To define the effects of sleep on glucose regulation, we analyzed plasma glucose levels, insulin secretion rates (ISR), and plasma growth hormone and cortisol levels in normal subjects receiving a constant glucose infusion during nocturnal sleep, nocturnal sleep deprivation, and daytime recovery sleep. Plasma glucose and ISR markedly increased during early nocturnal sleep and returned to presleep levels during late sleep. These changes in glucose and ISR appeared to reflect the predominance of slow-wave (SW) stages in early sleep and of rapid-eye-movement and wake stages in late sleep. Major differences in glucose and ISR profiles were observed during sleep deprivation as glucose and ISR remained essentially stable during the first part of the night and then decreased significantly, despite the persistence of bed rest and constant glucose infusion. During daytime recovery sleep, SW stages were increased, glucose levels peaked earlier than during nocturnal sleep, and the decreases of glucose and ISR in late sleep were reduced by one-half. Thus sleep has important effects on brain and tissue glucose utilization, suggesting that sleep disturbances may adversely affect glucose tolerance.