Sleep loss and circadian misalignment - mechanisms of Insulin Resistance - Sleep restriction, the reduction in sleep resulting from insufficient or interrupted sleep, affects a third of adults in the US. It arises from shortened sleep periods, environmental disturbances, and disrupted sleep from obstructive sleep apnea, movement disorders, or other pathology. Night shift work, in addition to misaligning the timing of behavioral rhythms with the endogenous circadian rhythm, interferes with the homeostatic regulation of sleep, leading to sleep loss. Night shift workers comprise 10-15% of the workforce, experience both sleep loss and circadian misalignment, and higher rates of metabolic diseases. Whereas sleep loss alone typically worsens insulin resistance by 20%, experimental studies show that adding circadian misalignment to sleep loss doubles this effect. Insulin resistance triggers the development of type 2 diabetes mellitus (T2DM) – a disorder that affects 38 million Americans at an estimated cost of $413 billion/year. The mechanisms underlying induction of insulin resistance (IR) from sleep restriction remain unknown, although the major stress hormone, cortisol, appears to play a major role. Until the precise mechanisms underlying rising IR are unveiled, targeted therapies cannot be developed. This proposal aims to establish that the shape and the timing of cortisol rhythms underlie IR development in men and women. We will also characterize the downstream 24- hour metabolomic and endocrine signatures that identify metabolic, inflammatory and other pathways. Interventions to modify release, timing or action of cortisol are eminently feasible, and will provide a means to ultimately alter the formidable increasing incidence of T2DM in this country, but the role of cortisol and its downstream pathways must initially be outlined. We will conduct 2 randomized placebo controlled trials (RCT) in 48 adults (24 women) aged 22-45 years across both studies. Studies will be of 7 days duration and sleep will be restricted to 4 hours/night for 3 nights followed by a 24-hour constant routine during which no sleep occurs. The first RCT simulates day shift work and will compare the effect of sleep restriction under conditions where the shape of the cortisol rhythm becomes altered versus conditions where the shape is fixed. The second RCT simulates night shift work (to induce circadian misalignment) and will compare the effect of sleep restriction with circadian misalignment under conditions where the timing of the cortisol rhythm is misaligned or aligned. Since there are sex differences in the regulation of cortisol and sleep architecture, we will maximize power to unveil underlying IR mechanisms that do or do not differ by sex by pooling data from both day and night shift work schedules. The goal is to understand how shortened and misaligned sleep lead to metabolic ill-health, and to unveil the underpinning endocrine/metabolomic mechanisms. The studies have the potential to exert a major impact on understanding the mechanisms contributing to T2DM, which is closely associated with sleep-disordered breathing, night shift work and other conditions which alter sleep at substantial national health cost.
