Glucocorticoid Effect
Conditions
Keywords
cortisol, glucocorticoids, starvation, caloric restriction, fasting
Brief summary
In a randomized, cross-over study, 20 healthy volunteers will receive a block and replace therapy that mimics physiological GC rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical fasting periods with each treatment. With the block and replace therapy, fasting-induced GC peak will be suppressed. Metabolic and autonomic parameters will be compared to reveal whether GCs mediate the physiological adaptions to caloric restriction. Understanding acute effects of GCs upon caloric restriction is critical, since repetitive disruptions of GC secretion may become harmful in chronic conditions.
Detailed description
Obesity is one of the major causes of morbidity and mortality worldwide. Achieving long-term weight loss is challenging, as the body counteracts weight loss to preserve energy by increasing appetite and lowering energy expenditure. These physiological defense mechanisms are the main obstacle to successful weight reduction in obese people. Therefore, identifying the signals that defend body weight during caloric restriction is essential for developing new antiobesity drugs. Corticosteroids mediate the physiological defense to starvation in rodents. Whether cortisol has the same impact on humans is unknown. Therefore, we investigate whether cortisol regulates the physiological adaptions to caloric restriction in humans. The general objective of this project is to investigate whether cortisol mediates physiological adaptions to caloric restriction. The primary objective is to test whether cortisol mediates the increased appetite during caloric restriction. Secondary objectives are to test whether the cortisol response to caloric restriction affects satiation, satiety, energy expenditure, substrate utilization, blood pressure, weight, body composition, secretion of neuroendocrine hormones, lipids, glucose, ketone bodies, sympathetic nervous system activity, immune cells, and inflammatory markers. This is a double-blind, randomized, placebo-controlled crossover study. After screening, subjects will be randomized to two crossover 7-day study periods with a wash-out period of 28 days: A) Participants will receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone capsules per os (starting with a dose of 500 mg/d on day 1 to 3000mg/d on day 5, and then will be kept constant until day 7). B) Participants will receive a placebo (0,9% NaCl solution) subcutaneously via a pump in a pulsed fashion and identical-looking placebo capsules per os with the same regimen as for metyrapone. During both study periods, participants will undergo two days of caloric restriction.
Interventions
During one phase of the study: Metyrapone (pills of 250mg) on empty stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0
DRUGHydrocortisone 19.9mg s.c., pulsatile with a flow rate of 10μl/s
Hydrocortisone will be delivered subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7 in a total daily dose of 19.9mg
During another phase of the study: identical looking placebo pills starting Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0
Placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 7
Sponsors
Eleonora Seelig
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
Placebo-controlled
Intervention model description
Double-blind, randomized, placebo-controlled cross-over study
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI 18.5 - 27 kg/m2 * Weight stability for 6 months prior to the trial (+/- 2kg)
Exclusion criteria
* Previous medical history for any chronic condition in the last three months, active disease or abnormal physical examination as verified by a qualified physician. * Casual smoking (\>6 cigarettes per day) * Frequent, heavy alcohol consumption (\>30g/day) * Frequent, heavy caffeine consumption (\>4 caffeinated drinks/day) * Regular physical exercise (\>4hrs per week) * Shift workers * Participation in an investigational drug trial within the past two months * Intake of any drugs (prescribed, over the counter or recreational), within 48 hours of the study initiation * Intake of any steroids (including topical or inhaler) six month prior to the study * Known allergy to metyrapone or hydrocortisone * Inability or unwillingness to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Satiation | Two 7-day intervention periods | Amount of food intake with ad libitum buffet |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Satiety | Two 7-day intervention periods | Appetite rating by visual analog scale, minimum value 0, maximum value 100 |
| Food preference | Two 7-day intervention periods | Amount of fat/ protein/carbohydrates consumed during ad libitum buffet |
| Energy expenditure | Two 7-day intervention periods | Basal metabolic rate, diet-induced thermogenesis |
| Substrate utilization | Two 7-day intervention periods | Respiratory quotient |
| Blood pressure | Two 7-day intervention periods | Blood pressure |
| Weight | Two 7-day intervention periods | Body weight |
| Body composition | Two 7-day intervention periods | measured with DEXA-Scans and body impedance analysis |
| Neuroendocrine hormones | Two 7-day intervention periods | Leptin, thyroid hormones, insulin, c-peptide, growth hormone, IGF1, catecholamines, GLP-1, GIP, glucagon, PYY, CCK, ghrelin, GDF-15, cortisol total and free, ACTH, renin, aldosterone, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, oxytocin, FGF-21 |
| Lipids | Two 7-day intervention periods | Total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides |
| Glucose | Two 7-day intervention periods | measured via blood sample |
| Ketone bodies | Two 7-day intervention periods | measured via blood sample |
| Sympathetic nervous system activity | Two 7-day intervention periods | measured via ECG: Heart rate, interbeat interval, high-frequency activity, low-frequency activity, root mean square of successive differences |
| Immune cells | Two 7-day intervention periods | Peripheral blood mononuclear cells (PBMCs) |
| Inflammatory markers | Two 7-day intervention periods | IL-6, IL-1RA, IL-8, CRP |
| Motivation to eat | Two 7-day intervention periods | clicking speed computer test |
| Pleasure from eating | Two 7-day intervention periods | Fonts rating test |
| Measure of behavioural approach and behavioural inhibition system | Two 7-day intervention periods | Questionnaire |
| Eating behaviour type | Two 7-day intervention periods | Questionnaire |
| Insulin sensitivity | Two 7-day intervention periods | measured via blood sample |
Countries
Switzerland
Outcome results
None listed