The purpose of this study is to examine the impact of timed cortisol release or differently timed cortisol rhythms on insulin resistance in both men and women undergoing sleep restriction. Chronic sleep loss is highly prevalent, affecting 1 in 3 adults in the US. Chronic sleep loss causes stress which induces insulin resistance and leads to obesity and type 2 diabetes. Many factors contribute to sleep loss including shift work, environmental disturbances, sleep/circadian disorders and comorbid medical and mental health conditions. Sleep loss increases the stress hormone cortisol in the evening and decreases daytime testosterone. Examining these hormones in a controlled laboratory environment under different sleep schedules may help researchers find solutions for adults experiencing negative health consequences related to chronic sleep loss.
Sleep loss causes stress, induces insulin resistance (IR) and leads to obesity and type 2 diabetes mellitus (T2D). Sleep loss is highly prevalent, affecting 1 in 3 adults in the USA. Many factors contribute to sleep loss including extended work hours, night shift work, environmental disturbances, sleep/circadian disorders and comorbid medical and mental health conditions. Sleep loss induces changes that typify the autonomic stress response, increases the stress hormone cortisol in the evening, and decreases daytime testosterone. The investigators discovered that preventing cortisol and testosterone from changing during sleep loss, by means of a dual-hormone clamp, stabilizes metabolism and mitigates (reduces by 50%) the induction of IR. This finding unequivocally identifies cortisol and testosterone signaling to be major pathways by which sleep loss imbalances metabolic processes and triggers IR - a critical pathogenic factor for T2D. These hormonal pathways are now prime candidates for developing mechanistically informed methods to avert IR and its devastating consequences, because no other putative pathway has been verified experimentally in humans. While groundbreaking, prior findings were only in men, and actions of cortisol and testosterone could not be separated because both were manipulated together. The next step is to characterize the distinct role of cortisol signaling and its metabolomic consequences in both sexes to unveil common and sex-dependent underlying pathways. This approach is logical because IR is induced in both sexes by increasing evening cortisol, whereas IR is induced in men by decreasing testosterone, and in women by increasing testosterone. Night shift work misaligns the timing of behavioral rhythms with the endogenous circadian rhythm, which interferes with the homeostatic regulation of sleep and often leads to sleep loss. Circadian misalignment (CM) itself induces IR, triggers metabolic changes that are observed metabolomically, and harms health. Combining CM from simulated night shift work with experimental sleep loss induces IR to a 2-fold greater extent than sleep loss alone. These findings explain why night shift workers, which comprise 10-15% of the entire workforce, are at elevated risk for developing T2D and other metabolic disorders. Whereas IR from sleep loss relates to alterations in the shape of the cortisol rhythm (an increase in evening cortisol which flattens the diurnal cortisol slope), IR from CM in night shift workers relates to misalignment of the timing of the central cortisol rhythm to peripheral signals that follow shifted behavioral cycles. The investigators hypotheses are that (a) sleep restriction and CM induce IR through changes in the shape and timing of cortisol rhythms, respectively; and (b) downstream 24-hour metabolomic and endocrine signatures characterize the putatively sex-dependent underlying metabolic and other pathways. The investigators will examine the induction of IR and the response to normalizing the cortisol rhythm during sleep restriction alone (Aim 1), or in combination with CM (Aim 2), as well as sex differences therein (Aim 3). The investigators will conduct 2 randomized experiments in a total of 48 adults (50% women) aged 18-45 y to address these 3 aims. Studies are in-laboratory for 6 days (see Figure 4): sleep is restricted to 4 hours/night for 2 nights followed by a 24-hour constant routine protocol without sleep. Aim 1: Reveal disruption of the natural shape of the cortisol rhythm as a distinct mechanism by which sleep restriction induces IR. In 24 adults (12 women) undergoing sleep restriction during circadian alignment (with simulated day shift schedule), the investigators will compare IR when cortisol can change freely vs when fixed by a next-generation clamp that blocks endogenous production of cortisol and exogenously adds back cortisol to replicate mid-physiological circadian and ultradian rhythms via a portable pump. The investigators will also determine the metabolomic and endocrine signatures associated with these changes under constant routine. The investigators hypothesize that (a) IR will be largely diminished when the cortisol rhythm is clamped, demonstrating a pivotal role of the shape of the cortisol rhythm in the IR-inducing effect of sleep restriction; and (b) downstream 24-hour metabolomic and endocrine signatures will elucidate underlying mechanisms specific to sleep loss. Aim 2: Unveil timing misalignment of the cortisol rhythm vs behavior as a separate mechanism that induces IR. In another 24 adults (12 women) undergoing sleep restriction during CM (with simulated night shift schedule), the investigators will compare IR while the fixed cortisol rhythm is either misaligned or realigned to the behavioral rhythm using the clamp as in Aim 1. The investigators hypothesize that (a) IR will be diminished when the fixed cortisol rhythm is realigned with the behavioral rhythm, showing a critical role of timing of the cortisol rhythm in the IR-inducing effect of CM; and (b) downstream 24-hour metabolomic and endocrine signatures during constant routine will elucidate underlying mechanisms due to CM distinct from those due to sleep loss in Aim 1. Aim 3: Assess sex differences in the mechanisms underlying IR. There are sex differences in the regulation of cortisol, sleep, and other hormones. The investigators hypothesize that examining metabolomic and endocrine signatures of sleep loss during simulated day shift schedules and night shift schedules will separate underlying IR mechanisms that do or do not differ by sex. The investigators maximize power by pooling data from both shift schedules (from Aims 1 and 2) to simultaneously assess induction of IR with sleep loss alone and with CM. The importance of IR as a pathogenic factor for T2D (a disorder that causes blindness, renal failure, heart attack, stroke, and loss of limb) mandates the proposed research. The experiments will provide essential information on prime candidate pathways underlying IR through restricted sleep and circadian misalignment in both sexes. This information will guide development of mechanistically informed solutions for the millions of men and women facing high prevalence of T2D and metabolic disorders who cannot sleep more, or at night, due to life and occupational demands. The essential first step is to delineate the processes which lead to IR.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
DIAGNOSTIC
Masking
DOUBLE
Enrollment
24
Cortisol will be clamped with oral administration of Metyrapone, which blocks endogenous cortisol biosynthesis. A loading dose of 3,000mg will be given at 10:00 on day 2. Every 4 hours throughout the sleep restriction and sleep deprivation phases, 500mg will be administered beginning at 14:00 on day 2 and ending with a dose at 18:00 on day 5. Using a subcutaneous pump, hydrocortisone is administered here as physiological replacement, with pulses every 3 hours beginning at 10:00 on day 2. Participants assigned to the misaligned cortisol rhythm condition will receive: lowest doses (0.5mg) at 22:00 and 01:00; moderate doses (2.3mg) at 13:00, 16:00, and 19:00; and highest doses (4.0mg) at 04:00, 07:00, and 10:00. An oral 25mg dose of hydrocortisone will be given at the end of the constant routine period to prevent any future hypocortisolemia associated with the hormone clamp.
The frequently sampled intravenous glucose tolerance test is performed before and after sleep restriction, and is widely used and validated. This procedure requires intravenous administration of dextrose, 300 mg/kg as a bolus at time zero. Insulin (0.03 units/kg/min) will be slowly infused intravenously over a 5 minute period from 20 to 25 minutes. Few side effects are anticipated as both doses of glucose and insulin should result in a high, but physiological peak. Administration of insulin as 5-min infusion for clinical studies (rather than bolus) reduces the max concentrations achieved. It is not uncommon for glucose to dip below fasting glycemia at some point after the insulin administration. The concentration at the nadir depends on the subject's insulin sensitivity. Return to fasting level is a function of the waning of the insulin effect (incorporated into the minimal model) as well as counterregulation (which depends on the concentration at the nadir). This can be addressed,
The frequently sampled intravenous glucose tolerance test is performed before and after sleep restriction, and is widely used and validated. This procedure requires intravenous administration of dextrose, 300 mg/kg as a bolus at time zero. Insulin (0.03 units/kg/min) will be slowly infused intravenously over a 5 minute period from 20 to 25 minutes. Few side effects are anticipated as both doses of glucose and insulin should result in a high, but physiological peak. Administration of insulin as 5-min infusion for clinical studies (rather than bolus) reduces the max concentrations achieved. It is not uncommon for glucose to dip below fasting glycemia at some point after the insulin administration. The concentration at the nadir depends on the subject's insulin sensitivity. Return to fasting level is a function of the waning of the insulin effect (incorporated into the minimal model) as well as counterregulation (which depends on the concentration at the nadir). This can be addressed,
Sleep and Performance Research Center
Spokane, Washington, United States
Insulin resistance-Minimal Model (Mi)
Insulin resistance-minimal model (Mi) will be measured from the frequently sampled intravenous glucose tolerance test (FSIVGTT) and reflects glucose disposal rate during the insulin response. it will be calculated as the change from baseline (by subtraction).
Time frame: Change from day 1 (first day) to day 6 (last day) of the study.
Insulin Resistance-Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) will be measured from the frequently samples intravenous glucose tolerance test (FSIVGTT) and reflects the fasting insulin resistance. It will be calculated as the change from baseline (by subtraction).
Time frame: Change from day 1 (first day) to day 6 (last day) of the study.
Insulin Resistance-Insulin Sensitivity Index (Si)
The Insulin Sensitivity Index (Si) will be measured from the frequently sampled intravenous glucose tolerance test (FSIVGTT). Si is calculated using the minimal model and measures whole-body insulin sensitivity. It will be calculated as the change from baseline (by subtraction).
Time frame: Change from day 1 (first day) to day 6 (last day) of the study.
Psychomotor Vigilance Test (PVT) Lapses
The number of lapses of attention, defined as any reaction time (RTs) \>500ms will be assessed during each PVT test session. Higher RTs indicate greater impairment/lower sustained attention.
Time frame: From enrollment into the lab (day 1) to the end of experimentation (day 6)
Karolinska Sleepiness Scale (KSS) Scores
Subjective ratings of sleepiness will be collected on a 9-point scale ranging from 1 (extremely wide awake) to 9 (very sleepy, fighting sleep) at regular intervals throughout laboratory experimentation to assess changes in levels of sleepiness. Higher scores indicate increased sleepiness/lowered alertness.
Time frame: From enrollment into the lab (day 1) to the end of experimentation (day 6)
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