Cortisol and Nutritional Sympathetic Responsiveness

This study is not yet open for participant recruitment.
Verified January 2013 by Baker Heart Research Institute
Sponsor:
Information provided by (Responsible Party):
Nora E. Straznicky, Baker Heart Research Institute
ClinicalTrials.gov Identifier:
NCT01620684
First received: June 12, 2012
Last updated: January 15, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Metabolic Syndrome
Obesity
Insulin Resistance
Drug: metyrapone
Drug: placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: The Effects of Cortisol Blockade on Nutritional Sympathetic Nervous System Responsiveness in Overweight and Obese Subjects With Metabolic Syndrome

Resource links provided by NLM:


Further study details as provided by Baker Heart Research Institute:

Primary Outcome Measures:
  • Nutritional sympathetic nervous system responsiveness [ Time Frame: 12-hours ] [ Designated as safety issue: No ]
    Effects of acute overnight metyrapone treatment will be studied


Secondary Outcome Measures:
  • insulin sensitivity [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    Acute effects of overnight metyrapone treatment will be studied


Estimated Enrollment: 24
Study Start Date: February 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: metyrapone
Overnight metyrapone treatment (total dose of 30 mg/kg)
Drug: metyrapone
Overnight treatment (15 mg/kg at midnight and 15 mg/kg at 6 am)
Other Name: Metopirone (Novartis)
Placebo Comparator: sugar pill
Overnight treatment with placebo capsules
Drug: placebo
placebo capsules

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   45 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01620684

Contacts
Contact: Nora E Straznicky, PhD MPH 61 3 8532 1371 nora.straznicky@bakeridi.edu.au
Contact: Mariee T Grima, MDiet 61 3 8532 1523 mariee.grima@bakeridi.edu.au

Locations
Australia, Victoria
Heart Centre, Alfred Hospital Not yet recruiting
Prahran, Melbourne, Victoria, Australia, 3181
Contact: Nora E Straznicky, BPharm PhD MPH    61 3 8532 1371    nora.straznicky@bakeridi.edu.au   
Principal Investigator: Nora E Straznicky, PhD MPH         
Sponsors and Collaborators
Baker Heart Research Institute
Investigators
Principal Investigator: Nora E Straznicky, PhD MPH Baker IDI Heart & Diabetes Institute
  More Information

No publications provided

Responsible Party: Nora E. Straznicky, Senior Research Officer, Baker Heart Research Institute
ClinicalTrials.gov Identifier: NCT01620684     History of Changes
Other Study ID Numbers: Metyrapone, Heart Foundation G11M5892
Study First Received: June 12, 2012
Last Updated: January 15, 2013
Health Authority: Alfred Hospital Human Research Ethics Committee, Australia:
Baker IDI Heart & Diabetes Institute, Australia:

Additional relevant MeSH terms:
Insulin Resistance
Metabolic Syndrome X
Glucose Metabolism Disorders
Metabolic Diseases
Obesity
Hyperinsulinism
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Hydrocortisone
Metyrapone
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014