ESPE Abstracts

In healthy humans, plasma glucose excursions depend on the time of day of glucose ingestion, with higher glucose tolerance in the morning compared to the evening. Recent studies using a circadian desynchrony protocol clearly demonstrated that the diurnal rhythm in glucose tolerance is robustly regulated by the circadian timing system, separate from behavioral and environmental changes. The mammalian circadian timing system consists of a central brain clock and peripheral clocks in tissues throughout the body, including muscle, adipose tissue, and liver. Environmental light synchronizes the approximately 24-hour (i.e. circadian) rhythm of the brain clock with the exact 24-hour rhythm of the environment. The entrained timing signal from the brain clock is forwarded via neural and hormonal signals to the peripheral tissue clocks. The molecular mechanism of the central and peripheral clocks is based on transcriptional translational feedback loops, which are present in virtually every cell of the human body. Molecular clocks in different tissues and organs are involved in the control of the daily rhythm in glucose tolerance, insulin sensitivity and insulin secretion. The first clue that the circadian timing system may be involved in the pathophysiology of insulin resistance was the observation in the 1960s of an altered daily rhythm in glucose tolerance in patients with diabetes mellitus. Later, observations including the development of metabolic syndrome in the Clock mutant mouse, food intake at the wrong circadian phase causing obesity in mice and circadian misalignment resulting in decreased glucose tolerance in humans led to the circadian disruption hypothesis. Sophisticated tissue specific pancreatic, hepatic, muscle, and adipose transgenic and knockout models gave further support for this hypothesis. Taken together, it is likely that disturbance of the central and/or tissue clock rhythms contributes to the pathophysiology of insulin resistance. Circadian disruption may also cause misalignment of nutrient fluxes, both between and within tissues. For instance, a mismatch between hepatic glucose production, muscle glucose uptake, and carbohydrate intake, may contribute to elevated glucose levels, and metabolic inflexibility in muscle tissue may result in insulin resistance. Randomized clinical trials investigating the effects of natural light/dark exposure, sleep improvement, time restricted feeding, and the daily timing of exercise to prevent these metabolic complications are needed.