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

University of Aarhus10 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

QUADRUPLE

Enrollment

Conditions

Healthy

Interventions

PrednisoloneDRUG

see arm description

PlaceboOTHER

Placebo similar to prednisolone

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Department of Endocrinology and Internal Medicine

Aarhus, State, Denmark

Outcomes

Primary Outcomes

Change in Sleeping RER

Change in respiratory exchange ratio (RER) during sleep between placebo and prednisolone

Time frame: Study day 1 and 2 (7 weeks apart)

Change in TEE

Change in Total Energy Expenditure between placebo and prednisolone

Time frame: Study day 1 and 2 (7 weeks apart)

Change in REE

Change in Resting Energy Expenditure between placebo and prednisolone and morning/evening

Time frame: 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

Time frame: Study day 1 and 2 (7 weeks apart)

Secondary Outcomes

Change in PAEE

Change in Physical Activity related Energy Expenditure (PAEE) between placebo and prednisolone and morning/evening

Time frame: Study day 1 and 2 (7 weeks apart)

Change in SEE

Change in Sleeping Energy Expenditure (PAEE) between placebo and prednisolone

Time frame: 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

Time frame: Study day 1 and 2 (7 weeks apart)

Change in clock gene mRNA levels leukocytes

Data from ClinicalTrials.gov

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Change in mRNA expression levels in blood leukocytes between placebo and prednisolone and prednisolone and morning/evening

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Study day 1 and 2 (7 weeks apart)

Change in food intake at home

Measured by dietary registration during prednisolone and placebo

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Study day 1 and 2 (7 weeks apart)

Change in cortisol levels

Measured successively over 24 hours in serum during study days

Time frame: 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

Time frame: 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

Time frame: Study day 1 and 2 (7 weeks apart)

Change in physical activity levels

Measured by actigraph during study periods

Time frame: Intervention period 1 and 2 (7 weeks apart)

Change in IPAQ-7

Measured by Internation Physical Activity Questionnaire

Time frame: Intervention period 1 and 2 (7 weeks apart)

Change in sleep quality (measured)

Measured by actigraph during study periods

Time frame: Intervention period 1 and 2 (7 weeks apart)

Change in sleep quality (reported)

Measured by Pittsburgh Sleep Quality Index questionnaire

Time frame: Intervention period 1 and 2 (7 weeks apart)

Change in sleep quality

Measured by polysomnography

Time frame: 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)

Time frame: Intervention period 1 and 2 (7 weeks apart)