Pharmacological Activation of Brown Adipose Tissue Metabolism (GB6)

August 20, 2018 updated by: André Carpentier, Université de Sherbrooke

Pharmacological or Cold-induced Activation of Brown Adipose Tissue Metabolism

Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). The mechanisms leading to excess exposure of lean tissues to fatty acids involve metabolic dysfunctions of adipose tissues and lean tissues themselves. Understanding the role of white and brown adipose tissue in this metabolic dysfunction is particularly important in predicting, preventing and treating T2D and many of its associated cardiovascular complications.

A recent breakthrough has been the demonstration that the acute oral administration of a β3 adrenergic agonist, mirabegron (200 mg), significantly increases BAT glucose uptake in healthy individuals. This suggests that mirabegron could be used as a pharmacological tool to selectively activate BAT metabolism as part of the mechanistic studies on BAT. It also suggests that mirabegron could be used pharmacologically for chronic activation of BAT in clinical trials to treat obesity and T2D. However, there are some outstanding issues regarding the use of mirabegron to activate BAT. First, there has been no direct comparison of the effect of acute cold vs. mirabegron on BAT metabolism. Second, there has been no demonstration of the effect of mirabegron on BAT oxidative metabolism since glucose uptake is only a surrogate of BAT energy expenditure. Third, acute administration of mirabegron led to significant increases in blood pressure and cardiac work, suggesting that it may also enhance energy expenditure in other organs in addition to BAT, thus confounding the role of BAT in energy homeostasis. Therefore, much remains to be known about the effect of mirabegron on BAT and cardiac energy metabolism before this drug can be used as a selective activator of BAT oxidative metabolism. The purpose of this study is to directly compare BAT oxidative metabolism under cold vs. β3-adrenergic agonist stimulation in lean healthy individuals. The investigator hypothesizes that the acute oral administration of a lower dose of mirabegron (50 mg) will result in an increase in BAT oxidative metabolism and whole-body energy expenditure, to a similar extent as cold exposure, without influencing the cardiovascular responses previously seen with the higher dose (200 mg).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The first step of the study will be direct comparison of mirabegron (protocol A) vs. cold-induced (protocol B) BAT metabolic activation using 11C-acetate to measure BAT metabolic activity. The principle of this method is measurement of tissue fast disappearance of 11C, a marker of tissue 11CO2 production. This fast tissue 11C clearance thus gives an index of tissue oxidative metabolism. Ten healthy, non obese men will undergo two identical 5h procedures in which BAT metabolism will be stimulated with a β3-agonist (mirabegron 50mg) or using cold exposure, in random order. The investigator just received approval from Health Canada to use mirabegron as part of these metabolic investigations. In brief, baseline blood samples and indirect calorimetry will be performed between time -60 to -30 min followed by i.v. injection of 11C-acetate with 30 min dynamic PET/CT scanning at room temperature in both protocol A and B. Mirabegron will be administered orally at time 0 in protocol A whereas acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B. At time 210 min (i.e. Tmax of plasma mirabegron level or 90 min after the onset of cold exposure), i.v. injection of 11C-acetate will be repeated followed by 30 min dynamic PET/CT scanning. I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning to determine BAT net glucose uptake and a whole-body PET/CT scan to determine BAT volume of metabolic activity and organ-specific glucose partitioning.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
22

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Sherbrooke, Quebec, Canada, J1H 5N4
        • Centre de Recherche du CHUS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 45 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • BMI < 30 kg/m2
  • normal glucose tolerance (2-hour post 75g OGTT glucose at < 7.8 mmol/l
  • HbA1c < 5.8%

Exclusion Criteria:

  • overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG;
  • treatment with any drug known to affect lipid or carbohydrate metabolism;
  • presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness;
  • smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day;
  • prior history or current fasting plasma cholesterol level > 7 mmol/l or fasting TG > 6 mmol/l.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: OTHER
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Mirabegron
Mirbetriq (Mirabegron) (50mg) will be administered orally at time 0 to activate brown adipose tissue.
Radiation: [3-3H]-glucose
i.v. administration of 1.5 uCi/min of [3-3H]-glucose
Other: [U-13C]-palmitate
i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate
Other: 2H-Glycerol
i.v. administration of 0.05 µmol/kg/min of 2H-glycerol
Drug: Mirbetriq (Mirabegron)
50mg of Mirabegron will be administered orally at time 0 in protocol A.
Other Names:
  • Mirabegron
Radiation: injection of 18FDG
I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning
Radiation: injection of 11C-acetate
i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning
ACTIVE_COMPARATOR: Cold exposure
Cold exposure protocol using a water-conditioned cooling suit will be applied
Radiation: [3-3H]-glucose
i.v. administration of 1.5 uCi/min of [3-3H]-glucose
Other: [U-13C]-palmitate
i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate
Other: 2H-Glycerol
i.v. administration of 0.05 µmol/kg/min of 2H-glycerol
Radiation: injection of 18FDG
I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning
Radiation: injection of 11C-acetate
i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning
Other: cold exposure
Acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
BAT net glucose uptake
Time Frame: 2 years
will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.
2 years
BAT oxidative metabolism
Time Frame: 2 years
will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning
2 years
BAT volume of metabolic activity
Time Frame: 2 years
will be determined using a total body CT (16 mA) followed by a PET acquisition.
2 years
whole body organ glucose partitioning
Time Frame: 2 years
will be determined using a total body CT (16 mA) followed by a PET acquisition be determined using a total body CT (16 mA) followed by a PET acquisition
2 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Insulin sensitivity
Time Frame: 2 years
will be determined using the HOMA-IR (based on fasting insulin and glucose levels)
2 years
Insulin secretion rate
Time Frame: 2 years
will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters
2 years
lipolysis rate
Time Frame: 2 years
will be measured using i.v. administration of [13C]-palmitate and [2H]-glycerol, using steele's non steady state equations
2 years
Glucose appearance rate
Time Frame: 2 years
will be determined using [3-3H]-glucose
2 years
Energy expenditure
Time Frame: 2 years
will be determined by indirect calorimetry from VO2 and VCO2 (Vmax29n, Sensormedics)
2 years
β-cell function
Time Frame: 2 years
will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin sensitivity.
2 years
metabolite responses
Time Frame: 2 years
will be determined using a multiplex assay system
2 years
Electrocardiogram
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Université de Sherbrooke

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: André Carpentier, M.D., Centre de Recherche du CHUS

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 5, 2016

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 24, 2018

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 5, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 14, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 20, 2016

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 23, 2016

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 22, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 20, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2016-1086

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 2 Diabetes

Clinical Trials on [3-3H]-glucose

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings