Cortisol and Nutritional Sympathetic Responsiveness

The Effects of Cortisol Blockade on Nutritional Sympathetic Nervous System Responsiveness in Overweight and Obese Subjects With Metabolic Syndrome

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.

Study Overview

• Status: Unknown
• Conditions: Obesity; Metabolic Syndrome; Insulin Resistance
• Intervention / Treatment: Drug: placebo; Drug: metyrapone

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Melbourne, Victoria, Australia, 3181
      • Recruiting
      • Heart Centre, Alfred Hospital
      • Contact: Nora E Straznicky, BPharm PhD MPH; Phone Number: 61 3 8532 1371; Email: nora.straznicky@bakeridi.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Metopirone (Novartis)
PLACEBO_COMPARATOR: sugar pill; Overnight treatment with placebo capsules	Drug: placebo; placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nutritional sympathetic nervous system responsiveness	Effects of acute overnight metyrapone treatment will be studied	12-hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity	Acute effects of overnight metyrapone treatment will be studied	12 hours

Collaborators and Investigators

• Sponsor: Baker Heart Research Institute
• Investigators: Principal Investigator: Nora E Straznicky, PhD MPH, Baker IDI Heart & Diabetes Institute

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ANTICIPATED): December 1, 2014

Study Registration Dates

• First Submitted: June 12, 2012
• First Submitted That Met QC Criteria: June 14, 2012
• First Posted (ESTIMATE): June 15, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2014
• Last Update Submitted That Met QC Criteria: September 8, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Hyperinsulinism; Syndrome; Metabolic Syndrome; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Metyrapone
• Other Study ID Numbers: Metyrapone; Heart Foundation G11M5892 (OTHER_GRANT: Heart Foundation of Australia)