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 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 20-min 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-to-evening 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 beta-cells to glucose.