Circadian Misalignment and Insulin Sensitivity

Study Overview
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Brief Summary
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This study will evaluate the effect of circadian misalignment on insulin sensitivity in healthy lean subjects in a randomized cross-over design. Subjects will be admitted to the research facility for two study periods of 3 and 3.5 days. In one of the study periods, the behavioral cycle will be shifted by 12 hours. Insulin sensitivity will be measured with a hyperinsulinemic euglycemic clamp.

Detailed Description
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Recent evidence shows that misalignment of the circadian rhythm (e.g. by rotating shift work) impairs glucose metabolism markedly, possibly by decreasing insulin sensitivity in peripheral tissues and liver. Nowadays our society is indispensably connected to a lifestyle that allows wakefulness at every time of the 24 hours cycle. Social jetlag is a phenomenon that affects a large part of the general population, thus circadian misalignment extends far beyond those who are on a shift work schedule. Therefore, decreased insulin sensitivity in individuals affected by circadian misalignment may help to explain the increased prevalence of T2DM in night shift workers that has been found in epidemiological studies. The study is an interventional randomized crossover trial in which each subject serves as it owns control. For the study, the investigators ask the subjects to participate in two study periods, one of 3 days length (control condition) and the other of 3.5 days length (misalignment condition). During the 3.5 day misalignment condition, subjects will shift their day-night rhythm by 12 hours, which will lead to maximal circadian misalignment. Insulin sensitivity will be measured by a hyperinsulinemic euglycemic clamp. Secondary parameters will include ex-vivo skeletal muscle mitochondrial function and whole-body energy metabolism.

Official Title
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Impact of Circadian Misalignment on Insulin Sensitivity

Conditions
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Diabetes Mellitus, Type 2, Insulin Resistance

Intervention / Treatment
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* Behavioral: Circadian Misalignment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian Healthy (as determined by dependent physician based on medical questionnaire) Male Age: 18-35 years Normal BMI (18-25 kg/m2) Regular sleeping time (normally 7 - 9h daily) Habitual bedtime at 11 PM ± 2 hours Exclusion Criteria: Extreme early bird or extreme night person Heavily varying sleep-wake rhythm Shiftwork during last 3 months Travel across >1 time zone in the last 3 months Engagement in exercise > 3 hours total per week Using > 400mg caffeine daily Smoking Unstable body weight (weight gain or loss > 3kg in the last 3 months) Significant food allergies/intolerance (seriously hampering study meals) Participation in another biomedical study within 1 month before the first study visit Claustrophobia Medication use hampering the study (as determined by responsible physician) Recent blood donation. Any contra-indication to the telemetric pill: Any acute condition, exacerbation of chronic condition, or medical history that would in the investigator's opinion interfere with the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>3 days with normal circadian alignment. | |
| Experimental: Circadian Misalignment<br>3.5 days in which the subjects will undergo a maximal circadian misalignment of 12 hours by means of a midday nap during the second day, and a subsequent start of a new normal wake period, shifted 12 hours. | Behavioral: Circadian Misalignment<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Measured with hyperinsulinemic euglycemic clamp | 2 days after circadian misalignment and matched time in control arm. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxidative glucose disposal |  | 2 days after circadian misalignment and matched time in control arm. | 
| Non-oxidative glucose disposal |  | 2 days after circadian misalignment and matched time in control arm. | 
| Skeletal muscle mitochondrial function | Measured with high-resolution respirometry on permeabilized muscle fibers after muscle biopsy | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Whole body energy metabolism while awake | Measured by indirect calorimetry | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Sleeping metabolic rate | Measured by indirect calorimetry | 1.5 days after circadian misalignment and matched time in control arm | 
| Skeletal muscle mtDNA | Measured by qPCR | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Skeletal muscle mRNA | Measured by qPCR and Western Blotting | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Skeletal muscle proteins | Measured by Western Blotting | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Metabolic compounds in the blood (e.g. glucose, insulin, FFA's, Triglycerides, cholesterol) |  | 1 and 2 days after circadian misalignment and matched times in control arm | 
| Core-body-temperature | Measured by a telemetric pill | 1 day after circadian misalignment and matched time in control arm | 
| Peripheral skin temperature | Measured by skin temperature sensors | 1 day after circadian misalignment and matched time in control arm | 
| Central skin temperature | Measured by skin temperature sensors | 1 day after circadian misalignment and matched time in control arm | 
| Heart rate | Measured by heart rate monitor | 1 day after circadian misalignment and matched time in control arm | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Circadian Rhythm, Circadian Misalignment, Insulin Sensitivity