase by
approximately 40% after 0600 h in NIDDM patients usually treated
by diet or oral drugs, and the magnitude of this increase was found to
be quite reproducible (119). Thus, it appears that the initial
description of the dawn phenomenon in NIDDM exaggerated the magnitude
of the morning elevation in insulin requirements.
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),
including a total of more than 100 patients, have examined overnight
changes in glucose levels in NIDDM (31, 94, 102, 121, 122, 123, 124, 125, 126). These
studies have differed in terms of subject population (degree of
obesity, age, severity and duration of diabetes, type of treatment) as
well as in terms of duration of the fast preceding the overnight period
of study. Indeed, in some studies, the last meal was a dinner on the
day preceding the study (i.e., 30 h of fast before
midnight; 102 , whereas in others an evening snack was given on
the day of the study (i.e., 3–4 h before midnight; Refs. 31
and 126). None of the studies included polygraphic sleep recordings so
that the role of sleep quality in modulating overnight glucose
regulation could not be evaluated.
A significant elevation in plasma glucose levels between the
middle of the night (i.e., 0300–0400 h) and the morning
(i.e., 0800 h) was observed in four of the nine studies
(102, 121, 122, 126). Some of the largest elevations (illustrated in
Fig. 6) were observed in the study in
which the patients underwent a 30-h period of total fast and the
overnight study period corresponded to the last 12 h of the fast
(102). Despite continued fasting, plasma glucose levels stopped
declining in the evening and subsequently rose throughout the night to
reach a morning maximum (+ 24% above the evening nadir). Elevated
plasma glucose levels persisted until approximately noon. In another
study in which the subjects were fasted for 6 h before midnight
(121), a significant, although modest, overnight plasma glucose rise (+
1.4 mmol/liter from 0300 to 0800 h) was observed, and the
magnitude of this dawn phenomenon was greater in diabetic patients
treated by diet and oral hypoglycemic agents, who had also the worst
metabolic control as assessed by their HbA1c level, than in
patients treated by diet alone who showed the best overall glycemic
control (121). In another study, where blood samples were drawn at
30-min intervals between 2100 and 0800 h, a marked dawn
increase in plasma glucose levels (+ 2.2 mmol/liter between 0400 and
0800 h, P < 0.05) was observed in poorly
controlled NIDDM patients (126). The last meal was given at 1600
h, i.e., 8 h before midnight, but a snack was ingested
at 2000 h. Interestingly, in this study, the dawn phenomenon
disappeared completely after 3 weeks of insulin therapy, which improved
the overall glycemic control and decreased fasting plasma glucose
levels by half. Finally, our group has obtained some evidence
suggesting that the occurrence of an early morning increase in plasma
glucose levels in patients with NIDDM may be partially dependent on the
size and timing of the last meal on the previous day (122). The
profiles of plasma glucose resulting from different types of temporal
distribution of daily caloric intake were compared in the same group of
patients, and a dawn phenomenon was only consistently observed when the
last meal was ingested early in the evening and included no more than
30% of the total daily caloric requirements. As further discussed
below, this observation is consistent with the concept that the dawn
phenomenon in NIDDM patients during a normal overnight fast partially
reflects counterregulatory mechanisms activated by the fasting
condition. In several other studies in which 30-min interval sampling
was performed over a 24-h period, no significant overnight rises in
plasma glucose and insulin concentrations were observed in various
populations of NIDDM patients: modestly overweight patients with mild
or severe NIDDM (94, 125), both lean and obese patients with severe
hyperglycemia (31), and obese, poorly controlled, patients (124).
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). Such abnormal patterns reflect the well
known decreased B cell responsiveness to glucose of NIDDM patients.
This reduced responsiveness could contribute to the greater nocturnal
glucose rise seen in diabetic patients as compared to nondiabetic
control subjects (102). In NIDDM patients showing a nocturnal glucose
elevation after a prolonged fast (102), no increase in insulin
clearance across the night could be detected, ruling out a contribution
of increased clearance of the hormone in causing the nocturnal
elevation observed in these patients. In two other studies (31, 124),
changes in plasma insulin levels were confirmed by parallel changes in
plasma C peptide levels, consistent with a lack of overnight changes in
insulin clearance.
b. Counterregulatory hormones.
Unfortunately, in the studies
performed on patients with NIDDM under the usual conditions of
overnight fast after a normal daytime meal schedule (31, 94, 123, 124, 125),
the circulating levels of counterregulatory hormones were not measured.
The only exception is a study where plasma GH levels were measured at
hourly intervals in subjects studied before and after insulin therapy
(126). A dawn phenomenon was observed before, but not after, treatment,
but there were no detectable changes in the overnight GH profiles
between the two conditions. When GH and cortisol profiles were measured
in NIDDM patients and nondiabetic control subjects studied after a
prolonged fast (Fig. 6), cortisol concentrations were found to be
higher in diabetic subjects throughout the study period, but
particularly so during the evening and nighttime periods (102). In both
groups of subjects, the nocturnal glucose elevation was temporarily and
quantitatively correlated with the magnitude of the early morning
cortisol rise. The secretion of GH was increased in the evening and
nighttime periods compared with the daytime values, and in NIDDM
patients, but not in control subjects, the size of the nocturnal
glucose elevation was directly related to the magnitude of the increase
in GH secretion (r = 0.88, P < 0.01).
Glucagon concentrations were similar in both groups of subjects and
remained essentially constant throughout the study period. Thus, the
higher nocturnal glucose elevation in fasting NIDDM patients as
compared with control subjects appears to be caused by increased
evening and nighttime cortisol secretion associated with a simultaneous
increase in GH release and a defective response of insulin secretion
(102). Overall, in both nondiabetic and diabetic subjects, the
overnight pattern of glucose changes after a day of total fast appears
to partially reflect counterregulatory activation of cortisol and GH by
the prolonged fasting condition.
c. Glucose production vs. glucose utilization.
Few studies
have measured glucose fluxes during an overnight fast in NIDDM
patients. In one study performed in severely hyperglycemic diabetic
patients who took their last evening meal at 1800 h, both
Ra and Rd decreased progressively from
2200–0900 h, and no dawn phenomenon was detected (94). In another
study where a clear-cut dawn phenomenon was evidenced in moderately
hyperglycemic NIDDM patients, the late night increase in plasma glucose
levels appeared due to accelerated hepatic glucose production,
primarily via enhanced gluconeogenesis from lactate (126). Furthermore,
in these subjects, suppression of the dawn phenomenon after 3 weeks of
insulin therapy resulted from inhibition of Ra, achieved by
a decrease in the proportion of lactate diverted toward
gluconeogenesis. In addition, plasma FFA concentrations showed a robust
increase at dawn, and both overall nocturnal FFA concentrations and
dawn FFA rise were markedly decreased after 3-week insulin therapy
(126).
In a recent study involving the maintenance of a hyperglycemic clamp for 72 h in NIDDM patients, a marked and reproducible diurnal variation in the rate of infusion of exogenous glucose needed to maintain stable glucose levels was demonstrated (111). The rate of glucose infusion dropped by more than half from late afternoon to approximately the middle of the night (i.e., 0300–0400 h), and isotopic measurements indicated that this variation reflected a pronounced increase in glucose production across the evening and first half of the usual sleep period. During the second half of the night and throughout the morning, glucose production appeared to decrease, as the rate of glucose infusion needed to maintain stable blood glucose levels more than doubled. This diurnal pattern was interpreted as reflecting changes in insulin sensitivity (111). In addition, during nighttime sleep, it is possible that the reduction in cerebral glucose utilization that normally occurs during sleep in nondiabetic subjects (68, 69, 70, 71, 72), may have contributed to the observed decrease in glucose infusion rate.
C. Significance and clinical implications
From the numerous and often contradictory studies on daytime and
nighttime variations in glucose regulation in NIDDM, it is possible to
conclude that at least two types of alterations characterize the
diabetic, as compared with the nondiabetic, state. First, glucose
tolerance increases from morning to evening, partially because of
improved insulin sensitivity. This is in sharp contrast to the normal
situation, where glucose tolerance and insulin sensitivity are maximal
in the morning, rather than the evening. Studies examining the effect
of time of day on meal tolerance in diabetic subjects are thus needed
to derive guidelines regarding optimal composition of breakfast, lunch,
and dinner in NIDDM patients. Second, an elevation of glucose levels at
the end of an overnight fast, i.e., a so-called dawn
phenomenon, may be observed in some NIDDM patients. The existence of a
dawn phenomenon seems to be more frequent in patients who are severely
hyperglycemic and to be facilitated by an extended duration of fast
before bedtime. Causal mechanisms underlying these alterations in the
chronobiology of glucose regulation in NIDDM remain to be identified.
Limited evidence (58, 102, 111) suggests that abnormalities in the
interactions between the rhythmicity of cortisol levels, insulin
secretion, and insulin sensitivity could be involved.
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VI. Alterations of 24-h Rhythmicity of Glucose Regulation in Insulin-Dependent Diabetes Mellitus (IDDM) |
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B. Alterations in nighttime variations in glucose tolerance
Several studies have shown that the rate of subcutaneous (134, 135) or intravenous (136, 137) insulin infusion necessary to maintain
overnight plasma glucose concentration in the normal range in IDDM
patients increases during the second part of the night. If the greater
insulin requirements in the early morning hours are not met,
hyperglycemia develops. Such phenomenon may correspond to the so-called
"dawn phenomenon." However, in IDDM patients, and in contrast to
other populations examined in the preceding sections of this review,
morning hyperglycemia may have several other causes (138). Strictly
speaking, the term "dawn phenomenon" in IDDM should be limited to
indicate specifically the increase in insulin requirements (or
development of hyperglycemia if the greater need for insulin is not
met) in the later part of the night in the absence of declining insulin
delivery (due to waning of evening injected insulin), as well as in the
absence of early nocturnal hypoglycemia (leading to reactive
posthypoglycemic late hyperglycemia known as the Somogyi effect) (139, 140). Because in most insulin-treated diabetic patients, plasma insulin
concentrations usually fall overnight (135), the contribution of
relative insulin deficiency and that of the dawn phenomenon cannot be
separated. Consequently, the contribution of the dawn phenomenon to
fasting hyperglycemia cannot be quantified merely on clinical grounds,
but requires an experimental assessment.
1. The dawn phenomenon
a. During intravenous insulin infusion.
There are two general
methods of documenting the dawn phenomenon in insulin-requiring
diabetic patients: to infuse insulin at a constant rate and measure the
rise of glucose concentrations or to clamp blood glucose at a constant
level and measure the infusion rate of insulin necessary to maintain
it. Table 2 summarizes the studies of the
dawn phenomenon that have used these methods. Unfortunately, most of
these studies were performed using the so-called artificial pancreas
(Biostator) (118, 136, 141, 142, 143, 144, 145), and it was subsequently shown that
the delivery of biologically active insulin by this device may wane
over a period of time because of aggregation of insulin in the plastic
tube and/or heat inactivation of insulin by the peristaltic pump (46).
This artifact may have contributed to overestimate the magnitude of the
dawn phenomenon in IDDM patients. When insulin was infused overnight
using a Harvard syringe pump (137, 146, 147, 148, 149), which does not inactivate
the insulin contained in the solution, or albumin was added to the
solution to prevent the reduction in biologically active insulin, the
magnitude of the late nocturnal increase in insulin requirements was
generally 20–40%, which is considerably lower than that reported by
earlier studies using the Biostator (50–100%). These estimates are
necessarily approximate because, as indicated in the summary given in
Table 2, markedly different periods were used for comparison of early
night (ranging from 2300–0600 h) and early morning (ranging from
0500–0900 h) in various studies, and different procedures were used to
express the results (either at a given time-point or as an average over
several hours). None of the studies of the dawn phenomenon in IDDM
included sleep recordings, so that the impact of sleep duration and
quality could not be estimated.
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), although a marked dawn rise in blood glucose is rare when a
single but adequate basal infusion rate is used (152, 153). Figure 7 shows hourly measurements of blood
glucose, plasma-free insulin, glucagon, GH, and cortisol from
2200–0700 h in 10 IDDM patients treated by continuous subcutaneous
insulin infusion and demonstrates a lack of dawn phenomenon under these
conditions. Furthermore, when an early morning glucose elevation is
present, it may be obviated by a carefully determined step-up in
nocturnal basal insulin infusion rate (134, 135). Nevertheless, under
usual clinical conditions, unless insulin is given at variable rates
overnight, some degree of modest presleep and preawakening
hyperglycemia must usually be tolerated to avoid nocturnal hypoglycemia
(140).
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2. Causal mechanisms underlying the dawn phenomenon
a. Insulin availability, clearance, and action.
The
progressive rise of plasma glucose levels from the early to the later
part of the night may result from defective insulinization or increased
insulin resistance. In patients with type 1 diabetes mellitus, the role
of endogenous insulin may be considered as negligible, and insulin
availability depends only on exogenous insulin administration. As
already discussed, insulin availability may decrease during the second
part of the night because of waning of insulin injected subcutaneously
the evening before or, when a peristaltic pump is used, because of the
degradation of the infused insulin. In several studies, the insulin
clearance has been reported to increase in the early morning hours, and
it has been suggested that this may be the primary mechanism of the
dawn phenomenon in type 1 diabetes (154, 155). However, as discussed by
several authors (139, 140), the finding was probably more apparent than
real as it probably reflected insulin degradation by the Biostator and
may also have been confounded by difficulties in measuring plasma-free
insulin concentrations in diabetic patients with insulin antibodies
(154, 155). At least four studies carried out under appropriate
experimental conditions have concluded that the clearance of plasma
insulin does not change appreciably overnight in patients with type 1
diabetes (146, 147, 156, 157). However, a few more recent studies,
which also avoided artifacts in insulin delivery and plasma-free
insulin measurements, did demonstrate an increased MCR of insulin
during the dawn period (158, 159) and, in addition, suggested that this
effect may be at least partially related to pulsatile GH secretion
during the early part of the night. Thus, the presence or absence of
altered insulin clearance and its possible relationship to GH secretion
remains controversial. In any case, most authors now agree that the
predominant cause of the dawn phenomenon is reduced insulin
sensitivity, which may result in increased glucose production and/or
impaired glucose utilization during the later part of the night (149, 157).
b. Glucose production vs. glucose utilization.
In IDDM
patients, well documented studies have shown that insulin resistance in
the early morning period results in fasting hyperglycemia primarily
because of a failure to adequately inhibit glucose production from the
liver (160, 161). Increased hepatic glucose production starts around
the middle of the night (0300 h) and can be prevented by increasing the
insulin delivery rate, as has been shown, for example, in diabetic
patients treated with continuous subcutaneus insulin infusion (135).
Despite the presence of hyperglycemia, glucose utilization does not
begin to increase until the early morning (0600–0700 h), and the
increase is not commensurate with the accelerated rate of production
(which averages 65%), suggesting the presence of insulin resistance in
peripheral (mainly muscular) tissues in addition to that observed in
the liver (160). It is thus the mismatch (both in timing and in size)
between the increase in glucose production and the increase in glucose
utilization that is responsible for the morning hyperglycemia. Blackard
et al. (162) have noted that the increase of glucose
production may reflect the normal effect of arousal from sleep, a state
associated with a marked decrease in glucose production (29), and
suggested that the dawn phenomenon be renamed "sleep phenomenon."
Since none of these studies has included sleep recordings, the role for
sleep-wake transitions in the pathogenesis of the dawn phenomenon
remains to be elucidated.
In three studies in which insulin sensitivity has been examined in subjects with type 1 diabetes mellitus by means of the classic euglycemic hyperinsulinemic clamp technique, no difference in insulin action between the early part of the night and the early morning hours has been found (154, 155, 156). However, in another study (157), insulin-mediated glucose disposal during a glucose clamp was found to be impaired at dawn as compared with the beginning of the night, both at low and high levels of plasma-free insulin, suggesting that decreased insulin sensitivity at that time of the day affects all insulin-dependent tissues, rather than only the liver. However, because of the dose-response curve of the effects of insulin on production and utilization of glucose (163), glucose overproduction may play the predominant role during the later part of the night when insulin levels are relatively low, whereas impaired glucose uptake may play a more important role soon after breakfast when plasma insulin levels become higher (140).
c. Roles of hormonal rhythmicity.
The obvious parallelism
between the elevation of plasma cortisol during the second part of the
night and the dawn phenomenon originally suggested that cortisol may
play a major role in the early morning hyperglycemia (136). However,
the fact that the two phenomena occur essentially simultaneously does
not support the hypothesis that the early morning cortisol elevation is
responsible for the increase in insulin resistance (58, 78).
Furthermore, suppression of cortisol secretion using metyrapone (164)
or dexamethasone (141) does not significantly reduce dawn insulin
requirements of type 1 diabetic patients. Plasma glucagon levels do not
change overnight in IDDM individuals (137, 143, 153, 160), and plasma
catecholamines show only a very modest rise at dawn (51, 132, 141, 143, 160). Pharmacological blockade of both 
- and ß-adrenergic
receptors does not prevent the late night increase in insulin
requirement (160). Thus, the counterregulatory effects of cortisol,
glucagon, and epinephrine do not seem to play a significant role in the
dawn phenomenon of IDDM patients.
In contrast, consistent evidence indicates that early nocturnal GH surges are implicated in the development of the dawn phenomenon in type 1 diabetes mellitus. First, the integrated responses to nocturnal GH secretion correlate with insulin requirements and/or hyperglycemia at dawn in most (137, 148, 157, 160) but not all, studies (161). Second, suppression of nocturnal GH secretion by anticholinergc agents (121, 148, 165, 166) or somatostatin (157, 160, 167, 168) results in a virtual disappearance of the dawn phenomenon. Third, GH-deficient patients with type 1 diabetes do not exhibit a dawn phenomenon (169). Finally, when nocturnal surges in GH secretion are simulated by intravenous injection of GH in IDDM subjects in whom endogenous GH secretion has been suppressed by somatostatin, plasma glucose levels and glucose production increase and glucose clearance decreases to values observed in control experiments (160).
The precise mechanism by which GH contributes to the dawn phenomenon remains unclear. In addition to possible direct effects of GH on glucose metabolism (170) or on insulin clearance (169), one other explanation might be that GH appears to be a key factor regulating lipolysis during the night in patients with IDDM (170) and that elevating FFA levels may compete for glucose utilization and stimulate gluconeogenesis. However, even if such process has been documented, its precise contribution to the dawn phenomenon remains controversial (169). The role of GH in the pathogenesis of the dawn phenomenon in IDDM provides an explanation for several clinical features of this condition. Nocturnal surges in plasma GH levels are higher in such patients with suboptimal control (171, 172) and correlate with the overnight glucose increase (143). On the other hand, normalizing plasma GH levels by optimization of glycemic control may explain the attenuation of early morning hyperglycemia in diabetic patient receiving intensive insulin therapy (149).
C. Significance and clinical implications
Intrinsic daytime variations in glucose tolerance are probably of
minor importance in IDDM patients when compared with the role played by
other factors: regimen of insulin therapy (type of insulin, dosage,
timing of injection, variability of subcutaneous absorption, etc.),
diet habits (meal sizes, composition, and timing), and physical
activity (intensity, duration, and timing). In contrast, although the
magnitude of the dawn phenomenon and its underlying mechanisms are
still controversial, nighttime variations in glucose tolerance have
been well demonstrated in IDDM subjects and may be of clinical
importance.
The discrete nature of insulin administration exposes the IDDM patient to an increased risk of hypoglycemia in the early to middle part of the night. In the later part of the night and in the morning, hyperglycemia frequently occurs. These problems may be avoided by the use of a basal-bolus insulin regimen (delaying the injection of evening intermediate insulin from supper to bedtime) instead of the classic twice-daily injection schedule. However, the time course of action of the most frequently used intermediate insulin preparations may be unsatisfactory to ensure the adequacy of basal insulin delivery, as such preparations are usually too potent during the first 4–8 h but not sufficiently active 10–14 h after subcutaneous injection. Pharmaceutical companies manufacturing insulin are currently investigating new preparations of long acting insulin with a flatter and more reproducible time course of activity. In some cases, nocturnal insulinization may be optimized by the use of a continuous subcutaneous insulin infusion via a portable pump where the delivery rate can be precisely adjusted to the nighttime variations of glucose tolerance of the individual patient.
Finally, glycemic control may be disturbed in diabetic patients who undergo jet lag or shift work rotations. In daily practice, such conditions require a careful adjustment of insulin therapy with the type, dose/ and/or timing of insulin administration being modified according to the new sleep-wake and meal schedules. This adjustment usually necessitates an increased frequency of ambulatory blood glucose monitoring to minimize the risks of hypo- and hyperglycemic episodes.
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VII. Conclusions |
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Major alterations of glucose tolerance occur during sleep, and sleep quality markedly influences nocturnal brain and tissue glucose utilization. The sleep state occupies approximately one third of the day throughout the adult lifetime. Therefore, chronic sleep disturbances, such as those occurring in elderly adults, in night workers, and in subjects with sleep apnea, may be associated with disturbances of glucose regulation. The demonstration of a robust sleep-induced decrease in glucose tolerance also strongly argues for the need to carefully monitor the maintenance of wakefulness in subjects undergoing metabolic testing, whether for research or diagnostic purposes. It is a common occurrence that subjects doze off during oral or intravenous glucose tolerance tests in the morning after an overnight fast. It is likely that falling asleep during such tests will markedly affect their results and increase the risk of false-positive diagnoses of impaired glucose tolerance.
Thus, the modulatory effects of sleep and circadian rhythmicity on glucose regulation appear to have important clinical implications for the diagnosis and treatment of abnormalities in carbohydrate metabolism.
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Footnotes |
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1 Supported by NIH Grants DK-41814, DK-31842, and AG-11412 and by the
MacArthur Foundation (Chicago, IL). 
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References |
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 J. Mendoza, P. Pevet, and E. Challet High-fat feeding alters the clock synchronization to light J. Physiol., December 15, 2008; 586(24): 5901 - 5910. [Abstract] [Full Text] [PDF]
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 H. Duez and B. Staels The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism Diabetes and Vascular Disease Research, June 1, 2008; 5(2): 82 - 88. [Abstract] [PDF]
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 A. C Nilsson, E. M Ostman, Y. Granfeldt, and I. M. Bjorck Effect of cereal test breakfasts differing in glycemic index and content of indigestible carbohydrates on daylong glucose tolerance in healthy subjects Am. J. Clinical Nutrition, March 1, 2008; 87(3): 645 - 654. [Abstract] [Full Text] [PDF]
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 L.-F. M. Taub and N. S. Redeker Sleep Disorders, Glucose Regulation, and Type 2 Diabetes Biol Res Nurs, January 1, 2008; 9(3): 231 - 243. [Abstract] [PDF]
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 C. Roberge, A. C. Carpentier, M.-F. Langlois, J.-P. Baillargeon, J.-L. Ardilouze, P. Maheux, and N. Gallo-Payet Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1465 - E1478. [Abstract] [Full Text] [PDF]
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 M. T. Gailliot and R. F. Baumeister The Physiology of Willpower: Linking Blood Glucose to Self-Control Personality and Social Psychology Review, November 1, 2007; 11(4): 303 - 327. [Abstract] [PDF]
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 D. J. Kennaway, J. A. Owens, A. Voultsios, M. J. Boden, and T. J. Varcoe Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1528 - R1537. [Abstract] [Full Text] [PDF]
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H. Ogata, K. Tokuyama, S. Nagasaka, A. Ando, I. Kusaka, N. Sato, A. Goto, S. Ishibashi, K. Kiyono, Z. R. Struzik, et al. Long-range negative correlation of glucose dynamics in humans and its breakdown in diabetes mellitus Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1638 - R1643. [Abstract] [Full Text] [PDF]
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 K. Spiegel, K. Knutson, R. Leproult, E. Tasali, and E. V. Cauter Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes J Appl Physiol, November 1, 2005; 99(5): 2008 - 2019. [Abstract] [Full Text] [PDF]
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 E. B. Klerman Clinical Aspects of Human Circadian Rhythms J Biol Rhythms, August 1, 2005; 20(4): 375 - 386. [Abstract] [PDF]
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 S. A. Shea, M. F. Hilton, C. Orlova, R. T. Ayers, and C. S. Mantzoros Independent Circadian and Sleep/Wake Regulation of Adipokines and Glucose in Humans J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2537 - 2544. [Abstract] [Full Text] [PDF]
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 R. G. Smith, L. Betancourt, and Y. Sun Molecular Endocrinology and Physiology of the Aging Central Nervous System Endocr. Rev., April 1, 2005; 26(2): 203 - 250. [Abstract] [Full Text] [PDF]
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 A. Kalsbeek, S. La Fleur, C. Van Heijningen, and R. M. Buijs Suprachiasmatic GABAergic Inputs to the Paraventricular Nucleus Control Plasma Glucose Concentrations in the Rat via Sympathetic Innervation of the Liver J. Neurosci., September 1, 2004; 24(35): 7604 - 7613. [Abstract] [Full Text] [PDF]
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 J. Tonelli, W. Li, P. Kishore, U. B. Pajvani, E. Kwon, C. Weaver, P. E. Scherer, and M. Hawkins Mechanisms of Early Insulin-Sensitizing Effects of Thiazolidinediones in Type 2 Diabetes Diabetes, June 1, 2004; 53(6): 1621 - 1629. [Abstract] [Full Text] [PDF]
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 M. Rewers, D. Zaccaro, R. D'Agostino, S. Haffner, M. F. Saad, J. V. Selby, R. Bergman, and P. Savage Insulin Sensitivity, Insulinemia, and Coronary Artery Disease: The Insulin Resistance Atherosclerosis Study Diabetes Care, March 1, 2004; 27(3): 781 - 787. [Abstract] [Full Text] [PDF]
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J. S. Rana, K. J. Mukamal, J. P. Morgan, J. E. Muller, and M. A. Mittleman Circadian Variation in the Onset of Myocardial Infarction: Effect of Duration of Diabetes Diabetes, June 1, 2003; 52(6): 1464 - 1468. [Abstract] [Full Text] [PDF]
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R. Leproult, E. F. Colecchia, A. M. Berardi, R. Stickgold, S. M. Kosslyn, and E. Van Cauter Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R280 - R290. [Abstract] [Full Text] [PDF]
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V. Jayagopal, E. S. Kilpatrick, P. E. Jennings, D. A. Hepburn, and S. L. Atkin Biological Variation of Homeostasis Model Assessment-Derived Insulin Resistance in Type 2 Diabetes Diabetes Care, November 1, 2002; 25(11): 2022 - 2025. [Abstract] [Full Text] [PDF]
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 R. J. Troisi, C. C. Cowie, and M. I. Harris Diurnal Variation in Fasting Plasma Glucose: Implications for Diagnosis of Diabetes in Patients Examined in the Afternoon JAMA, December 27, 2000; 284(24): 3157 - 3159. [Abstract] [Full Text] [PDF]
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K. Spiegel, R. Leproult, E. F. Colecchia, M. L'Hermite-Baleriaux, Z. Nie, G. Copinschi, and E. Van Cauter Adaptation of the 24-h growth hormone profile to a state of sleep debt Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R874 - R883. [Abstract] [Full Text] [PDF]
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C. Simon, L. Weibel, and G. Brandenberger Twenty-four-hour rhythms of plasma glucose and insulin secretion rate in regular night workers Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E413 - E420. [Abstract] [Full Text] [PDF]
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L. Plat, R. Leproult, M. L’Hermite-Baleriaux, F. Fery, J. Mockel, K. S. Polonsky, and E. Van Cauter Metabolic Effects of Short-Term Elevations of Plasma Cortisol Are More Pronounced in the Evening Than in the Morning J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3082 - 3092. [Abstract] [Full Text]
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E. Challet, O. van Reeth, and F. W. Turek Altered circadian responses to light in streptozotocin-induced diabetic mice Am J Physiol Endocrinol Metab, August 1, 1999; 277(2): E232 - E237. [Abstract] [Full Text] [PDF]
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A. J. Scheen, O. M. Buxton, M. Jison, O. Van Reeth, R. Leproult, M. L'Hermite-Baleriaux, and E. Van Cauter Effects of exercise on neuroendocrine secretions and glucose regulation at different times of day Am J Physiol Endocrinol Metab, June 1, 1998; 274(6): E1040 - E1049. [Abstract] [Full Text] [PDF]
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