Circadian modulation to meals: relationship EVE VAN CAUTER, HARTMUT TILLIL,

of glucose and insulin responses to cortisol rhythm

E. TIMOTHY SHAPIRO, AND KENNETH S. POLONSKY

Department of Medicine, University of Chicago, Chicago, Illinois 60637; and Institute of Interdisciplinary Research, Universitk Libre de Bruxelles, B-1070 Brussels, Belgium Van Cauter, Eve, E. Timothy Shapiro, Hartmut Tillil, and Kenneth S. Polonsky. Circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythm. Am. J. Physiol. 262 (Endocrinol. Metab. 25): E467-E475, 1992.-To determine whether glucose and insulin responses to a mixed meal are influenced by time of day irrespective of duration of prior fast, eight normal subjects (4 males, 4 females) were studied on two separate occasions, involving ingestion of identical meals at either 6- or 12-h intervals. The 24-h profiles of plasma glucose, serum insulin, and plasma C-peptide were obtained at 200min intervals. Plasma cortisol levels were measured on each sample to evaluate possible relationship between diurnal variations in metabolic responses and circadian rhythm of cortisol. Rates of secretion of insulin and cortisol were mathematically derived from peripheral concentrations by deconvolution using two-compartment models for clearance kinetics. Postmeal responses of glucose, insulin, and insulin secretion rate were evaluated by calculating maximum postmeal increment, total area under curve, area under curve for 2 h after meal ingestion, and total duration of response. Postmeal cortisol responses were quantified by increment in plasma level and amount secreted in postmeal pulse. For glucose responses, irrespective of duration of prior fast, all four parameters characterizing the response were significantly greater in the evening than in the morning, with total area under curve and 2-h area under curve being approximately twofold larger in the evening than in the morning. Time of day did not significantly influence maximum postmeal increment in insulin secretion rate or duration of insulin secretory response, but total and 2-h areas under curve were 25-50% greater in the evening than in the morning. Meal ingestion was followed by a significant pulse of cortisol secretion in 37 of 40 cases. Magnitude of morning-toevening increase in insulin response to meals was correlated with magnitude of morning-to-evening decrease in cortisol level. We conclude that glucose and insulin responses to mixed meals in normal adults of both sexes are profoundly modulated by circadian rhythmicity and that this diurnal variation in meal tolerance may be mediated at least partially by circulating cortisol concentrations. In the evening, failure of insulin secretion to increase in proportion to changes in postmeal glucose responses suggests that, in addition to circadian changes in insulin sensitivity, there may be a circadian variation in responsiveness of &cells to glucose. circadian rhythmicity; food intake; glucose tolerance; insulin secretion THE ROLE

OF CIRCADIAN

RHYTHMICITY

in modulating

human endocrine function is well established for systems directly dependent on the hypothalamopituitary axes. It is often assumed that the function of more peripheral endocrine systems, such as the pancreas, is not significantly influenced by central mechanisms responsible for circadian timing. However, in normal humans, a series of studies have suggested that the set point of glucose regulation may be under circadian control. Indeed, glu-

cose tolerance to an oral glucose load or to a single intravenous injection of glucose is decreased in the afternoon compared with the morning (8). With the use of experimental designs involving constant glucose infusion for 24-30 h, we have shown that glucose tolerance continues to deteriorate as the evening progresses and reaches a minimum around midsleep (19,22). In a recent study, we have further demonstrated that the diurnal variation in glucose levels during constant glucose infusion is paralleled by a similar variation of insulin secretion, which is inversely related to the circadian rhythm of cortisol concentrations (21). These observations obtained during constant glucose infusion suggest that there may be a systematic circadian variation in the glucose and insulin responses to a mixed meal, with larger responses in the evening than in the morning, and that this effect of time of day on meal responses could be partially mediated by cortisol. The existence of such a consistent effect of time of day on meal tolerance could be of importance in the design of meal schedules, which would optimize glucose control for subjects with impaired glucose tolerance and in the development of strategies to cope with conditions of abnormal circadian rhythmicity (i.e., “jet lag” or shift work), which are frequently associated with gastrointestinal disorders. In all previous studies designed to examine the possible effects of time of day on meal tolerance, the response to the morning meal, which was presented after a lo- to 12h fast, was compared with the response to the evening meal, which was presented after a 4- to 5-h fast. Thus, when morning vs. evening differences in meal responses were observed, it could not be determined whether they reflected differences in the duration of prior fast or true circadian modulation. Reduced carbohydrate tolerance to mixed meals absorbed later in the day has been shown in some, but not all, studies involving identical meals given at various times of day after varying durations of prior fast (1, 10,12,13,17). The presence and magnitude of a diurnal variation seemed to be dependent on meal size and composition (1,12,17). Two studies by the same group have indicated that the effects of time of day may be more prominent in women than in men (1, 12). It is noteworthy that, in all these previous studies, the “evening” meal was actually given in the late afternoon, between 1630 and 1800 h, at a time when, according to our 24-h studies during constant glucose infusion (19, 22), glucose tolerance has only begun to deteriorate. Thus larger and more consistent effects of time of day may occur when the evening meal is consumed later, as is often the case under ordinary conditions of daily living. The present study was therefore undertaken to com-

0193-1849/92 $2.00 Copyright 0 1992 the American Physiological

Society

E46’7

Downloaded from www.physiology.org/journal/ajpendo by ${individualUser.givenNames} ${individualUser.surname} (139.184.014.150) on August 12, 2018. Copyright © 1992 American Physiological Society. All rights reserved.

E468

CIRCADIAN

VARIATION

pare the responses to identical meals given at 0800 and at 2000 h while controlling for the duration of the prior fast. To delineate the size, duration, and dynamics of the meal responses, peripheral levels of glucose, insulin, and C-peptide were determined at 20-min intervals over a 24-h span, and insulin secretion rates were derived from the C-peptide levels by deconvolution. Cortisol levels were measured on all samples to evaluate the relationship between diurnal variations in metabolic responses to meals and the circadian periodicity of cortisol secretion. SUBJECTS

AND

METHODS

Subjects

Eight normal subjects, four men and four women aged 2235 yr, were studied. All were of normal weight [body mass index 21.5 $- 2.2 (SD) k g/ m2, range 18.8-24.5 kg/m2], and none had a personal or family history of diabetes. Fasting glucose and insulin levels averaged 4.94 t 0.16 (SD) mmol/l and 45.9 t 4.3 pmol/l, respectively. Shift workers or subjects who had experienced a transmeridian flight

Circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythm.

To determine whether glucose and insulin responses to a mixed meal are influenced by time of day irrespective of duration of prior fast, eight normal ...
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