Cortisol and Nutritional Sympathetic Responsiveness

NCT01620684 | Unknown Phase 4

• 2 other identifiers: MetyraponeHeart Foundation G11M5892
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metabolic Syndrome; Obesity; Insulin Resistance

Outcome Measures

Primary Outcomes (1)

• Nutritional sympathetic nervous system responsiveness

  Effects of acute overnight metyrapone treatment will be studied

  12-hours

Secondary Outcomes (1)

• insulin sensitivity

  12 hours

Study Arms (2)

metyrapone

ACTIVE COMPARATOR

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

Drug: metyrapone

sugar pill

PLACEBO COMPARATOR

Overnight treatment with placebo capsules

Drug: placebo

Interventions

metyrapone DRUG

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

Also known as: Metopirone (Novartis)

metyrapone

placebo DRUG

placebo capsules

sugar pill

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• Baker Heart Research Institute: lead

Study Sites (1)

Heart Centre, Alfred Hospital

Prahran, Melbourne, Victoria, 3181, Australia

RECRUITING

MeSH Terms

Conditions

Metabolic Syndrome; Obesity; Insulin Resistance

Interventions

Metyrapone; lactitol

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nora E Straznicky, PhD MPH

  Baker IDI Heart & Diabetes Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nora E Straznicky, PhD MPH

CONTACT

61 3 8532 1371; nora.straznicky@bakeridi.edu.au

Mariee T Grima, MDiet

CONTACT

61 3 8532 1523; mariee.grima@bakeridi.edu.au

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Research Officer

Study Record Dates

• First Submitted: June 12, 2012
• First Posted: June 15, 2012
• Study Start: February 1, 2013
• Primary Completion: December 1, 2014
• Last Updated: September 9, 2014

Record last verified: 2014-09

Locations

AU (1)