The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation (Gluco-Starve)

The Role of Glucocorticoids to Maintain Energy Homeostasis During Starvation

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 fasting periods with each treatment. With the block and replace therapy, fasting-induced GC peak will be suppressed. Metabolic and autonomic parameters will be compared to reveal whether GCs mediate the physiological adaptions to caloric restriction.

Understanding acute effects of GCs upon caloric restriction 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 major causes of morbidity and mortality worldwide. Achieving long-term weight loss is challenging, as the body counteracts weight loss to preserve energy by increasing appetite and lowering energy expenditure. These physiological defense mechanisms are the main obstacle to successful weight reduction in obese people.

Therefore, identifying the signals that defend body weight during caloric restriction is essential for developing new antiobesity drugs. Corticosteroids mediate the physiological defense to starvation in rodents. Whether cortisol has the same impact on humans is unknown.

Therefore, we investigate whether cortisol regulates the physiological adaptions to caloric restriction in humans.

The general objective of this project is to investigate whether cortisol mediates physiological adaptions to caloric restriction.

The primary objective is to test whether cortisol mediates the increased appetite during caloric restriction.

Secondary objectives are to test whether the cortisol response to caloric restriction affects satiation, satiety, energy expenditure, substrate utilization, blood pressure, weight, body composition, secretion of neuroendocrine hormones, lipids, glucose, ketone bodies, sympathetic nervous system activity, immune cells, and inflammatory markers.

This is a double-blind, randomized, placebo-controlled crossover study.

After screening, subjects will be randomized to two crossover 7-day study periods with a wash-out 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 capsules per os (starting with a dose of 500 mg/d on day 1 to 3000mg/d on day 5, and then will be kept constant until day 7).

B) Participants will receive a placebo (0,9% NaCl solution) subcutaneously via a pump in a pulsed fashion and identical-looking placebo capsules per os with the same regimen as for metyrapone.

During both study periods, participants will undergo two days of caloric restriction.

• Study Type: Interventional
• Enrollment (Actual): 24
• 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: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• BMI 18.5 - 27 kg/m2
• Weight stability for 6 months prior to the trial (+/- 2kg)

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 trial within the past two months
• Intake of any drugs (prescribed, over the counter or recreational), within 48 hours of the study initiation
• Intake of any steroids (including topical or inhaler) six month prior to the study
• Known allergy to metyrapone or hydrocortisone
• 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 3000mg/d is achieved).	Drug: Metyrapone 250 mg Oral Tablets; During one phase of the study: Metyrapone (pills of 250mg) on empty stomach: Day 1 0-1-1, day 2 1-2-2, day 3 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0; 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 7 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 2-3-3 day 4 3-4-4 day 5 4-4-4 day 6 4-4-4 day 7 4-0-0; 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 7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satiation	Amount of food intake with ad libitum buffet	Two 7-day intervention periods

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satiety	Appetite rating by visual analog scale, minimum value 0, maximum value 100	Two 7-day intervention periods
Food preference	Amount of fat/ protein/carbohydrates consumed during ad libitum buffet	Two 7-day intervention periods
Energy expenditure	Basal metabolic rate, diet-induced thermogenesis	Two 7-day intervention periods
Substrate utilization	Respiratory quotient	Two 7-day intervention periods
Blood pressure	Blood pressure	Two 7-day intervention periods
Weight	Body weight	Two 7-day intervention periods
Body composition	measured with DEXA-Scans and body impedance analysis	Two 7-day intervention periods
Neuroendocrine hormones	Leptin, thyroid hormones, insulin, c-peptide, growth hormone, IGF1, catecholamines, GLP-1, GIP, glucagon, PYY, CCK, ghrelin, GDF-15, cortisol total and free, ACTH, renin, aldosterone, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, oxytocin, FGF-21	Two 7-day intervention periods
Lipids	Total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides	Two 7-day intervention periods
Glucose	measured via blood sample	Two 7-day intervention periods
Insulin sensitivity	measured via blood sample	Two 7-day intervention periods
Ketone bodies	measured via blood sample	Two 7-day intervention periods
Sympathetic nervous system activity	measured via ECG: Heart rate, interbeat interval, high-frequency activity, low-frequency activity, root mean square of successive differences	Two 7-day intervention periods
Immune cells	Peripheral blood mononuclear cells (PBMCs)	Two 7-day intervention periods
Inflammatory markers	IL-6, IL-1RA, IL-8, CRP	Two 7-day intervention periods
Motivation to eat	clicking speed computer test	Two 7-day intervention periods
Pleasure from eating	Fonts rating test	Two 7-day intervention periods
Measure of behavioural approach and behavioural inhibition system	Questionnaire	Two 7-day intervention periods
Eating behaviour type	Questionnaire	Two 7-day intervention periods

Collaborators and Investigators

• Sponsor: Eleonora Seelig

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2023
• Primary Completion (Actual): July 25, 2024
• Study Completion (Actual): July 25, 2024

Study Registration Dates

• First Submitted: March 3, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): August 14, 2024
• Last Update Submitted That Met QC Criteria: August 13, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: cortisol; fasting; starvation; caloric restriction; glucocorticoids
• Additional Relevant MeSH Terms: Nutrition Disorders; Malnutrition; Starvation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites; Hydrocortisone; Metyrapone
• Other Study ID Numbers: EKNZ 2022-01837

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