Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance
Trial statusRecruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexAll
Age18-45
SponsorWashington State University
About this trial
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.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
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.
No current medical or drug treatment (to include steroids or hormones of any type including contraceptives), as assessed by questionnaire.
Disqualifiers
None
Trial design
Design model
Parallel
Treatments tested in this trial
Metyrapone And Hydrocortisone
DrugCortisol 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.
Dextrose
DrugThe 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,
insulin
DrugThe 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,
Treatment groups
48 Participants
are divided into 4 treatment groupsGroup A: Misaligned cortisol rhythm-night shift conditionActive comparator 3 interventions
Group B: Realigned cortisol rhythm-night shift conditionActive comparator 3 interventions
Group C: Fixed cortisol shape condition- day shift conditionActive comparator 3 interventions
Group D: Unfixed cortisol shape condition-day shift conditionPlacebo comparator 2 interventions
Trial outcomes
Primary outcomes
1
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).
Time frame
Change from baseline collection.2
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 baseline collection.3
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).
Time frame
Change from baseline collection.Secondary outcomes
1
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)2
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.
Time frame
Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).3
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)4
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.
Time frame
Collected every 4 hours throughout a constant routine protocol (days 4-5 of experimentation).Sponsors and contacts
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Washington State University
Lead sponsor
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Collaborator
Source ClinicalTrials.gov