Glucocorticoids, Overeating, Overweight and Obesity
Conditions
Brief summary
The investigator aim to understand whether food-induced glucocorticoids influence fat mass in overweight and obese people. In a randomized, cross-over study, 23 overweight and obese volunteers will receive a block and replace therapy that mimics physiological glucocorticoid (GC) rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical overfeeding periods with each treatment. With the block and replace therapy food-induced GC peak will be suppressed. Metabolic and immunological parameters will be compared to reveal the effects of GCs during excessive overfeeding, particularly to understand changes in body fat.
Detailed description
Obesity is one of the most serious health problems of the 21st century, and new therapies are urgently needed. Glucocorticoids (GCs) increase with acute food intake. Several clinical studies have found that glucocorticoids contribute to common obesity, but the underlying mechanisms remain unknown. Here, the investigator aim to understand whether GCs influence the total body fat in obese and overweight study participants during excessive overfeeding. In a randomized, cross-over study, 23 overweight and obese individuals will receive a block and replace therapy that mimics physiological GC rhythm (Metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical overfeeding periods with each treatment. With the block and replace therapy, food-induced GC peak will be suppressed. Metabolic, autonomic, and immunological parameters will be compared. A) Participants will receive hydrocortisone 19.9mg/d day 1 to day 6 and 12mg on day 7 subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone per os (starting with a dose of 750mg/d on day 1 to 2500mg on day 3, which will be kept constant until day 6 and then reduced to 750mg on day 7) B) Participants will receive placebo (0,9% NaCl solution) 19.9mg/d day 1 to day 6 and 12mg on day 7 subcutaneously via a pump in a pulsed fashion (eight times/day) and placebo pills per os (starting with a dose of 750mg/d on day 1 to 2500mg on day 3, which will be kept constant until day 6 and then reduced to 750mg on day 7)
Interventions
Drug: Metyrapone 250 mg Oral Tablets During one phase of the study: Metyrapone (pills of 250mg) on full stomach: Day 1 0-1-2, day 2 1-2-2, day 3 3-3-4 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-0-0 Drug: Hydrocortisone 19,9mg/12mg 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 6 in a total daily dose of 19.9mg and 12mg on day 7
DRUGPlacebo
Drug: Placebo 250 mg Tablets During another phase of the study: identical looking placebo pills starting Day 1 During one phase of the study: Metyrapone (pills of 250mg) on full stomach: Day 1 0-1-2, day 2 1-2-2, day 3 3-3-4 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-0-0 Drug: Placebo (0,9% NaCl solution) 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 6 and 12mg on day 7
Sponsors
Eleonora Seelig
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Double-blind, randomized, placebo-controlled cross-over study
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Males aged 18 to 50 years * BMI≥ 25 kg/m² with a stable weight within past three months before study initiation
Exclusion criteria
* Any severe acute or chronic disease, including diabetes mellitus type 2 * Intake of GLP-1 agonists or hormone therapy * Hypercortisolism * Casual smoking (more than 6 cigarettes per day) * Frequent, heavy alcohol consumption (more than 30g/day) * Frequent, heavy caffeine consumption (more than 4 caffeinated drinks/day) * Regular physical exercise (more than 4hrs per week) * Shift work * Participation in an investigational drug trial within the past two months * Intake of any steroid-containing drugs, including topical steroids and inhalers, within 4 weeks of the study initiation * Known allergy to metyrapone * Inability or unwillingness to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total body fat | Two 7-day intervention periods | Change in total body fat assessed with a Dual-Energy-X-Ray-Absorptiometry (DXA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total lean mass | Two 7-day intervention periods | Change in total lean mass assessed with DXA |
| Insulin sensitivity | Two 7-day intervention periods | Change in insulin sensitivity assessed with a mixed meal tolerance test |
| Glucose | Two 7-day intervention periods | Change in Glucose assessed with a mixed meal tolerance test |
| Insulin | Two 7-day intervention periods | Change in Insulin assessed with a mixed meal tolerance test |
| C-peptide | Two 7-day intervention periods | Change in C-peptide assessed with a mixed meal tolerance test |
| Energy expenditure | Two 7-day intervention periods | Basal metabolic rate measured with indirect calorimetryy |
| Substrate utilization | Two 7-day intervention periods | Respiratory quotient assessed with indirect calorimetry |
| Systolic and diastolic blood pressure | Two 7-day intervention periods | Assessment of blood pressure with a standard blood pressure monitor. |
| Weight | Two 7-day intervention periods | Measurement of weight with a standard scale |
| Lipids (mmol/l) ((total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides) | Two 7-day intervention periods | Blood sample |
| Immune cells (peripheral blood mononuclear cells) | Two 7-day intervention periods | Blood sample |
| Satiation | Two 7-day intervention periods | Amount of food intake with ad libitum buffet |
| Satiety | Two 7-day intervention periods | Appetite rating with visual analogue scale (VAS) from 0mm-100mm (0mm=not at all and 100mm=extreme) |
| Motivation | Two 7-day intervention periods | Motivation to eat measured with a speed clicking test |
| IL-6 (Inflammatory markers) | Two 7-day intervention periods | Blood sample |
| IL-1RA (Inflammatory markers) | Two 7-day intervention periods | Blood sample |
| IL-8 (Inflammatory markers) | Two 7-day intervention periods | Blood sample |
| CRP (Inflammatory markers) | Two 7-day intervention periods | Blood sample |
| Thyroid hormones | Two 7-day intervention periods | Blood sample |
| Growth hormone | Two 7-day intervention periods | Blood sample |
| IGF1 | Two 7-day intervention periods | Blood sample |
| Catecholamines | Two 7-day intervention periods | Blood sample |
| GLP-1 | Two 7-day intervention periods | Blood sample |
| GIP | Two 7-day intervention periods | Blood sample |
| Glucagon | Two 7-day intervention periods | Blood sample |
| PYY | Two 7-day intervention periods | Blood sample |
| CCK | Two 7-day intervention periods | Blood sample |
| FGF21 | Two 7-day intervention periods | Blood sample |
| Leptin | Two 7-day intervention periods | Blood sample |
| Ghrelin | Two 7-day intervention periods | Blood sample |
| GDF15 | Two 7-day intervention periods | Blood sample |
| Cortisol | Two 7-day intervention periods | Blood sample |
| Aldosterone | Two 7-day intervention periods | Blood sample |
| Renin | Two 7-day intervention periods | Blood sample |
| ACTH | Two 7-day intervention periods | Blood sample |
| Pregnenolone | Two 7-day intervention periods | Blood sample |
| Progesterone | Two 7-day intervention periods | Blood sample |
| 11-deoxycorticosterone | Two 7-day intervention periods | Blood sample |
| Corticosterone | Two 7-day intervention periods | Blood sample |
| 18-hydroxycorticosterone | Two 7-day intervention periods | Blood sample |
| 17-hydroxypregnenolone | Two 7-day intervention periods | Blood sample |
| 17-hydroxyprogesterone | Two 7-day intervention periods | Blood sample |
| 11-deoxycortisol | Two 7-day intervention periods | Blood sample |
| Oxytocin | Two 7-day intervention periods | Blood sample |
Countries
Switzerland
Contacts
PRINCIPAL_INVESTIGATOREleonora Seelig, PD Dr.med.
Sponsor and principal investigator
Outcome results
None listed