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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.
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)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metyrapone And Hydrocortisone | Experimental | During one of the study periods, subjects receive hydrocortisone 19.9 mg/d day 1 to day 6 and 12 mg/d on day 7 subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone per os (starting with a dose of 750 mg/d, then the dose will be increased on day 3, where 2500mg/d is achieved and reduced on day 7 to 750mg). |
|
| Placebo | Placebo Comparator | During the other study period, subjects receive placebo (0,9% NaCl solution) the same dose of placebo instead of hydrocortisone subcutaneously via a pump in a pulsed fashion and the same dose of placebo tablets p.o instead of metyrapone. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metyrapone And Hydrocortisone | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Total body fat | Change in total body fat assessed with a Dual-Energy-X-Ray-Absorptiometry (DXA) | Two 7-day intervention periods |
| Measure | Description | Time Frame |
|---|---|---|
| Total lean mass | Change in total lean mass assessed with DXA | Two 7-day intervention periods |
| Insulin sensitivity | Change in insulin sensitivity assessed with a mixed meal tolerance test |
| Measure | Description | Time Frame |
|---|---|---|
| Untargeted metabolomics of blood | Blood sample | Two 7-day intervention periods |
| Untargeted metabolomics of adipose tissue | Adipose tissue sample |
Inclusion Criteria:
Exclusion Criteria:
Since hormone fluctuations associated with the menstrual cycle may alter cortisol levels, women will not be included in the study. Although diversity will be reduced and the statements of the study cannot be applied to the female sex, these strict inclusion criteria allow an optimal homogeneity and increase statistical power.
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| Name | Affiliation | Role |
|---|---|---|
| Eleonora Seelig, PD Dr.med. | Sponsor and principal investigator | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Basel | Basel | Canton of Basel-City | 4031 | Switzerland |
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| ID | Term |
|---|---|
| D050177 | Overweight |
| D009765 | Obesity |
| D006963 | Hyperphagia |
| ID | Term |
|---|---|
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
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| ID | Term |
|---|---|
| D008797 | Metyrapone |
| D006854 | Hydrocortisone |
| ID | Term |
|---|---|
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011282 | Pregnenediones |
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Double-blind, randomized, placebo-controlled cross-over study
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|
| Placebo | Drug | 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 |
|
| Two 7-day intervention periods |
| Glucose | Change in Glucose assessed with a mixed meal tolerance test | Two 7-day intervention periods |
| Insulin | Change in Insulin assessed with a mixed meal tolerance test | Two 7-day intervention periods |
| C-peptide | Change in C-peptide assessed with a mixed meal tolerance test | Two 7-day intervention periods |
| Energy expenditure | Basal metabolic rate measured with indirect calorimetryy | Two 7-day intervention periods |
| Substrate utilization | Respiratory quotient assessed with indirect calorimetry | Two 7-day intervention periods |
| Systolic and diastolic blood pressure | Assessment of blood pressure with a standard blood pressure monitor. | Two 7-day intervention periods |
| Weight | Measurement of weight with a standard scale | Two 7-day intervention periods |
| Lipids (mmol/l) ((total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides) | Blood sample | Two 7-day intervention periods |
| Immune cells (peripheral blood mononuclear cells) | Blood sample | Two 7-day intervention periods |
| Satiation | Amount of food intake with ad libitum buffet | Two 7-day intervention periods |
| Satiety | Appetite rating with visual analogue scale (VAS) from 0mm-100mm (0mm=not at all and 100mm=extreme) | Two 7-day intervention periods |
| Motivation | Motivation to eat measured with a speed clicking test | Two 7-day intervention periods |
| IL-6 (Inflammatory markers) | Blood sample | Two 7-day intervention periods |
| IL-1RA (Inflammatory markers) | Blood sample | Two 7-day intervention periods |
| IL-8 (Inflammatory markers) | Blood sample | Two 7-day intervention periods |
| CRP (Inflammatory markers) | Blood sample | Two 7-day intervention periods |
| Thyroid hormones | Blood sample | Two 7-day intervention periods |
| Growth hormone | Blood sample | Two 7-day intervention periods |
| IGF1 | Blood sample | Two 7-day intervention periods |
| Catecholamines | Blood sample | Two 7-day intervention periods |
| GLP-1 | Blood sample | Two 7-day intervention periods |
| GIP | Blood sample | Two 7-day intervention periods |
| Glucagon | Blood sample | Two 7-day intervention periods |
| PYY | Blood sample | Two 7-day intervention periods |
| CCK | Blood sample | Two 7-day intervention periods |
| FGF21 | Blood sample | Two 7-day intervention periods |
| Leptin | Blood sample | Two 7-day intervention periods |
| Ghrelin | Blood sample | Two 7-day intervention periods |
| GDF15 | Blood sample | Two 7-day intervention periods |
| Cortisol | Blood sample | Two 7-day intervention periods |
| Aldosterone | Blood sample | Two 7-day intervention periods |
| Renin | Blood sample | Two 7-day intervention periods |
| ACTH | Blood sample | Two 7-day intervention periods |
| Pregnenolone | Blood sample | Two 7-day intervention periods |
| Progesterone | Blood sample | Two 7-day intervention periods |
| 11-deoxycorticosterone | Blood sample | Two 7-day intervention periods |
| Corticosterone | Blood sample | Two 7-day intervention periods |
| 18-hydroxycorticosterone | Blood sample | Two 7-day intervention periods |
| 17-hydroxypregnenolone | Blood sample | Two 7-day intervention periods |
| 17-hydroxyprogesterone | Blood sample | Two 7-day intervention periods |
| 11-deoxycortisol | Blood sample | Two 7-day intervention periods |
| Oxytocin | Blood sample | Two 7-day intervention periods |
| Two 7-day intervention periods |
| Untargeted metabolomics of muscle | Muscle tissue sample | Two 7-day intervention periods |
| Gene expression analysis of adipose tissue | Adipose tissue sample | Two 7-day intervention periods |
| Gene expressions analysis of muscle tissue | Muscle tissue sample | Two 7-day intervention periods |
| D012816 |
| Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012817 | Signs and Symptoms, Digestive |
| D011283 |
| Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |