Glucose Intolerance, Sleep, Sleep Deprivation
Conditions
Keywords
Chronic Sleep Restriction, Artificial Light At Night, Glucose Intolerance, Melatonin, Sleep
Brief summary
This project is designed to test for the first time whether glucose metabolism is differentially impaired by sleep restriction with and without additional exposure to artificial light at night (ALAN).
Detailed description
Laboratory studies have shown that sleep restriction to 4-6h per night for durations varying from one to 14 days reduces glucose tolerance in otherwise healthy adults, but the mechanisms by which insufficient sleep impairs glucose metabolism are still unknown. Current theories are based on the premise that the adverse metabolic consequences are caused by reduction in the duration of sleep per se. However, sleep curtailment is typically accompanied by longer exposure to artificial light at night (ALAN), which is an environmental endocrine disrupter that profoundly disrupts circadian rhythms. The investigators have previously reported that acute circadian misalignment induced hyperglycemia comparable to pre-diabetic states in a third of otherwise healthy participants. Since then, the investigators have shown that even when the circadian phase of participants was realigned, prior exposure to 2 ½ weeks of chronic sleep restriction combined with a history of recurrent circadian disruption induced even more deleterious effects on glucose metabolism, in which pancreatic beta cells failed to respond adequately to increased glucose levels. Moreover, both night and rotating shift work (which induce circadian disruption) are associated with increased risk for metabolic problems. Night shifts can lead to acute increases in glucose and insulin levels, although some studies report reduced insulin release in response to meals consumed during the night. Given that circadian disruption has been shown to independently adversely affect metabolism, and exposure to ALAN adversely impacts metabolism in animals, it is important to understand the extent to which circadian disruption contributes to the observed impact of sleep curtailment on metabolism. No previous studies of the metabolic impact of sleep restriction in humans have controlled for this additional exposure to ALAN, thus confounding the effects of sleep restriction with the effects of circadian disruption caused by extended exposure to ALAN.
Interventions
OTHERSleep Restriction with ALAN first, then Sleep Restriction without ALAN
Sleep restriction with 90 lux lighting for 19hr/day first, followed by Sleep restriction with 90 lux lighting for 14hr/day
OTHERSleep Restriction without ALAN first, then sleep restriction with ALAN
Sleep restriction with 90 lux lighting for 14hr/day first, followed by Sleep restriction with 90 lux lighting for 19hr/day
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
The order in which subjects undergo the two sleep interventions will be randomized.
Intervention model description
This study uses a within-subjects randomized crossover design to compare the effects of sleep restriction with and without ALAN on glucose metabolism. The order in which subjects undergo the two sleep interventions will be randomized.
Eligibility
Sex/Gender
ALL
Age
20 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adults with conventional and regular sleep-wake timing * Non-smokers * Completion of medical, psychological, and sleep screening tests * Able to spend 33 consecutive days/nights in the laboratory * Normal color vision
Exclusion criteria
* History of neurological or psychiatric disorder * History of sleep disorder or regular use of sleep-promoting medication * Current prescription, herbal, or over-the-counter medication use * Traveling across 2 or more time zones within past 3 months * Donating blood within past 8 weeks * Worked night or rotating shift work within past 3 years * Hearing impairment, visual impairment * History of eye trauma or surgery * Drug or alcohol dependency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Impairment of Insulin Sensitivity | Change between Study Day 7 vs. Study Day 15 and Study Day 24 vs. Study Day 32 | Insulin sensitivity (Si) is assessed via minimal model analysis, a mathematical model developed by Bergman and colleagues. Higher values represent better insulin sensitivity and lower values represent impaired insulin sensitivity. The mean change in Si between exposure and baseline is reported for each arm. |
| Impairment of Glucose Tolerance | Change between Study Day 6 vs. Study Day 14 and Study Day 23 vs. Study Day 31 | Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will induce greater impairment of glucose tolerance than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Glucose tolerance will be calculated as the area under the curve from minutes 0-120 following a mixed meal tolerance test |
| Duration of Nocturnal Melatonin Secretion | Change between Study Day 14-15 (overnight) vs. Study Day 31-32 (overnight) | Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will acutely reduce the duration of nocturnal melatonin secretion as compared to baseline more than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Duration of nocturnal melatonin secretion will be determined by the duration of time at which melatonin levels are above a threshold calculated as 25% of peak-to-trough amplitude at baseline in dim light. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Insulin Response to Glucose | Change from study day 7 to 15 compared to change from study day 24 to 32 | Acute Insulin Response as calculated with minimal model analysis, a mathematical model developed by Bergman and colleagues, and represents early insulin release in the body to manage blood glucose levels. Higher values represent a better response and lower values represent a worse response. The mean change in AIRg between exposure and baseline is reported for each arm. |
| Duration of Endogenous Melatonin Secretory Profile | Study Day 15-16 vs Study Day 32-33 | Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will reduce the duration of the endogenous melatonin secretory profile more than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Duration of nocturnal melatonin secretion will be determined by the duration of time at which melatonin levels are above a threshold calculated as 25% of peak-to-trough amplitude at baseline in dim light. |
| Glucose Effectiveness | Change from study day 7 to 15 vs change from study day 24 to 32 | Glucose Effectiveness as calculated using minimal model analysis, a mathematical model developed by Bergman and colleagues. It represents how well the body can normalize blood glucose independent of insulin. Higher glucose effectiveness (Sg) is generally associated with better metabolic health outcomes. |
| Insulin Area-under-the-curve | Change between Study Day 6 vs. Study Day 14 and Study Day 23 vs. Study Day 31 | Insulin area under the curve (AUC) as calculated with trapezoidal method between 0-120min following mixed meal tolerance test. |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers were recruited through online advertisements between October 2021-December 2023.
Pre-assignment details
Two participants were excluded prior to randomization; one was due to an undisclosed surgery that excluded them from the study, and the other was due to ending study enrollment before they were admitted.
Participants by arm
| Arm | Count |
|---|---|
| Sleep Restriction Without ALAN, Then Sleep Restriction With ALAN Participants first received Sleep Restriction without extended duration Artificial Light At Night (ALAN), during which sleep episodes were shortened to 5 hours but participants were kept in dim light for the extra time awake (14h room light, 5h dim light, 5h darkness). After a washout of 10 days, participants received Sleep Restriction with extended duration ALAN, during which sleep episodes were shortened to 5 hours and participants remained in room lighting for the full wake episode (19h room light, 5h darkness). | 5 |
| Sleep Restriction With ALAN, Then Sleep Restriction Without ALAN Participants first received Sleep Restriction with extended duration Artificial Light At Night (ALAN), during which sleep episodes were shortened to 5 hours and participants remained in room lighting for the full wake episode (19h room light, 5h darkness). After a washout of 10 days, participants received Sleep Restriction without extended duration Artificial Light At Night (ALAN), during which sleep episodes were shortened to 5 hours but participants were kept in dim light for the extra time awake (14h room light, 5h dim light, 5h darkness). | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unable to complete study due to poor IV access | 1 | 1 |
Baseline characteristics
| Characteristic | Sleep Restriction Without ALAN, Then Sleep Restriction With ALAN | Sleep Restriction With ALAN, Then Sleep Restriction Without ALAN | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 2 / 12 | 6 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Duration of Nocturnal Melatonin Secretion
Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will acutely reduce the duration of nocturnal melatonin secretion as compared to baseline more than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Duration of nocturnal melatonin secretion will be determined by the duration of time at which melatonin levels are above a threshold calculated as 25% of peak-to-trough amplitude at baseline in dim light.
Time frame: Change between Study Day 14-15 (overnight) vs. Study Day 31-32 (overnight)
Population: Unable to calculate melatonin duration for one participant under the Without ALAN condition due to IV sampling difficulties
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Duration of Nocturnal Melatonin Secretion | 432.9 minutes | Standard Deviation 90.3 |
| Without ALAN | Duration of Nocturnal Melatonin Secretion | 579.6 minutes | Standard Deviation 44.8 |
Primary
Impairment of Glucose Tolerance
Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will induce greater impairment of glucose tolerance than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Glucose tolerance will be calculated as the area under the curve from minutes 0-120 following a mixed meal tolerance test
Time frame: Change between Study Day 6 vs. Study Day 14 and Study Day 23 vs. Study Day 31
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Impairment of Glucose Tolerance | 524.4 mg/dL*min | Standard Deviation 376.7 |
| Without ALAN | Impairment of Glucose Tolerance | 179.1 mg/dL*min | Standard Deviation 1121.6 |
Primary
Impairment of Insulin Sensitivity
Insulin sensitivity (Si) is assessed via minimal model analysis, a mathematical model developed by Bergman and colleagues. Higher values represent better insulin sensitivity and lower values represent impaired insulin sensitivity. The mean change in Si between exposure and baseline is reported for each arm.
Time frame: Change between Study Day 7 vs. Study Day 15 and Study Day 24 vs. Study Day 32
Population: One participant excluded from Without ALAN condition due to non-physiological assay results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Impairment of Insulin Sensitivity | -0.80 (mU/L)^-1 min^-1 | Standard Deviation 1.63 |
| Without ALAN | Impairment of Insulin Sensitivity | 0.55 (mU/L)^-1 min^-1 | Standard Deviation 4.18 |
Secondary
Acute Insulin Response to Glucose
Acute Insulin Response as calculated with minimal model analysis, a mathematical model developed by Bergman and colleagues, and represents early insulin release in the body to manage blood glucose levels. Higher values represent a better response and lower values represent a worse response. The mean change in AIRg between exposure and baseline is reported for each arm.
Time frame: Change from study day 7 to 15 compared to change from study day 24 to 32
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Acute Insulin Response to Glucose | -110.41 (mU/L)^-1 min^-1 | Standard Deviation 472.51 |
| Without ALAN | Acute Insulin Response to Glucose | -37.04 (mU/L)^-1 min^-1 | Standard Deviation 203.45 |
Secondary
Duration of Endogenous Melatonin Secretory Profile
Test the hypothesis that exposure to one week of sleep restriction with concurrent exposure to extended duration ALAN (LD 19:5) will reduce the duration of the endogenous melatonin secretory profile more than exposure to one week of sleep restriction without extended duration ALAN (LD 14:10). Duration of nocturnal melatonin secretion will be determined by the duration of time at which melatonin levels are above a threshold calculated as 25% of peak-to-trough amplitude at baseline in dim light.
Time frame: Study Day 15-16 vs Study Day 32-33
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Duration of Endogenous Melatonin Secretory Profile | 581.7 minutes | Standard Deviation 51.1 |
| Without ALAN | Duration of Endogenous Melatonin Secretory Profile | 609.6 minutes | Standard Deviation 66.1 |
Secondary
Glucose Effectiveness
Glucose Effectiveness as calculated using minimal model analysis, a mathematical model developed by Bergman and colleagues. It represents how well the body can normalize blood glucose independent of insulin. Higher glucose effectiveness (Sg) is generally associated with better metabolic health outcomes.
Time frame: Change from study day 7 to 15 vs change from study day 24 to 32
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Glucose Effectiveness | -0.00049 min^-1 | Standard Deviation 0.0051 |
| Without ALAN | Glucose Effectiveness | -0.0012 min^-1 | Standard Deviation 0.0073 |
Secondary
Insulin Area-under-the-curve
Insulin area under the curve (AUC) as calculated with trapezoidal method between 0-120min following mixed meal tolerance test.
Time frame: Change between Study Day 6 vs. Study Day 14 and Study Day 23 vs. Study Day 31
Population: We were unable to obtain meal response data for 2 participants due to IV access issues.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALAN | Insulin Area-under-the-curve | 663.4 uIu/mL*min | Standard Deviation 917.7 |
| Without ALAN | Insulin Area-under-the-curve | -71.6 uIu/mL*min | Standard Deviation 702.5 |