Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance

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

Interventions

DRUG

Metyrapone And Hydrocortisone

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.

DRUG

Dextrose

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,

DRUG

insulin

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,

Sponsors & Collaborators

• Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

  collaborator OTHER

• Washington State University

  lead OTHER

Principal Investigators

• Peter Liu, MBBS, PhD · Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center

• Hans P.A. Van Dongen, PhD · Washington State University

Study Design

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2026-07-01

Primary Completion

2029-03-31

Completion

2029-07-31

FDA Drug

Yes

Countries

• United States

Study Locations