Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance

Washington State University

Status and phase: Begins enrollment this month; Phase 4

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

Treatments: Drug: insulin; Drug: Metyrapone And Hydrocortisone; Drug: Dextrose

Study type: Interventional

Funder types: Other

Identifiers

NCT07494084

R01HL177106 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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 (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.

Enrollment: 24 estimated patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

1. Must be between 18-45 years old.

2. Has a BMI of 18-25 kg/m2 stable weight over the previous 6 weeks.

3. 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

4. No current medical or drug treatment (to include steroids or hormones of any type including contraceptives), as assessed by questionnaire.

5. Has a negative pregnancy test (women), no clinically significant abnormalities in blood and urine, and free of traces of drugs.

6. No history of clinically relevant psychiatric illness.

7. No previous history of drug or alcohol abuse.

8. Not a current smoker.

9. No history of brain injury or of learning disability.

10. No previous adverse reaction to sleep deprivation, jet lag, shift work or any of the drugs to be administered.

11. Not vision or hearing impairment unless corrected back to normal.

12. 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).

13. No sleep or circadian disorder.

14. Has good habitual sleep with regular bedtimes (between 6 and 10 hours in duration).

15. Not extreme morning- nor extreme evening-type using Horne-Ostberg Morningness-Eveningness criteria.

16. No travel across time zones within one month of entering the study.

17. No shift work within three months of entering the study.

18. No anemia (hematocrit <38% in men, <34% in women).

19. No blood donation within the previous 8 weeks.

20. No concurrent participation in another research study.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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24 participants in 2 patient groups

Misaligned cortisol rhythm

Active Comparator group

Description:

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.

Treatment:

Drug: Dextrose

Drug: Metyrapone And Hydrocortisone

Drug: insulin

Realigned cortisol rhythm

Active Comparator group

Description:

Participants assigned to the misaligned cortisol rhythm condition (Condition A) 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. Participants assigned to the realigned cortisol rhythm condition (Condition B) 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. In both conditions, the last subcutaneous dose will be administered at 19:00 on day 5. Each pulse is delivered at a rate of 0.1mg/sec (of hydrocortisone diluted to 10mg/mL) and replicates an extensively validated protocol developed by others, and refined by us. 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.

Treatment:

Drug: Dextrose

Drug: Metyrapone And Hydrocortisone

Drug: insulin