Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals - A Double-blind, Randomized, Placebo-controlled Cross-over Study
Trial Snapshot
- Phase
- Early Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Insulin sensitivity
Study Overview
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 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
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:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Prevention
- Masking
- Double (Participant, Investigator)
Masking Description
Placebo-controlled
Eligibility Criteria
- Ages
- 18 Years to 40 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
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
Arms & Interventions
Metyrapone And Hydrocortisone
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).
Intervention: Metyrapone 250 mg Oral Tablets (Drug)
Metyrapone And Hydrocortisone
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).
Intervention: Hydrocortisone 19,9mg s.c., pulsatile with a flow rate of 10μl/s (Drug)
Placebo
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.
Intervention: Placebo 250 mg Tablets (Drug)
Placebo
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.
Intervention: Placebo (0,9% NaCl solution) (Drug)
Outcomes
Primary Outcomes
Insulin sensitivity
Time Frame: Two 8-day intervention periods
Change in insulin sensitivity assessed with a mixed meal tolerance test
Secondary Outcomes
- GLP-1 (nmol/l)(Two 8-day intervention periods)
- PYY (pg/ml)(Two 8-day intervention periods)
- Aldosterone (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- 17-Hydroxypregnenolon (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- Substrate utilisation(Two 8-day intervention periods)
- Renin(Two 8-day intervention periods)
- Pregnenolon (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- TSH (mIU/l)(Two 8-day intervention periods)
- Progesteron (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- 11-Deoxycorticosteron (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- T3 (nmol/l)(Two 8-day intervention periods)
- Satiation(Two 8-day intervention periods)
- Cortisol (nmol/l) total and free(Two 8-day intervention periods)
- Corticosteron (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- 18-Hydroxycorticosteron (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- 17-Hydroxyprogesteron (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- 11-Deoxycortisol (Adrenal Steroid Hormones)(Two 8-day intervention periods)
- GIP (nmol/l)(Two 8-day intervention periods)
- T4 (nmol/l)(Two 8-day intervention periods)
- Lipids (mmol/l) ((total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides)(Two 8-day intervention periods)
- Systolic and diastolic blood pressure(Two 8-day intervention periods)
- Weight(Two 8-day intervention periods)
- Energy expenditure(Two 8-day intervention periods)
- Satiety(Two 8-day intervention periods)
- HGH (mIU/l)(Two 8-day intervention periods)
- GDF-15 (pg/mL)(Two 8-day intervention periods)
- Sympathetic nervous system activity(Two 8-day intervention periods)
Investigators
Eleonora Seelig
Principal Investigator
University Hospital, Basel, Switzerland