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Pharmacological Activation of Brown Adipose Tissue Metabolism (GB6)

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ClinicalTrials.gov Identifier: NCT02811289
Recruitment Status : Completed
First Posted : June 23, 2016
Last Update Posted : August 22, 2018
Sponsor:
Information provided by (Responsible Party):
André Carpentier, Université de Sherbrooke

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Mirbetriq (Mirabegron) Other: cold exposure Radiation: injection of 18FDG Radiation: injection of 11C-acetate Radiation: [3-3H]-glucose Other: [U-13C]-palmitate Other: 2H-Glycerol Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pharmacological or Cold-induced Activation of Brown Adipose Tissue Metabolism
Actual Study Start Date : August 5, 2016
Actual Primary Completion Date : May 24, 2018
Actual Study Completion Date : July 5, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Mirabegron

Arm Intervention/treatment
Experimental: Mirabegron
Mirbetriq (Mirabegron) (50mg) will be administered orally at time 0 to activate brown adipose tissue.
Drug: Mirbetriq (Mirabegron)
50mg of Mirabegron will be administered orally at time 0 in protocol A.
Other Name: 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

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

Active Comparator: Cold exposure
Cold exposure protocol using a water-conditioned cooling suit will be applied
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

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

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




Primary Outcome Measures :
  1. BAT net glucose uptake [ Time Frame: 2 years ]
    will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.

  2. BAT oxidative metabolism [ Time Frame: 2 years ]
    will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning

  3. BAT volume of metabolic activity [ Time Frame: 2 years ]
    will be determined using a total body CT (16 mA) followed by a PET acquisition.

  4. 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


Secondary Outcome Measures :
  1. 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. Glucose appearance rate [ Time Frame: 2 years ]
    will be determined using [3-3H]-glucose

  3. Energy expenditure [ Time Frame: 2 years ]
    will be determined by indirect calorimetry from VO2 and VCO2 (Vmax29n, Sensormedics)

  4. Insulin sensitivity [ Time Frame: 2 years ]
    will be determined using the HOMA-IR (based on fasting insulin and glucose levels)

  5. Insulin secretion rate [ Time Frame: 2 years ]
    will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters

  6. 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.

  7. metabolite responses [ Time Frame: 2 years ]
    will be determined using a multiplex assay system

  8. Electrocardiogram [ Time Frame: 2 years ]


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02811289


Locations
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Canada, Quebec
centre de recherche du CHUS
Sherbrooke, Quebec, Canada, J1H 5N4
Sponsors and Collaborators
Université de Sherbrooke
Investigators
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Principal Investigator: André Carpentier, M.D. Centre de recherche du CHUS
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: André Carpentier, Tenured professor, Université de Sherbrooke
ClinicalTrials.gov Identifier: NCT02811289    
Other Study ID Numbers: 2016-1086
First Posted: June 23, 2016    Key Record Dates
Last Update Posted: August 22, 2018
Last Verified: August 2018
Additional relevant MeSH terms:
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Mirabegron
Glycerol
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents
Cryoprotective Agents
Protective Agents