Activation of Brown Adipose Tissue Metabolism Using Mirabegron

Not Applicable

Completed

• Conditions: Type 2 Diabetes
• Interventions: Drug: Mirabegron; Drug: Bisoprolol Fumarate

• Registration Number: NCT04823442
• Lead Sponsor: Université de Sherbrooke

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.

Study Timeline

• Study Start: 2021-01-21
• Study First Submitted: 2021-03-26
• Study First Submitted QC: 2021-03-26
• Study First Posted: 2021-03-30
• Primary Completion: 2022-04-04
• Study Completion: 2022-04-04
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-04
• Last Update Posted: 2024-12-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 9

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Study B	Bisoprolol Fumarate	Metabolic PET study with mirabegron and bisoprolol
Study A	Mirabegron	Metabolic PET study with mirabegron
Study B	Mirabegron	Metabolic PET study with mirabegron and bisoprolol

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Centre de recherche du CHUS; 🇨🇦 Sherbrooke, Quebec, Canada