Activation of Brown Adipose Tissue Metabolism Using Mirabegron (GB9)

Sympathomimetics and Sympatholytics in Type 2 Diabetes: Teaching Old Drugs New Tricks

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Mirabegron; Drug: Bisoprolol Fumarate

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study A; Metabolic PET study with mirabegron	Drug: Mirabegron; Mirabegron: a single dose of 200 mg mirabegron (4 tablets of 50 mg); Other Names: Myrbetriq
Experimental: Study B; Metabolic PET study with mirabegron and bisoprolol	Drug: Mirabegron; Mirabegron: a single dose of 200 mg mirabegron (4 tablets of 50 mg); Other Names: Myrbetriq; Drug: Bisoprolol Fumarate; a single dose of 10 mg (2 tablets of 5 mg); Other Names: Apo Bisoprolol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)	Measured with 11C-acetate using dynamic PET/CT acquisition.	30 minutes before and 210 minutes after drug administration
BAT glucose uptake	Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning	240 minutes after drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole-body glucose partitioning	Assessed using i.v. injection of 18FDG with static PET/CT scanning	300 minutes after drug administration
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.	150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
Hepatic Glucose production	Systemic appearance rate of glucose determined by perfusion of [6,6 D2]-glucose	150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
Substrate utilisation	VO2 and VCO2 will be measured by indirect calorimetry to calculate carbohydrate and fatty acid oxidation rates.	150 minutes before and mean of time 210 and 270 minutes after drug administration (steady state).
BAT lipolysis	Estimated by quantifying changes in tissue radiodensity with CT.	baseline and 300 minutes after drug administration
Changes in pancreatic and gut hormones	measured with ELISA and Milliplex.	150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: Laval University
• Investigators: Principal Investigator: Denis Blondin, Universite de Sherbrooke

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2021
• Primary Completion (Actual): April 4, 2022
• Study Completion (Actual): April 4, 2022

Study Registration Dates

• First Submitted: March 26, 2021
• First Submitted That Met QC Criteria: March 26, 2021
• First Posted (Actual): March 30, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-3 Receptor Agonists; Bisoprolol; Mirabegron
• Other Study ID Numbers: 2021-3791

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No