Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals (Gluco-Feed)

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

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.

Study Overview

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

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:

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)

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4031
      • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Metyrapone 250 mg Oral Tablets; 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; Drug: Hydrocortisone 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 8 in a total daily dose of 19.9mg
Placebo Comparator: 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.	Drug: Placebo 250 mg Tablets; 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; 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 8

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL-6 (Inflammatory markers)	Blood Sample	Two 8-day intervention periods
IL-1RA (Inflammatory markers)	Blood Sample	Two 8-day intervention periods
IL-8 (Inflammatory markers)	Blood Sample	Two 8-day intervention periods
CRP (Inflammatory markers)	Blood Sample	Two 8-day intervention periods
Metabolomics	Metabolomics will be performed in blood plasma	Two 8-day intervention periods

Collaborators and Investigators

• Sponsor: Eleonora Seelig

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2022
• Primary Completion (Actual): June 8, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): August 23, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: insulin sensitivity; cortisol; glucocorticoids; overfeeding
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites; Hydrocortisone; Metyrapone
• Other Study ID Numbers: EKNZ 2021-01507

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No