Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals

Study Overview
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Brief Summary
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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 overfeeding periods with each treatment. With the block and replace therapy, food-induced GC peak will be suppressed. Metabolic and autonomic parameters will be compared to reveal, whether GCs mediate the physiological adaptions to excessive food intake. Understanding acute effects of GCs upon food intake is critical, since repetitive disruptions of GC secretion may become harmful in chronic conditions.

Detailed Description
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Obesity is one of the most serious health problems of the 21st century. To understand how we regulate our body weight is crucial for developing new treatment targets. Even though body mass index of populations is increasing, the body weight of adults is usually kept stable over time. Indeed, acute excessive food intake triggers a set of adaptions in order to prevent weight gain. The signal that triggers these beneficial adaptions is still unknown. Glucocorticoid (GC) secretion increases with acute food intake and many physiological adaptions to overfeeding coincide with classical glucocorticoid actions. The investigators therefore hypothesize that GCs are the signal that prevents weight gain during acute overfeeding. The objective of this project is to test whether food-induced GCs represent the physiological signal that defends against weight gain. The primary objective is to investigate whether reduction in insulin sensitivity is abolished with the block and replace therapy. Secondary objectives are to investigate whether suppression of GC secretion during excessive food intake impairs the activation of sympathetic nervous system, satiety, satiation, energy expenditure, substrate utilization, blood pressure, secretion of neuroendocrine hormones, lipids and immune cells. This is a double-blind, randomized, placebo-controlled cross-over study. After screening, subjects will be randomized to two crossover 8-day study periods with a washout 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 per os (starting with a dose of 500 mg/d on day 1 to 2500mg/d on day 4, and then will be kept constant until day 8) B) Participants will receive placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion and placebo pills per os (starting with a dose of 500 mg/d on day 1 to 2500mg/d on day 4, and then will be kept constant until day 8)

Official Title
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Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals - A Double-blind, Randomized, Placebo-controlled Cross-over Study

Conditions
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Glucocorticoid Effect

Intervention / Treatment
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* Drug: Metyrapone 250 mg Oral Tablets
* Drug: Placebo 250 mg Tablets
* Drug: Hydrocortisone 19,9mg s.c., pulsatile with a flow rate of 10μl/s
* Drug: Placebo (0,9% NaCl solution)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI 18.5 - 25 kg/m2 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 trail within the past two months Intake of any drugs (prescribed, over the counter or recreational) including topical steroids and inhalers, within 48 hours of the study initiation Known allergy to metyrapone Inability or unwillingness to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind, randomized, placebo-controlled cross-over study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metyrapone And Hydrocortisone<br>During one of the study periods, subjects receive hydrocortisone 19.9 mg/d subcutaneously via a pump in a pulsed fashion (eight times/day) and metyrapone per os (starting with a dose of 500 mg/d, then the dose will be increased the next days until 2500mg/d is achieved). | Drug: Metyrapone 250 mg Oral Tablets<br>* During one phase of the study: Metyrapone (pills of 250mg) on full stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-2-3 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-3-4 day 8 3-0-0<br>Drug: Hydrocortisone 19,9mg s.c., pulsatile with a flow rate of 10μl/s<br>* Hydrocortisone will be delivered subcutaneously via a pump in a pulsed fashion with a flow rate of 10μl/s from day 1 to day 8 in a total daily dose of 19.9mg<br>|
| Placebo Comparator: Placebo<br>During the other study period, subjects receive placebo (0,9% NaCl solution) 19.9 mg/d subcutaneously via a pump in a pulsed fashion and the same dose of placebo tablets p.o instead of metyrapone. | Drug: Placebo 250 mg Tablets<br>* During another phase of the study: identical looking placebo pills starting Day 1 0-1-1, day 2 1-2-2, day 3 2-2-3 day 4 3-3-4 day 5 3-3-4 day 6 3-3-4 day 7 3-3-4 day 8 3-0-0<br>Drug: Placebo (0,9% NaCl solution)<br>* 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 8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Change in insulin sensitivity assessed with a mixed meal tolerance test | Two 8-day intervention periods | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortisol (nmol/l) total and free | Blood sample | Two 8-day intervention periods | 
| Renin | Blood Sample | Two 8-day intervention periods | 
| Aldosterone (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| Pregnenolon (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| Progesteron (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| 11-Deoxycorticosteron (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| Corticosteron (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| 18-Hydroxycorticosteron (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| 17-Hydroxypregnenolon (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| 17-Hydroxyprogesteron (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| 11-Deoxycortisol (Adrenal Steroid Hormones) | Blood Sample | Two 8-day intervention periods | 
| GLP-1 (nmol/l) | Blood sample | Two 8-day intervention periods | 
| GIP (nmol/l) | Blood Sample | Two 8-day intervention periods | 
| PYY (pg/ml) | Blood Sample | Two 8-day intervention periods | 
| T3 (nmol/l) | Blood Sample | Two 8-day intervention periods | 
| T4 (nmol/l) | Blood Sample | Two 8-day intervention periods | 
| TSH (mIU/l) | Blood Sample | Two 8-day intervention periods | 
| HGH (mIU/l) | Blood Sample | Two 8-day intervention periods | 
| Lipids (mmol/l) ((total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides) | Blood Sample | Two 8-day intervention periods | 
| GDF-15 (pg/mL) | Blood Sample | Two 8-day intervention periods | 
| Sympathetic nervous system activity | Heart rate variability analysis | Two 8-day intervention periods | 
| Systolic and diastolic blood pressure | Assessment of blood pressure with a standard blood pressure monitor. | Two 8-day intervention periods | 
| Weight | Measurement of weight with a standard scale | Two 8-day intervention periods | 
| Energy expenditure | Basal metabolic rate measured with indirect calorimetry | Two 8-day intervention periods | 
| Substrate utilisation | Respiratory quotient assessed with indirect calorimetry | Two 8-day intervention periods | 
| Satiety | Appetite rating with visual analogue scale (VAS) from 0mm-100mm (0mm=not at all and 100mm=extreme) | Two 8-day intervention periods | 
| Satiation | Amount of food intake with ad libitum buffet | Two 8-day intervention periods | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cortisol, overfeeding, glucocorticoids, insulin sensitivity