CIRcadian Rhythms and CortisoL. Effects on Substrate Metabolism and Clock Gene Expression and Functioning

Study Overview
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Brief Summary
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The aim of this project is to study the effects of exogenous glucocorticoid exposure on substrate metabolism, energy expenditure and correlates of circadian rhythmicity in healthy adults. The hypotheses are: Short-term high dose glucocorticoid exposure in healthy subjects disrupts: The inherent circadian pattern of the respiratory exchange ratio and REE Sleep quality, appetite and food intake Clock gene expression and function in adipose tissue, skeletal muscle and blood leukocytes

Official Title
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CIRcadian Rhythms and CortisoL. Effects on Substrate Metabolism and Clock Gene Expression and Functioning

Conditions
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Healthy

Intervention / Treatment
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* Drug: Prednisolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male sex BMI 20-30 kg/m2 Written informed consent Exclusion Criteria: Any chronic disease requiring daily medication excluding atopic skin or hay fever Alcohol consumption >21 units per week Strong CYP3A4 inhibitors or inducers Use of glucocorticoid (GC) formulations: Inhaled corticosteroids, intra-articular or intramuscular injections, steroid creams European steroid group IV-V used in the genital area Permitted glucocorticoid formulations: eye-drops, nasal spray, GC creams European steroid group I-III, and European steroid group IV-V used in the non-genital area only Shift work Severe claustrophobia Use of melatonin Previous diagnosis of a sleep disorder Known severe sleep apnea (>30 respiration breaks/hour over 10 seconds) Deemed unable to complete the study safely by investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisolone first, then placebo<br>Prednisolone 12.5 mg twice daily for 5 days. Placebo twice daily for 5 days | Drug: Prednisolone<br>* see arm description<br>Other: Placebo<br>* Placebo similar to prednisolone<br>|
| Experimental: Placebo first, then prednisolone<br>Placebo twice daily for 5 days Prednisolone 12.5 mg twice daily for 5 days. | Drug: Prednisolone<br>* see arm description<br>Other: Placebo<br>* Placebo similar to prednisolone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sleeping RER | Change in respiratory exchange ratio (RER) during sleep between placebo and prednisolone | Study day 1 and 2 (7 weeks apart) | 
| Change in TEE | Change in Total Energy Expenditure between placebo and prednisolone | Study day 1 and 2 (7 weeks apart) | 
| Change in REE | Change in Resting Energy Expenditure between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in RER from fasting to feeding | Change in respiratory exchange ratio (RER) after standard meal between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PAEE | Change in Physical Activity related Energy Expenditure (PAEE) between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in SEE | Change in Sleeping Energy Expenditure (PAEE) between placebo and prednisolone | Study day 1 and 2 (7 weeks apart) | 
| Change in DIT | Change in diet-induced thermogenesis between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in clock gene mRNA levels leukocytes | Change in mRNA expression levels in blood leukocytes between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in clock gene mRNA levels adipose tissue | Change in mRNA expression levels in adipose tissue biopsies between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in clock gene mRNA levels skeletal muscle | Change in mRNA expression levels in skeletal muscle tissue biopsies between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in appetite | Measured by numerical rating scale on parameters hunger, fullness, satiety, desire and prospective consumption with values 1 (not at all) to 10 (maximally present) before and after ad libitum meal and standard meal, and between placebo and prednisolone and morning/evening. The scale is adapted from PMID: 20122136 | Study day 1 and 2 (7 weeks apart) | 
| Change in ad libitum food intake | Measured by caloric intake between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in food intake at home | Measured by dietary registration during prednisolone and placebo | Intervention period 1 and 2 (7 weeks apart) | 
| Change in fasting lipid oxidation rates | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in lipid oxidation rates from fasting to fed | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in glucose oxidation rates from fasting to fed | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in fasting glucose oxidation rates | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in fasting protein oxidation rates | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in protein oxidation rates from fasting to fed | Measured by whole room Indirect calorimetry between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in ghrelin levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in LEAP-2 levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in GLP-1 levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in GIP levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in Glucose levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in Insulin levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in Glucagon levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in Gastrin levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in CCK levels | Measured in serum before and after ad libitum meals and standard meals; between placebo and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in cortisol levels | Measured successively over 24 hours in serum during study days | Study day 1 and 2 (7 weeks apart) | 
| Change in FAP cells in skeletal muscle | Fibro-adipogenic progenitor cells levels and characteristics in skeletal muscle tissue biopsies between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in FAP cells in adipose tissue | Fibro-adipogenic progenitor cells levels and characteristics in adipose tissue biopsies between placebo and prednisolone and prednisolone and morning/evening | Study day 1 and 2 (7 weeks apart) | 
| Change in physical activity levels | Measured by actigraph during study periods | Intervention period 1 and 2 (7 weeks apart) | 
| Change in IPAQ-7 | Measured by Internation Physical Activity Questionnaire | Intervention period 1 and 2 (7 weeks apart) | 
| Change in sleep quality (measured) | Measured by actigraph during study periods | Intervention period 1 and 2 (7 weeks apart) | 
| Change in sleep quality (reported) | Measured by Pittsburgh Sleep Quality Index questionnaire | Intervention period 1 and 2 (7 weeks apart) | 
| Change in sleep quality | Measured by polysomnography | Study day 1 and 2 (7 weeks apart) | 
| Change in HADS | Measured by Hospital Anxiety and Depression Scale (HADS), a 14-question instrument with 7 questions measuring anxiety and 7 measuring depression. Each is scored between 0 (no impairment) and 3 (severe impairment) | Intervention period 1 and 2 (7 weeks apart) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucocorticoids, circadian rhythm, metabolism