Cortisol and Nutritional Sympathetic Responsiveness

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

24 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-02-28

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

This project will examine whether short-term (over a 12-hour period) pharmacological lowering of the stress hormone 'cortisol' improves the nervous system response to food intake in overweight or obese individuals who have metabolic syndrome.

The investigators know from our previous research that overweight/obese persons who are insulin resistant, have a blunted sympathetic nervous response to carbohydrate ingestion. This means that they are less able to dissipate energy from caloric intake, which would favour the maintenance of the obese state. Cortisol adversely impacts on insulin action and transport into the brain and cortisol levels are often elevated in persons with central (abdominal) obesity.

A randomized, double-blind, placebo controlled, cross-over design will be used to compare the effects of overnight treatment with metyrapone (15 mg/kg at midnight and 15 mg/kg at 6 am) versus placebo on sympathetic nervous system activity in response to a standard 75-g oral sugar (glucose) tolerance test. A 2 week washout will separate treatments.

Metyrapone is a drug that reversibly inhibits the enzyme 11beta-hydroxylase, and therefore the production of cortisol. It is used clinically to test the activity of the adrenal gland (the key site of cortisol production) and the pituitary gland. The investigators anticipate that at the dosage used, it will lower blood cortisol concentration by 44 to 64% during the experimental morning.

The study protocol comprises two screening visits and two experimental mornings. Key procedures will include:

* Assessment of insulin action (sensitivity) using the gold standard 'clamp' method.
* Measurement of sympathetic nervous system activity by both biochemical methods (isotope dilution which provides a measure of the apparent rate of release of 'noradrenaline'-the key neurotransmitter in the sympathetic nervous system) and direct intra-neuronal nerve recordings from the peroneal nerve in the lower leg.
* Indirect calorimetry to assess resting metabolic rate and the response to sugar ingestion.
* DEXA scan to quantify fat and lean mass.
* Assessment of arterial elasticity and calf blood flow by non-invasive methods.
* A standard 75g oral sugar tolerance test.

The results will provide important new information regarding the role of cortisol on nervous system function in overweight/obese individuals.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

Prevention of Metabolic Complications of Glucocorticoid Excess

NCT01319994

Iatrogenic Cushing Disease

COMPLETED PHASE2/PHASE3

Short-term Effects of Leptin in People With Lipodystrophy

NCT01778556

Lipodystrophy

COMPLETED PHASE2

Effect of Ghrelin on Sympathetic Nervous System

NCT00912587

Healthy Obesity

COMPLETED NA

Compassionate Use of Metreleptin in Previously Treated People With Partial Lipodystrophy

NCT02262806

Diabetes Lipodystrophy Hyperlipidemia

ACTIVE_NOT_RECRUITING PHASE2

Cardiac Rest and Stress Metabolism in Patients With Type 2 Diabetes

NCT04009642

Diabetes Mellitus, Type 2 Metabolic Cardiomyopathy Metabolic Disturbance +1 more

COMPLETED

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

Similarities between metabolic syndrome obesity and hypercortisolemic conditions such as Cushing's syndrome have raised interest in the pathogenic role of glucocorticoid excess in this clinical setting. Cortisol is a well known counter-regulator of insulin action and increased levels of serum cortisol have been linked to insulin resistance in many studies. Moreover, treatment with the synthetic glucocorticoid dexamethasone reduced central nervous system insulin uptake by 49% in dogs. We have previously identified in metabolic syndrome subjects, an inverse relationship between morning fasting cortisol levels and sympathetic neural responsiveness to oral glucose ingestion. This concurs with other evidence that cortisol and synthetic glucocorticoids have sympathoinhibitory effects.

This project will test the hypothesis that short-term lowering of plasma cortisol levels by overnight metyrapone treatment, will improve nutritional sympathetic nervous system responses to carbohydrate ingestion in obese insulin resistant subjects with metabolic syndrome.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Metabolic Syndrome Obesity Insulin Resistance

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

metyrapone

Overnight metyrapone treatment (total dose of 30 mg/kg)

Group Type ACTIVE_COMPARATOR

metyrapone

Intervention Type DRUG

Overnight treatment (15 mg/kg at midnight and 15 mg/kg at 6 am)

sugar pill

Overnight treatment with placebo capsules

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

placebo capsules

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

metyrapone

Overnight treatment (15 mg/kg at midnight and 15 mg/kg at 6 am)

Intervention Type DRUG

placebo

placebo capsules

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Metopirone (Novartis)

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

* un-medicated,
* overweight or obese subjects (12 men and 12 postmenopausal women),
* weight-stable,
* non-smoking,
* aged 45-65 years
* will be recruited on the basis of having \> 3 MetS criteria as per the newly harmonized definition.
* elevated waist circumference will be defined as \> 102 cm in men and \> 88 cm in women.
* all subjects will also be insulin resistant (HOMA index \> 2.5 and/or euglycaemic hyperinsulinemic clamp derived M/I value \< 8 mg per kg fat free mass per minute per mU/L x 100).

Exclusion Criteria

* adrenocortical insufficiency,
* pituitary dysfunction or tumour,
* sleep apnoea treated with CPAP,
* cardiovascular disease (previous MI, angina, stroke, heart failure, secondary hypertension),
* renal or hepatic disease (serum creatinine \> 0.2 mmol/L; \> 1 proteinuria on dipstick; alanine transferase \> 2.5 times upper limit of normal, active liver disease) or
* diseases which may affect measured parameters (e.g. thyroid, Cushing's or Addison's diseases).

Minimum Eligible Age

45 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No