Shift Work SchedulePhase 4NCT07494084
Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance
A Phase 4 study testing Metyrapone And Hydrocortisone, Dextrose and insulin in people with Shift Work Schedule and Circadian Rhythm, run by Washington State University at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Shift Work Schedule, Circadian Rhythm, Insulin Resistance
- What is being tested?
- Metyrapone And Hydrocortisone, Dextrose and insulin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 48 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jul 2026to Jul 2029
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Must be between 18-45 years old.
- Has a BMI of 18-25 kg/m2 stable weight over the previous 6 weeks.
- Is physically and psychologically healthy (incl. regular menstrual cycles in women, no clinical disorders and/or illnesses). Women will be studied during the follicular phase of their menstrual cycle.
- Menstrual cycle criteria (using PMID 10941950) 18 to 25 years - Cycle variation ≤9 days 26 to 41 years - Cycle variation ≤7 days 42 to 45 years - Cycle variation ≤9 days
- No current medical or drug treatment (to include steroids or hormones of any type including contraceptives), as assessed by questionnaire.
- Has a negative pregnancy test (women), no clinically significant abnormalities in blood and urine, and free of traces of drugs.
Show all 21Show fewer
- No history of clinically relevant psychiatric illness.
- No previous history of drug or alcohol abuse.
- Not a current smoker.
- No history of brain injury or of learning disability.
- No previous adverse reaction to sleep deprivation, jet lag, shift work or any of the drugs to be administered.
- Not vision or hearing impairment unless corrected back to normal.
- No endocrine disorder (no abnormal thyroid function tests; no abnormal morning blood cortisol; no primary gonadal disease as indicated by serum LH or FSH concentration > 10 or > 15 IU/L, respectively; and no hyperprolactinemia indicated by prolactin > 25 μg/L).
- No sleep or circadian disorder.
- Has good habitual sleep with regular bedtimes (between 6 and 10 hours in duration).
- Not extreme morning- nor extreme evening-type using Horne-Ostberg Morningness-Eveningness criteria.
- No travel across time zones within one month of entering the study.
- No shift work within three months of entering the study.
- No anemia (hematocrit <38% in men, <34% in women).
- No blood donation within the previous 8 weeks.
- No concurrent participation in another research study.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Sleep and Performance Research Center
Spokane, Washington, 99202
Olivia Brooks, MS, 509-358-7750, olivia.brooks@wsu.edu
Devon Hansen, PhD, 509-358-7754, devon.hansen@wsu.edu
About this study
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.
Read the detailed description
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: 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.
- Being tested
- Metyrapone And Hydrocortisone, Dextrose, insulin
- Keywords
- Shift work, insulin resistance, sleep, circadian rhythm, type 2 diabetes
- Medical subject headings
- Insulin Resistance, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metyrapone And HydrocortisoneDrug
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 will receive 3 tiers of doses: low (0.5mg), moderate (2.3mg) and high (4.0mg), the timing of which is specified by their condition assignment. For all participants, 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.
DextroseDrug
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,
insulinDrug
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,
| Study group | Role | What they receive |
|---|---|---|
| Misaligned cortisol rhythm-night shift condition | Active comparator | 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. Receives: Drug: Metyrapone And Hydrocortisone; Drug: Dextrose; Drug: insulin |
| Realigned cortisol rhythm-night shift condition | Active comparator | 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. Participants will receive their doses at a 12-hour offset from the misaligned condition, with: lowest doses (0.5mg) at 10:00 and 13:00; moderate doses (2.3mg) at 01:00, 04:00, and 07:00; and highest doses (4.0mg) at 16:00, 19:00, and 22:00. The last subcutaneous dose will be administered at 19:00 on day 5. 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. Receives: Drug: Metyrapone And Hydrocortisone; Drug: Dextrose; Drug: insulin |
| Fixed cortisol shape condition- day shift condition | Active comparator | 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 06:00 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 fixed cortisol shape 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. The last subcutaneous dose will be administered at 07:00 on day 5. 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. Receives: Drug: Metyrapone And Hydrocortisone; Drug: Dextrose; Drug: insulin |
| Unfixed cortisol shape condition-day shift condition | Placebo comparator | Participants will receive a metyrapone placebo at times matching the doses in Condition A (i.e., at 10:00 on day 2 and continuing every 4 hours until 06:00 on day 5). Using a subcutaneous pump, placebo hydrocortisone is administered matching the doses in Condition A (i.e., with pulses every 3 hours beginning at 10:00 on day 2 until 07:00 on day 5). A placebo matching the oral hydrocortisone will be administered at 10:00 on day 5. Receives: Drug: Dextrose; Drug: insulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Insulin resistance-Minimal Model (Si)
Insulin resistance-minimal model (Si) 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).
Measured: Change from baseline collection.
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).
Measured: Change from baseline collection.
Insulin Resistance-Insulin Sensitivity Index (Mi)
The Insulin Sensitivity Index (Mi) 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).
Measured: Change from baseline collection.
Secondary outcomes (4)
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.
Measured: From enrollment into the lab (day 1) to the end of experimentation (day 6)
Metabolomics
Plasma samples will be analyzed using four complementary liquid chromatography tandem mass spectrometry (LC-MS)-based methods that couple distinct metabolite extraction and LC techniques with high resolution, accurate mass (HRAM) MS profiling to provide a hybrid analysis of hundreds of metabolites of confirmed identity and thousands of LC-MS peaks from yet to be identified compounds.
Measured: Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).
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.
Measured: From enrollment into the lab (day 1) to the end of experimentation (day 6)
Delta-4 steroid hormones
Delta-4 steroid hormones will be measured by liquid chromatography tandem mass spectrometry. These steroids are extracted from blood and quantified simultaneously using spiked commercially available internal standards. The steroids measured discern steroidogenic pathways and include recognized prototypical androgen (testosterone), estrogen (estradiol), progestin (progesterone), glucocorticoid (cortisol) and mineralocorticoid (aldosterone), as well as other steroids that activate multiple steroids receptors classes.
Measured: Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2026
- Study start16 Jul 2026
- Primary completionMar 2029 (estimated)
- Study completionJul 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Shift Work ScheduleStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- For the 3 active comparator arms of the study, cortisol will be clamped using oral Metyrapone, which blocks endogenous cortisol synthesis. A 3,000 mg loading dose will be given at 10:00 on day 2, followed by 500 mg every 4 hours from 14:00 on day 2 through 18:00 on day 5. Cortisol will be replaced by subcutaneous hydrocortisone pulses every 3 hours from 10:00 on day 2 to 22:00 on day 5, replicating circadian and ultradian rhythms. In the misaligned condition, participants receive 0.5 mg at 22:00 and 01:00; 2.3 mg at 13:00, 16:00, 19:00; and 4.0 mg at 04:00, 07:00, 10:00. In the realigned condition, doses follow a 12-hour offset. The final dose occurs at 19:00 on day 5. Each pulse is delivered at 0.1 mg/sec using hydrocortisone diluted to 10 mg/mL. A final 25 mg oral hydrocortisone dose will be given after the constant routine to prevent hypocortisolemia.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 48 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Washington State University
- Sponsor type
- University, hospital or other
- Collaborators
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Responsible party
- Sponsor
- Investigators
- Peter Liu, MBBS, PhD, Principal investigator, Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical CenterHans P.A. Van Dongen, PhD, Principal investigator, Washington State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07494084
- Sponsor's protocol ID
- R01HL177106
- Other IDs
- R01HL177106
- Status last verified
- Sep 2026
- First submitted
- 9 Mar 2026
- Last updated
- 18 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Study data will be released via the PIs for reasonable requests or in adherence to sponsor requirements.
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance
- ClinicalTrials.gov ID
- NCT07494084
- Acronym / sponsor ID
- R01HL177106
- Keywords
- Shift work, insulin resistance, sleep, circadian rhythm, type 2 diabetes
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 48 participants (estimated)
- Lead sponsor
- Washington State UniversityUniversity, hospital or other
- Collaborators
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Study start
- 16 Jul 2026 (actual)
- Primary completion
- Mar 2029 (estimated)
- Study completion
- Jul 2029 (estimated)
- First posted
- 27 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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: 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 design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- Model description
- For the 3 active comparator arms of the study, cortisol will be clamped using oral Metyrapone, which blocks endogenous cortisol synthesis. A 3,000 mg loading dose will be given at 10:00 on day 2, followed by 500 mg every 4 hours from 14:00 on day 2 through 18:00 on day 5. Cortisol will be replaced by subcutaneous hydrocortisone pulses every 3 hours from 10:00 on day 2 to 22:00 on day 5, replicating circadian and ultradian rhythms. In the misaligned condition, participants receive 0.5 mg at 22:00 and 01:00; 2.3 mg at 13:00, 16:00, 19:00; and 4.0 mg at 04:00, 07:00, 10:00. In the realigned condition, doses follow a 12-hour offset. The final dose occurs at 19:00 on day 5. Each pulse is delivered at 0.1 mg/sec using hydrocortisone diluted to 10 mg/mL. A final 25 mg oral hydrocortisone dose will be given after the constant routine to prevent hypocortisolemia.
| Arm | Type | Receives |
|---|---|---|
| Misaligned cortisol rhythm-night shift condition | Active comparator | Drug: Metyrapone And Hydrocortisone, Drug: Dextrose, Drug: insulinCortisol 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. |
| Realigned cortisol rhythm-night shift condition | Active comparator | Drug: Metyrapone And Hydrocortisone, Drug: Dextrose, Drug: insulinCortisol 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. Participants will receive their doses at a 12-hour offset from the misaligned condition, with: lowest doses (0.5mg) at 10:00 and 13:00; moderate doses (2.3mg) at 01:00, 04:00, and 07:00; and highest doses (4.0mg) at 16:00, 19:00, and 22:00. The last subcutaneous dose will be administered at 19:00 on day 5. 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. |
| Fixed cortisol shape condition- day shift condition | Active comparator | Drug: Metyrapone And Hydrocortisone, Drug: Dextrose, Drug: insulinCortisol 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 06:00 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 fixed cortisol shape 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. The last subcutaneous dose will be administered at 07:00 on day 5. 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. |
| Unfixed cortisol shape condition-day shift condition | Placebo comparator | Drug: Dextrose, Drug: insulinParticipants will receive a metyrapone placebo at times matching the doses in Condition A (i.e., at 10:00 on day 2 and continuing every 4 hours until 06:00 on day 5). Using a subcutaneous pump, placebo hydrocortisone is administered matching the doses in Condition A (i.e., with pulses every 3 hours beginning at 10:00 on day 2 until 07:00 on day 5). A placebo matching the oral hydrocortisone will be administered at 10:00 on day 5. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (21 listed)
- Must be between 18-45 years old.
- Has a BMI of 18-25 kg/m2 stable weight over the previous 6 weeks.
- Is physically and psychologically healthy (incl. regular menstrual cycles in women, no clinical disorders and/or illnesses). Women will be studied during the follicular phase of their menstrual cycle.
- Menstrual cycle criteria (using PMID 10941950) 18 to 25 years - Cycle variation ≤9 days 26 to 41 years - Cycle variation ≤7 days 42 to 45 years - Cycle variation ≤9 days
- No current medical or drug treatment (to include steroids or hormones of any type including contraceptives), as assessed by questionnaire.
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metyrapone And HydrocortisoneCortisol 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 will receive 3 tiers of doses: low (0.5mg), moderate (2.3mg) and high (4.0mg), the timing of which is specified by their condition assignment. For all participants, 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. | Drug | Fixed cortisol shape condition- day shift condition, Misaligned cortisol rhythm-night shift condition, Realigned cortisol rhythm-night shift condition |
| DextroseThe 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, | Drug | Fixed cortisol shape condition- day shift condition, Misaligned cortisol rhythm-night shift condition, Realigned cortisol rhythm-night shift condition, Unfixed cortisol shape condition-day shift condition |
| insulinThe 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, | Drug | Fixed cortisol shape condition- day shift condition, Misaligned cortisol rhythm-night shift condition, Realigned cortisol rhythm-night shift condition, Unfixed cortisol shape condition-day shift condition |
Primary outcome
Insulin resistance-Minimal Model (Si)
Time frame: Change from baseline collection.
Insulin resistance-minimal model (Si) 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).
Insulin Resistance-Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Time frame: Change from baseline collection.
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).
Insulin Resistance-Insulin Sensitivity Index (Mi)
Time frame: Change from baseline collection.
The Insulin Sensitivity Index (Mi) 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).
4 secondary outcomes
Psychomotor Vigilance Test (PVT) Lapses
Time frame: From enrollment into the lab (day 1) to the end of experimentation (day 6)
Metabolomics
Time frame: Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).
Karolinska Sleepiness Scale (KSS) Scores
Time frame: From enrollment into the lab (day 1) to the end of experimentation (day 6)
Delta-4 steroid hormones
Time frame: Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2026.
- Individual participant dataSharing planned: Undecided. Study data will be released via the PIs for reasonable requests or in adherence to sponsor requirements.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Peter Liu, MBBS, PhD principal investigator
Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center
Hans P.A. Van Dongen, PhD principal investigator
Washington State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metyrapone And Hydrocortisone, Dextrose and insulin in people with Shift Work Schedule and Circadian Rhythm, run by Washington State University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Devon A Hansen, PhD (509-358-7754, devon.hansen@wsu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Insulin resistance-Minimal Model (Si) (time frame: Change from baseline collection.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2026.