E. Van Cauter

Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.

The pattern of endogenous insulin secretion over a 24-h period, which included three mixed meals, was evaluated in 14 normal volunteers and 15 obese subjects. Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6 +/- 1.2 vs. 5.4 +/- 0.5 nmol/h) and in the 4 h after breakfast (139 +/- 15 vs. 63 +/- 5 nmol/4 h, P less than 0.001), lunch (152 +/- 16 vs. 67 +/- 5 nmol/4 h, P less than 0.001), and dinner (145 +/- 18 vs. 65 +/- 6 nmol/4 h, P less than 0.001). In the normal subjects, basal insulin secretion represented 50 +/- 2.1% of total 24-h insulin production, insulin secretion returned to baseline between meals, and equal quantities of insulin were secreted in the 4 h after breakfast, lunch, and dinner, despite the fact that subjects consumed half the number of calories at breakfast compared to lunch and dinner. Overall glucose responses were also similar after the three meals. In contrast, the pattern of insulin secretion in obese subjects was largely normal, albeit set at a higher level. However, the insulin secretion rate after meals did not return to baseline, and the secretion rate immediately before lunch (350.5 +/- 81.9 pmol/min) and dinner (373.6 +/- 64.8 pmol/min) was considerably higher than the secretion rate immediately before breakfast (175.5 +/- 18.5 pmol/min). In these overweight subjects, the glucose response after lunch was lower than after dinner. Analysis of individual 24-h insulin secretory profiles in the normal subjects revealed that insulin secretion was pulsatile. On average 11.1 +/- 0.5 pulses were produced in each 24-h period. The most prevalent temporal distribution of postmeal secretory pulses was two pulses after breakfast and three pulses after both lunch and dinner. Insulin secretion was also pulsatile during the period without meal stimuli: 3.9 +/- 0.3 pulses occurred during the period of overnight sampling and in the 3-h period before ingestion of the breakfast meal. In the obese subjects, the number and timing of secretory pulses was similar to those of normal volunteers, although the amplitude of the pulses was significantly greater. In both groups of subjects, greater than 80% of insulin pulses were concomitant with a pulse in glucose concentration in the postmeal period. The concomitancy rate was significantly lower in the interval without the meal stimuli, averaging 47% in both groups. Thus in obesity, although hypersecretion of insulin can be documented, the temporal pattern of secretion i s largely unaltered, which suggests that the functioning beta cell mass is enhance, but normal regulatory mechanisms influencing secretion are still operative.

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.

Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men.

The aim of this study was to investigate, in normal young men, whether gamma-hydroxybutyrate (GHB), a reliable stimulant of slow-wave (SW) sleep in normal subjects, would simultaneously enhance sleep related growth hormone (GH) secretion. Eight healthy young men participated each in four experiments involving bedtime oral administration of placebo, 2.5, 3.0, and 3.5 g of GHB. Polygraphic sleep recordings were performed every night, and blood samples were obtained at 15-min intervals from 2000 to 0800. GHB effects were mainly observed during the first 2 h after sleep onset. There was a doubling of GH secretion, resulting from an increase of the amplitude and the duration of the first GH pulse after sleep onset. This stimulation of GH secretion was significantly correlated to a simultaneous increase in the amount of sleep stage IV. Abrupt but transient elevations of prolactin and cortisol were also observed, but did not appear to be associated with the concomitant stimulation of SW sleep. Thyrotropin and melatonin profiles were not altered by GHB administration. These data suggest that pharmacological agents that reliably stimulate SW sleep, such as GHB, may represent a novel class of powerful GH secretagogues.

Quantitative analysis of the 24-hour blood pressure and heart rate patterns in young men.

To characterize the normal nycterohemeral blood pressure and heart rate profiles and to delineate the relative roles of sleep and circadian rhythmidty, we performed 24-hour ambulatory blood pressure monitoring with simultaneous polygraphic sleep recording in 31 healthy young men investigated in a standardized physical and social environment Electroencephalographic sleep recordings were performed during 4 consecutive nights. Blood pressure and heart rate were measured every 10 minutes for 24 hours starting in the morning preceding the fourth night of recording. Sleep quality was not significantly altered by ambulatory blood pressure monitoring. A best-fit curve based on the periodogram method was used to quantify changes in blood pressure and heart rate over the 24-hour cycle. The typical blood pressure and heart rate patterns were bimodal with a morning acrophase (around 10:00 AM), a small afternoon nadir (around 3:00 PM), an evening acrophase (around 8:00 PM), and a profound nocturnal nadir (around 3:00 AM). The amplitude of the nycterohemeral variations was largest for heart rate, intermediate for diastolic blood pressure, and smallest for systolic blood pressure (respectively, 19.9%, 14.1%, and 10.9% of the 24-hour mean). Before awakening, a significant increase in blood pressure and heart rate was already present Recumbency and sleep accounted for 65-75% of the nocturnal decline in blood pressure, but it explained only 50% of the nocturnal decline in heart rate. Thus, the combined effects of postural changes and the wake-sleep transition are the major factors responsible for the 24-hour rhythm in blood pressure. In contrast, the 24-hour rhythm of heart rate may reflect an endogenous circadian rhythm, amplified by the effect of sleep. We conclude that modulatory factors different from those controlling nycterohemeral changes in blood pressure influence the 24-hour variation in heart rate.

Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus.

Normal subjects demonstrate the presence of ultradian oscillations (period 80-150 min) in insulin secretion rate (ISR) tightly coupled to glucose oscillations of similar period. These oscillations appear to be a function of the feedback loop linking glucose and insulin. The present study was undertaken to determine whether the control by glucose of the ultradian oscillations in insulin secretion is altered in impaired glucose tolerance IGT and in non-insulin-dependent diabetes mellitus (NIDDM). Patients with NIDDM (n = 7), IGT (n = 4), and matched nondiabetic controls (n = 5) were studied under three separate protocols that involved administration of glucose at either a constant rate of 6 mg/kg per min for 28 h or in one of two oscillatory patterns at the same overall mean rate. The amplitude of the oscillations was 33% above and below the mean infusion rate, and their respective periods were 144 min (slow oscillatory infusion) or 96 min (rapid oscillatory infusion). Insulin, C-peptide, and glucose were sampled at 10-min intervals during the last 24 h of each study. ISRs were calculated by deconvolution of C-peptide levels. Analysis of the data showed that (a) the tight temporal coupling between glucose and ISR in the nondiabetic controls was impaired in the IGT and NIDDM groups as demonstrated by pulse analysis, cross-correlation analysis, and spectral analysis; (b) the absolute amplitude of the ISR pulses progressively declined with the transition from obesity to IGT to NIDDM; and (c) the absolute amplitude of the ISR oscillations failed to increase appropriately with increasing absolute amplitude of glucose oscillations in the IGT and NIDDM subjects compared with the control group. In conclusion, the present study demonstrates that important dynamic properties of the feedback loop linking insulin secretion and glucose are disrupted not only in established NIDDM but also in conditions where glucose tolerance is only minimally impaired. Further studies are needed to determine how early in the course of beta-cell dysfunction this lack of control by glucose of the ultradian oscillations in insulin secretion occurs and to define more precisely if this phenomenon plays a pathogenetic role in the onset of hyperglycemia in genetically susceptible individuals.

Alterations of Circadian Rhythmicity and Sleep in Aging: Endocrine Consequences

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30–40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.

The Roles of Time of Day and Sleep Quality in Modulating Glucose Regulation: Clinical Implications

Consistent variations in glucose regulation across the 24-hour cycle are present in normal subjects. These diurnal variations are altered in various states of impaired glucose tolerance (aging, obesity, diabetes). Changes in insulin secretion, clearance and/or action across the day have been demonstrated. Studies in subjects receiving continuous intravenous glucose infusion have shown that major alterations of glucose tolerance occur during sleep and that sleep quality markedly influences glucose utilization. Diurnal variations in glucose tolerance result from the alternation of wake and sleep states as well as from intrinsic effects of circadian rhythmicity. The important roles of physiological variations in levels of counterregulatory hormones which are markedly dependent on sleep (i.e. growth hormone) or circadian rhythmicity (i.e. cortisol) have only begun to be appreciated. The modulatory effects of sleep and circadian rhythmicity on glucose regulation may have important clinical implications for the diagnosis and treatment of abnormalities of carbohydrate metabolism.

Current concepts: I. The 24-hour profile of prolactin in depression.

Abstract The 24-hour profile of plasma PRL was studied in 10 patients with unipolar depression and 8 patients with bipolar depression and compared to 18 control profiles obtained in healthy subjects. Alterations in the basal PRL secretion as well as the characteristics of the 24-hour rhythm were found in all patients but differed strikingly according to the type of depressive illness. The basal PRL level was elevated in unipolars, mainly as a result of increased secretion during wakefulness, and lowered in bipolars because of a lack or reduction of sleep-associated elevation. The nocturnal rise of PRL was maintained in unipolars but absent in 75% of the bipolar subjects. The variability of PRL levels around the 24-hour mean appeared to be reduced in both types of affective illness. These abnormalities in the 24-hour profile of PRL could serve as a biological marker of sub-types of depression.

Control of circadian and episodic variations of adrenal androgens secretion in man

The 24-h profiles of plasma cortisol (F), 11-β-hydroxyandrostenedione (11OHAD), androstenedione (AD), dehydroisoandrosterone (DHEA) and testosterone (T) were obtained simultaneously in 11 normal males sampled at 15-min intervals. The data were submitted to a detailed quantitative analysis including the estimation of the circadian rhythm and of the episodic variations as well as the evaluation of the concomitance of episodic pulses of different hormones. A bimodal circadian rhythm was detected in the various individual profiles. The major acrophase occurred in the morning earlier for T (around 04:00 h) than for the hormones of totally or partially adrenal origin (around 07:00 h); the secondary acrophase (around 17:00 h) and the main midnight nadir were common to all hormones. The amplitude of the rhythm was highest for purely adrenal hormones (F and 11OHAD), averaging 79 and 75%, respectively, lower for hormones of mixed origin (DHEA and AD), averaging 44 and 42%, respectively, and minimal for T (22%). The possible relationship between the circadian and pulsatile variations of the various steroids was estimated in each individual by calculating Pearson’s standard coefficient of variation on all pairs of hormonal profiles. A very tight relationship (r > 0.75; p < 0.001) was found between the 4 adrenal hormones in each individual; a looser but significant correlation (r > 0.30; p< 0.001) was also detected between T and its partial precursors (AD and DHEA) and between T and the purely adrenal hormones: F and 11OHAD (r > 0.30; p < 0.01). The pulsatility of the corticotrophic axis was readily transmitted to the secretory pattern of 11OHAD, DHEA and AD. Ninety-six percent of the F pulses were reflected in at least one other hormonal profile. Finally, we showed that concomitant pulses common to the five adrenal and gonadal patterns were more frequent than would be expected on the basis of chance. These results: (1) demonstrate a total parallelism between the long-lasting secretory events and the episodic bursts of the 4 adrenal hormones showing that the reticular and fascicular zones of the adrenal respond to pituitary control as an homogeneous structure; (2) demonstrate the existence of a partial synchronization of adrenal and testicular pulsatile variations; (3) suggest that, throughout the afternoon, a common mechanism may influence the slow variations of adrenal hormones and of testicular testosterone.