Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance

NCT07494084 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: R01HL177106
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Shift Work Schedule; Circadian Rhythm; Insulin Resistance; Circadian Misalignment

Keywords

Shift work; insulin resistance; sleep; circadian rhythm; type 2 diabetes

Outcome Measures

Primary Outcomes (3)

• 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).

  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).

  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).

  Change from baseline collection.

Secondary Outcomes (4)

• Psychomotor Vigilance Test (PVT) Lapses

  From enrollment into the lab (day 1) to the end of experimentation (day 6)

• Metabolomics

  Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).

• Karolinska Sleepiness Scale (KSS) Scores

  From enrollment into the lab (day 1) to the end of experimentation (day 6)

• Delta-4 steroid hormones

  Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).

Study Arms (4)

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.

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.

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.

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.

Drug: Dextrose; Drug: insulin

Interventions

Metyrapone And Hydrocortisone DRUG

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.

Fixed cortisol shape condition- day shift condition; Misaligned cortisol rhythm-night shift condition; Realigned cortisol rhythm-night shift condition

Dextrose DRUG

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,

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

insulin DRUG

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,

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

Eligibility Criteria

• Age: 18 Years - 45 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Washington State University: lead
• Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center: collaborator

Study Sites (1)

Sleep and Performance Research Center

Spokane, Washington, 99202, United States

Location

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus, Type 2

Interventions

Metyrapone; Hydrocortisone; Glucose; Insulin

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Hexoses; Monosaccharides; Sugars; Carbohydrates; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Peter Liu, MBBS, PhD

  Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center

  PRINCIPAL INVESTIGATOR

• Hans P.A. Van Dongen, PhD

  Washington State University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Devon A Hansen, PhD

CONTACT

509-358-7754; devon.hansen@wsu.edu

Olivia Brooks, MS

CONTACT

509-358-7904; olivia.brooks@wsu.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 9, 2026
• First Posted: March 27, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): July 1, 2029
• Last Updated: May 15, 2026

Record last verified: 2026-05

Locations

US (1)