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Original Studies |
Department of Medicine, University of Chicago, Chicago, Illinois 60637; and Section of Endocrinology and Laboratory of Experimental Medicine, Erasme Hospital, Universite Libre de Bruxelles, B-1070 Brussels, Belgium
Address all correspondence and requests for reprints to: Eve Van Cauter, Ph.D., Department of Medicine, MC 1027, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: evcauter{at}medicine.bsd.uchicago.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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The initial effect of the hydrocortisone-induced cortisol pulse was a short-term inhibition of insulin secretion without concomitant glucose changes and was similar in the evening and in the morning. At both times of day, starting 4–6 h after hydrocortisone ingestion, glucose levels increased and remained higher than under placebo for at least 12 h. This delayed hyperglycemic effect was minimal in the morning but much more pronounced in the evening, when it was associated with robust increases in serum insulin and insulin secretion and with a 30% decrease in insulin clearance.
Thus, elevations of evening cortisol levels could contribute to alterations in glucose tolerance, insulin sensitivity, and insulin secretion.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The possibility that the variations in cortisol concentrations that normally occur over a 24-h period could contribute to the diurnal variation in glucose tolerance had been previously discarded because glucose tolerance is best in the morning (when cortisol levels are high) and worst in the early part of the night (when cortisol levels are low) (1, 13). Thus, in subjects receiving a constant glucose infusion, there is an inverse relationship between the profiles of glucose and insulin secretion rates (ISR), on the one hand, and that of plasma cortisol levels, on the other hand (10). However, we have recently shown that the time course of the effects of an acute elevation of morning plasma cortisol on the daytime profiles of plasma glucose, serum insulin, and ISR involves both immediate and delayed effects (12). The immediate effect is an abrupt inhibition of insulin secretion without change in glucose concentration; this rapid inhibitory effect of cortisol on insulin secretion had been previously demonstrated in in vitro (14, 15, 16, 17, 18, 19) and in vivo (13, 20, 21, 22) studies. The delayed effect is the appearance of a state of relative insulin resistance, 4–6 h after the cortisol elevation. This previous study demonstrated that the nature and time course of responses, in insulin secretion and glucose levels, to short-term elevations of morning cortisol concentrations are entirely consistent with the concept that the 24-h cortisol rhythmicity is responsible, at least in part, for the normal diurnal variation in glucose tolerance (12).
The 24-h cortisol rhythm is remarkably robust and persists in a wide variety of pathological conditions. However, a subtle abnormality, consisting of a modest elevation of evening cortisol levels, is present in normal older adults (23, 24, 25) and is also found in normal young adults after sleep deprivation (26). In both conditions, it has been hypothesized that this elevation of evening cortisol levels reflects an impairment in glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal (HPA) activity. Whether this evening elevation of cortisol levels adversely affects glucose regulation during the night and the next day, and may, in the long term, contribute to age-related decreases in glucose tolerance and insulin sensitivity, remains to be tested. This hypothesis would imply that a physiological elevation of plasma cortisol in the evening, when the HPA axis is normally quiescent, has more deleterious metabolic effects than a similar elevation in the morning, when the HPA axis is maximally activated.
The aim of the present study, therefore, was to determine whether elevations of cortisol levels in the evening (at an abnormal time of day) have more pronounced effects on glucose regulation than elevations of cortisol levels in the morning (at the normal time of day).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Experimental protocol
All investigations were performed in the Clinical Research Center (CRC) of the University of Chicago. Before the beginning of the study, the subjects were required to sleep 2 nights in the CRC to become habituated to the experimental environment. Throughout the entire study, the subjects agreed to maintain regular sleep-wake and meal schedules. Each subject participated in four studies. The studies were separated by at least 14 days, and their order was randomized.
Figure 1
provides a schematic
representation of the protocol. The protocol was designed to suppress,
at least partially, the circadian elevation of endogenous plasma
cortisol levels and to restore it by oral hydrocortisone
administration, either at a normal time of day (early morning;
0500 h) or at an abnormal time of day (late afternoon; 1700
h). The effects of hydrocortisone administration were
placebo-controlled. The subjects were blind to the experimental
condition.
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In two of the four studies, 50 mg hydrocortisone (Hydrocortisone, Roussel, France) or placebo was administered at the normal time of the circadian cortisol elevation (0500 h). In the other two studies, hydrocortisone or placebo was given 12 h later, when cortisol secretion is normally decreasing, towards the evening nadir.
Assays
All samples from the same subject were analyzed in the same assay. Plasma glucose was measured by the glucose analyzer STAT 2300 (Yellow Springs Instrument Co., Yellow Springs, OH), with a coefficient of variation of less than 2%. Insulin levels were determined by RIA, with a limit of sensitivity of 18 pmol/L and an intraassay coefficient of variation averaging 5% (27). Plasma C-peptide levels were determined by RIA, with a limit of sensitivity of 20 pmol/L and an intraassay coefficient of variation averaging 6% (28). Plasma cortisol levels were measured by RIA (Coat-A-Count; Diagnostic Products, Los Angeles, CA), with a limit of detection of 27 nmol/L and an average intraassay coefficient of variation of 5%.
Sleep recording and analysis
Polygraphic sleep recordings were visually scored at 30-sec intervals in stages: wake, I, II, III, IV, and rapid eye movement (REM), using standardized criteria (29), by an experienced scorer who was blind to the study condition. Sleep onset and morning awakening were defined, respectively, as the times of occurrence of the first and last 30-sec intervals scored II, III, IV, or REM. The sleep period was defined as the time interval separating sleep onset from morning awakening. Sleep efficiency was calculated as the total recording time minus the total duration of awakenings, expressed in percent of the total recording time. SW stage was defined as the sum of stages III and IV.
Determination of ISR
In each blood sampling interval, ISR was mathematically derived from plasma C-peptide levels, using a two-compartment model for C-peptide disappearance kinetics (30). The kinetic parameters were obtained from published demographic data adjusted for sex, age, and body surface area (31). The mean (+ SEM) parameter values were 4.36 ± 0.06 L for the volume of distribution, 32.70 ± 0.18 min for the long half-life. A constant short half-life of 4.95 min and a constant fraction associated with the short half-life of 0.76 were used in these calculations.
Estimation of insulin clearance
For each study, the clearance of secreted insulin was estimated, at 4-h intervals throughout the study period, as the ratio of the area under the ISR curve and the area under the curve of simultaneously measured serum insulin concentrations, as previously described (32).
Estimation of hydrocortisone clearance
For each time of hydrocortisone administration, the clearance of hydrocortisone was estimated as the time to achieve a 50% reduction from the maximum difference in plasma cortisol levels between the hydrocortisone and placebo conditions.
Data analysis
As in our previous study of glucose, insulin, and ISR profiles after hydrocortisone administration (12), three phases of the responses were defined: 0–4 h post treatment (inhibition of insulin secretion without changes in glucose levels), 5–16 h post treatment (increased glucose levels and insulin secretion), and 17–24 h post treatment (return to baseline glucose levels). For each phase of the response, mean cortisol levels, mean ISR, mean glucose levels, and mean insulin levels were calculated. In addition, during the 0–4 h phase, maximum/minimum levels of cortisol, ISR, and insulin were identified.
To quantify the overall degree of concordance between temporal fluctuations of cortisol and ISR, the coefficients of cross-correlation between the profiles of cortisol and ISR were calculated at lag 0, ± 20 min, ± 40 min ... ± 200 min (33). For each pair of individual series, the maximal coefficient of cross-correlation was identified, along with the lag at which it occurred, to compare the overall temporal relationship between cortisol and ISR in each study condition.
At each time of hydrocortisone administration, comparisons between hydrocortisone and placebo were performed using the paired t test. The effects of morning vs. evening cortisol elevations were then compared by calculating, at each time of day, the arithmetic difference between the levels of plasma cortisol, ISR, plasma glucose, and serum insulin observed after hydrocortisone administration and the corresponding levels observed after placebo. All group results are expressed as mean ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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summarizes the characteristics of sleep during each of the scheduled
bedtime periods. Sleep quality was similar during all 6 nights of
monitoring, irrespective of the study condition, and was consistent
with normal sleep of young healthy subjects studied in the laboratory
during blood sampling.
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Figure 2 depicts the mean cortisol
profiles observed under metyrapone suppression with hydrocortisone or
placebo in the early morning (left panel) or late afternoon
(right panel), compared with mean cortisol profiles obtained
in our laboratory in a separate study performed under the same
experimental conditions in a similar group of eight young healthy men
but in the absence of pharmacological treatment. Metyrapone treatment
resulted in a marked suppression of the morning elevation of cortisol
levels; but afternoon, evening, and nighttime levels did not differ
significantly from those observed in untreated subjects. Hydrocortisone
administration at 0500 h to metyrapone-treated subjects
(left panel) resulted in an elevation of cortisol levels
that was 30–40% higher than that occurring in untreated subjects at
the same time of day, i.e. within the physiologic range.
Peak levels of plasma cortisol, post hydrocortisone, were similar in
the morning and in the evening.
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Effects of cortisol elevation at normal time of day (0500 h)
Figure 3 compares the effects of
hydrocortisone vs. placebo, at 0500 h, on the profiles
of plasma cortisol, ISR, serum insulin, and plasma glucose. Visual
examination suggests the existence of an inverse relationship between
the cortisol profile and the ISR profile, under both conditions. This
visual impression was confirmed by cross-correlation analysis. In the
placebo condition, the coefficient of cross-correlation between
cortisol and ISR was maximal for ISR changes, lagging cortisol changes
by 23 ± 19 min, and averaged -0.58 ± 0.04
(P < 0.01). In the hydrocortisone condition, the
coefficient of cross-correlation was maximal for ISR, lagging cortisol
by 57 ± 11 min, and averaged -0.40 ± 0.05
(P < 0.01). These results suggest that short-term
changes in insulin secretion may reflect inhibitory effects of
circulating cortisol concentrations.
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summarizes the quantitative
analysis of posttreatment changes in glucose, cortisol, ISR, and
insulin for the placebo and hydrocortisone conditions. During the first
phase of the response (0–4 h), the elevation of plasma cortisol
associated with hydrocortisone ingestion was followed by a short-term
inhibition of insulin secretion without significant glucose changes.
Serum insulin levels tended to be lower under hydrocortisone than under
placebo, but the difference failed to reach statistical
significance.
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During the last 8 h of the study (third phase of response), glucose levels continued to be slightly higher in the hydrocortisone than in the placebo condition despite similar levels of insulin secretion and serum insulin.
The lower panels of Fig. 3
illustrate the mean values of
insulin clearance at 4-h intervals across the study period for both
conditions. Consistent with our previous observations, a trend for
higher clearance rates in the evening or early part of the night was
apparent for both study conditions but reached significance for the
hydrocortisone study only (P < 0.01). There were no
significant differences between the hydrocortisone and the placebo
condition at any time of day.
Effects of cortisol elevation at abnormal time of day (1700 h)
Figure 4 compares the effects of
hydrocortisone vs. placebo, at 1700 h, on the profiles
of plasma cortisol, ISR, serum insulin, and plasma glucose. An inverse
relationship between the cortisol profile and the profiles of ISR was
again apparent under both conditions. In the placebo condition, the
coefficient of cross-correlation between cortisol and ISR was maximal
for ISR changes, lagging cortisol changes by 74 ± 26 min, and
averaged -0.58 ± 0.04 (P < 0.01). In the
hydrocortisone condition, the coefficient of cross-correlation was
maximal for nearly simultaneous ISR and cortisol values (12 ± 19
min) and averaged -0.56 ± 0.03 (P < 0.01).
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summarizes the quantitative
analysis of posttreatment changes in glucose, cortisol, ISR, and
insulin for the two study conditions. The same three phases of the
response as in the study with the cortisol elevation at the normal time
of day could clearly be identified. During the first 4 h
(1700–2100 h), hydrocortisone administration was associated with a
significant inhibition of insulin secretion without change in glucose
levels. During the following 12 h (2100–0900 h), the normal
nocturnal elevation of glucose levels was markedly higher under
hydrocortisone than under placebo and was associated with significantly
higher rates of insulin secretion and levels of serum insulin. During
the final 17–24 h, differences in glucose levels were no longer
significant, but insulin secretion and serum insulin levels remained
higher in the hydrocortisone than in the placebo condition.
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illustrate the mean values of
insulin clearance, at 4-h intervals, across the study period for both
conditions. In the placebo condition, a significant diurnal variation
was detected, with maximal clearance rates in the early part of the
night (2100–0100 h; P < 0.001). Hydrocortisone
treatment resulted in a marked inhibition of insulin clearance, which
was maintained for the first 12 h post treatment and obliterated
the diurnal variation. Impact of timing of treatment on differences between hydrocortisone and placebo conditions
Figure 5 shows the mean differences
in plasma cortisol, ISR, serum insulin, plasma glucose, and insulin
clearance between the hydrocortisone and placebo conditions when the
cortisol elevation occurred in the early morning, i.e. at
the normal time of day (left panels), or in the early
evening, i.e. 12 h out of phase (right
panels). For plasma cortisol (top panels), the
difference between the hydrocortisone and placebo profiles represents
the net effect of hydrocortisone, isolated from concomitant variations
in endogenous cortisol secretion. Although peak levels of plasma
cortisol were essentially identical at both times of day, the impact of
hydrocortisone treatment on glucose levels, insulin secretion, serum
insulin, and insulin clearance during the next 24 h was minimal in
the morning but clearly evident in the evening.
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The largest effects of time of day were observed during the second
phase of the response (4–16 h post treatment). The clearance of
hydrocortisone (estimated as the time to achieve a 50% reduction from
the maximum difference in plasma cortisol levels between the
hydrocortisone and placebo conditions) was approximately 50% slower in
the evening than in the morning (156 ± 15 min vs.
109 ± 13 min, P < 0.003). The posttreatment
elevation of glucose levels, after the initial inhibition of insulin
secretion, was more than 2-fold higher in the evening than in the
morning (mean delta glucose was 0.68 ± 0.14 mmol/L in the evening
vs. 0.33 ± 0.09 mmol/L in the morning,
P < 0.005). Similarly, posthydrocortisone increases in
ISR and serum insulin were also larger in the evening than in the
morning (P < 0.01 and P = 0.06,
respectively). Hydrocortisone treatment had no significant impact on
insulin clearance in the morning, but it resulted in a significant
decrease in insulin clearance in the evening (lower panels
of Fig. 5; P < 0.05).
During the third phase of the study (16–24 h post treatment), the increases in glucose levels, insulin secretion, and serum insulin after hydrocortisone treatment remained significantly higher in the evening than in the morning (P < 0.04, P < 0.05, and P < 0.02, respectively). In the evening, but not in the morning, insulin clearance was still lower under hydrocortisone treatment than under placebo.
Correlations between parameters of cortisol elevations
Irrespective of time of day, there were no correlations between the maximum increase in cortisol levels after hydrocortisone administration and the subsequent levels of glucose, ISR, or serum insulin. Similarly, there were no correlations between the apparent clearance of hydrocortisone and the subsequent levels of glucose, ISR, or serum insulin.
In the evening, but not in the morning, the decrease in insulin clearance during the first 8 h (1700–0100 h) post hydrocortisone was negatively correlated with the apparent clearance of hydrocortisone (r = -0.77, P < 0.03). Thus, in the evening, the subjects with the longest plasma cortisol responses to hydrocortisone had also the largest decreases in insulin clearance.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As in our previous study (12), and consistent with a number of in
vitro and in vivo studies (13, 14, 15, 16, 17, 18, 19, 20, 21, 22), the initial effect
of the cortisol elevation was a short-term inhibition of insulin
secretion without concomitant changes in glucose levels. This first
phase of the response was similar in the evening and in the morning. At
both times of day, starting 4–6 h after hydrocortisone ingestion,
glucose levels increased and remained higher than under placebo for at
least 12 h. This delayed hyperglycemic effect of cortisol was
minimal in the morning but much more pronounced in the evening, when
glucose levels were nearly 20% higher under hydrocortisone treatment
than under placebo (Fig. 5). Furthermore, in the evening, but not in
the morning, the glucose elevation observed after hydrocortisone
treatment was associated with robust increases in serum insulin and
insulin secretion (reflecting a state of insulin resistance) and with a
decrease in insulin clearance that reached as much as 30%. This
combination of insulin resistance and reduced insulin clearance is
similar to that described in chronic situations of insulin resistance,
such as obesity (34, 35, 36), aging (37), essential hypertension (38, 39, 40),
and Cushing’s syndromes (41).
The mechanisms underlying the morning vs. evening differences in magnitude of metabolic effects of hydrocortisone observed in the present study remain to be elucidated. It is possible that the differences detected 5–20 h post hydrocortisone are related to the more prolonged exposure to elevated cortisol levels in the evening than in the morning. Indeed, peak cortisol concentrations were similar at both times of day, but the clearance of cortisol was approximately 50% longer in the evening than in the morning, consistent with an early report by Lacerda et al. (42). Thus, plasma cortisol concentrations during the second and third hour post hydrocortisone were 100–200 nmol/L higher in the evening than in the morning. This morning-to-evening variation in cortisol clearance could involve a diurnal variation in liver enzyme activities (43).
The more deleterious metabolic impact of evening vs. morning hydrocortisone treatment could also involve differences in glucocorticoid receptor regulation. Indeed, in the morning, hydrocortisone administration occurred almost 24 h after the previous circadian peak and coincided with low endogenous cortisol concentrations that presumably were associated with partial occupancy of the high-affinity mineralocorticoid receptors and minimal occupancy of low-affinity glucocorticoid receptors in peripheral tissues (44, 45). The effect of morning hydrocortisone thus probably resulted in the saturation of mineralocorticoid receptors and partial occupancy of glucocorticoid receptors. In contrast, evening hydrocortisone administration coincided with higher endogenous cortisol concentrations and occurred less than 12 h after the previous circadian peak. The effects of evening hydrocortisone thus probably involved only increased glucocorticoid receptor activity, because mineralocorticoid receptors were likely to be already saturated. The larger metabolic effect observed in the evening is consistent with this greater involvement of peripheral glucocorticoid receptors.
The extended exposure to cortisol after hydrocortisone administration in the evening resulted in a constellation of metabolic effects likely to involve multiple actions of corticosteroids on a variety of sites. The delayed hyperglycemic effects of prolonged glucocorticoid exposure probably reflect a stimulation of hepatic glucose output (45) and a decrease in glucose use by peripheral tissues, primarily skeletal muscles. The latter effect involves the well-known stimulation of lipolysis by glucocorticoids (45), resulting in increasing concentrations of free fatty acids, which, via a mechanism of substrate competition, leads to a reduced muscle glucose uptake. The increase in free fatty acids in the portal circulation may also have contributed to the reduction in insulin clearance, as observed in animal studies (46). Finally, because glucose tolerance is normally decreased in the evening, as compared with the morning (11), prolonged exposure to elevated cortisol levels after evening hydrocortisone may have had synergetic effects on some of the mechanisms underlying the nocturnal deterioration in glucose tolerance.
The present findings suggest that alterations in the 24-h profile of plasma cortisol, which result in an elevation of evening nadir concentrations, could be associated with disturbances of glucose regulation. The 24-h cortisol rhythm is remarkably robust and persists in a wide variety of pathological conditions (47). However, a subtle abnormality, consisting of a 50–150 nmol/L elevation of evening cortisol levels, is present in normal older adults and may also be found in normal young subjects after sleep loss or during a prolonged fast (23, 24, 25, 26, 48). In both conditions, it has been hypothesized that this elevation of evening cortisol levels reflects an impairment in glucocorticoid feedback inhibition of HPA activity. The failure to adequately suppress evening cortisol concentrations, resulting in prolonged exposure, could be associated with decreases in glucose tolerance, insulin sensitivity, and insulin clearance similar to those observed in the present study, although of lesser magnitude. The hormonal and metabolic profiles observed in the present study after late-afternoon hydrocortisone administration also bear a number of similarities with the condition of so-called hypothalamic arousal, documented by Rosmond et al. (49), where flattened cortisol 24-h profiles and lower dexamethasone suppressibility were correlated with increased insulin resistance.
In conclusion, alterations in glucose regulation, which occur in normal aging and in a variety of physiopathological conditions, could be directly related to elevations of evening cortisol levels, because qualitatively similar metabolic alterations can be obtained in healthy young adults by an increase in cortisol concentrations induced experimentally during the usual period of quiescence of the HPA axis.
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Acknowledgments |
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Footnotes |
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Received March 10, 1999.
Revised June 1, 1999.
Accepted June 3, 1999.
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References |
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