Back to resultsActivation of Brown Adipose Tissue Metabolism Using Mirabegron (GB9)
Primary Purpose
Type 2 Diabetes
Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Mirabegron
Bisoprolol Fumarate
Sponsored by
About this trial
This is an interventional basic science trial for Type 2 Diabetes
Eligibility Criteria
Inclusion Criteria:
- Healthy subjects with normal glucose tolerance determined according to an oral glucose tolerance test;
- BMI ≤ 30 kg/m2.
Exclusion Criteria:
- Plasma triglycerides > 5.0 mmol/L at fasting;
- More than 2 alcohol consumption per day;
- More than 1 cigarette per day;
- History of total cholesterol level > 7 mmol/L, of cardiovascular disease, hypertensive crisis;
- Treatment with fibrates, thiazolidinedione, insulin,betablockers or other drugs with effects on insulin resistance or lipid metabolism (exception for antihypertensive drugs, statins or metformin);
- Presence of a noncontrolled thyroid disease, renal or hepatic disease, history of pancreatitis, bleeding diatheses, cardiovascular disease or any other serious medical conditions;
- History of serious gastrointestinal disorders (malabsorption, peptic ulcer, gastroesophageal reflux having required a surgery, etc.); reflux having required a surgery, etc.);
- Presence of a pacemaker;
- Have undergone of PET study or CT scan in the past year;
- Chronic administration of any medication;
Sites / Locations
- Centre de recherche du CHUS
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Study A
Study B
Arm Description
Metabolic PET study with mirabegron
Metabolic PET study with mirabegron and bisoprolol
Outcomes
Primary Outcome Measures
Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)
Measured with 11C-acetate using dynamic PET/CT acquisition.
BAT glucose uptake
Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning
Secondary Outcome Measures
Whole-body glucose partitioning
Assessed using i.v. injection of 18FDG with static PET/CT scanning
Whole-body lipolysis
Systemic appearance rate of glycerol and fatty acid determined by perfusion of [1,1,2,3,3-2H]-glycerol, [U-13C]-palmitate tracers. and concentration of total NEFA, triglycerides, palmitate, oleate, linoleate, glycerol.
Hepatic Glucose production
Systemic appearance rate of glucose determined by perfusion of [6,6 D2]-glucose
Substrate utilisation
VO2 and VCO2 will be measured by indirect calorimetry to calculate carbohydrate and fatty acid oxidation rates.
BAT lipolysis
Estimated by quantifying changes in tissue radiodensity with CT.
Changes in pancreatic and gut hormones
measured with ELISA and Milliplex.
Full Information
NCT ID
NCT04823442
First Posted
March 26, 2021
Last Updated
October 31, 2022
Sponsor
Université de Sherbrooke
Collaborators
Laval University
1. Study Identification
Unique Protocol Identification Number
NCT04823442
Brief Title
Activation of Brown Adipose Tissue Metabolism Using Mirabegron
Acronym
GB9
Official Title
Sympathomimetics and Sympatholytics in Type 2 Diabetes: Teaching Old Drugs New Tricks
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
January 21, 2021 (Actual)
Primary Completion Date
April 4, 2022 (Actual)
Study Completion Date
April 4, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Université de Sherbrooke
Collaborators
Laval University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Could sympathomimetics and sympatholytics drugs safe for the management of Type 2 Diabetes (T2D)? Based on recent evidence, we propose that pharmacological stimulation of Beta-3 adrenergic receptor (ADBR3) at higher doses of Mirabegron may be required to elicit changes in glycemia, but should be combined with Beta-1 adrenergic receptor (ADRB1) antagonists to suppress the unwanted effects on the cardiovascular system.
Together, several results establish a previously unappreciated cross-talk between Gs-coupled ADRB1 and ADRB3 in adipose tissue for the control of glucose homeostasis. Moreover, these data suggest that antagonizing ADRB1 may be a good way to significantly lower the dose of ADRB3 agonist required for glucose control.
Therefore, we believe that there are therapeutic opportunities in targeting adrenergic receptors for the treatment of T2D at least in young/middle aged people.
Detailed Description
In brief, participants will take part in 2 metabolic studies (A and B) performed in random order and at an interval of 7 to 14 days. Each metabolic study will last 8.5 hours with a baseline period of 2.5 hours. Participants will ingest either 200 mg of the ADRB3 agonist mirabegron (Myrbetriq, Astellas Pharma Canada) alone (study A) or in combination with 10 mg of bisoprolol, an ADRB1-antagonist (study B), at time 0.
The radioactive PET tracers (PET: positron emission tomography) used in this study are the [11C]-acetate and [18F]-FDG to estimate BAT oxidative metabolism and glucose metabolism, respectively. The perfusion of [6,6 D2]-glucose, [1,1,2,3,3-2H]-glycerol and [U-13C]-palmitate stable isotopes will also be performed in this study from time -150 min. to +300 min to examine the systemic appearance rate of glucose, glycerol and fatty acids, respectively. These studies will be almost identical (same perfusion of stable and radioactive tracers, same number of PET acquisitions) except for the drug which will be administered orally at time 0.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Study A
Arm Type
Active Comparator
Arm Description
Metabolic PET study with mirabegron
Arm Title
Study B
Arm Type
Experimental
Arm Description
Metabolic PET study with mirabegron and bisoprolol
Intervention Type
Drug
Intervention Name(s)
Mirabegron
Other Intervention Name(s)
Myrbetriq
Intervention Description
Mirabegron: a single dose of 200 mg mirabegron (4 tablets of 50 mg)
Intervention Type
Drug
Intervention Name(s)
Bisoprolol Fumarate
Other Intervention Name(s)
Apo Bisoprolol
Intervention Description
a single dose of 10 mg (2 tablets of 5 mg)
Primary Outcome Measure Information:
Title
Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)
Description
Measured with 11C-acetate using dynamic PET/CT acquisition.
Time Frame
30 minutes before and 210 minutes after drug administration
Title
BAT glucose uptake
Description
Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning
Time Frame
240 minutes after drug administration
Secondary Outcome Measure Information:
Title
Whole-body glucose partitioning
Description
Assessed using i.v. injection of 18FDG with static PET/CT scanning
Time Frame
300 minutes after drug administration
Title
Whole-body lipolysis
Description
Systemic appearance rate of glycerol and fatty acid determined by perfusion of [1,1,2,3,3-2H]-glycerol, [U-13C]-palmitate tracers. and concentration of total NEFA, triglycerides, palmitate, oleate, linoleate, glycerol.
Time Frame
150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
Title
Hepatic Glucose production
Description
Systemic appearance rate of glucose determined by perfusion of [6,6 D2]-glucose
Time Frame
150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
Title
Substrate utilisation
Description
VO2 and VCO2 will be measured by indirect calorimetry to calculate carbohydrate and fatty acid oxidation rates.
Time Frame
150 minutes before and mean of time 210 and 270 minutes after drug administration (steady state).
Title
BAT lipolysis
Description
Estimated by quantifying changes in tissue radiodensity with CT.
Time Frame
baseline and 300 minutes after drug administration
Title
Changes in pancreatic and gut hormones
Description
measured with ELISA and Milliplex.
Time Frame
150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Healthy subjects with normal glucose tolerance determined according to an oral glucose tolerance test;
BMI ≤ 30 kg/m2.
Exclusion Criteria:
Plasma triglycerides > 5.0 mmol/L at fasting;
More than 2 alcohol consumption per day;
More than 1 cigarette per day;
History of total cholesterol level > 7 mmol/L, of cardiovascular disease, hypertensive crisis;
Treatment with fibrates, thiazolidinedione, insulin,betablockers or other drugs with effects on insulin resistance or lipid metabolism (exception for antihypertensive drugs, statins or metformin);
Presence of a noncontrolled thyroid disease, renal or hepatic disease, history of pancreatitis, bleeding diatheses, cardiovascular disease or any other serious medical conditions;
History of serious gastrointestinal disorders (malabsorption, peptic ulcer, gastroesophageal reflux having required a surgery, etc.); reflux having required a surgery, etc.);
Presence of a pacemaker;
Have undergone of PET study or CT scan in the past year;
Chronic administration of any medication;
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Denis Blondin
Organizational Affiliation
Université de Sherbrooke
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre de recherche du CHUS
City
Sherbrooke
State/Province
Quebec
ZIP/Postal Code
J1H 5N4
Country
Canada
12. IPD Sharing Statement
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Activation of Brown Adipose Tissue Metabolism Using Mirabegron
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