Activation of Brown Adipose Tissue Metabolism Using Mirabegron

Type 2 Diabetes Clinical Trial

— GB9  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04823442
• Other study ID #: 2021-3791
• Status: Completed
• Phase: N/A
• Start date: January 21, 2021
• Est. completion date: April 4, 2022

Study information

• Verified date: May 2024
• Source: Université de Sherbrooke
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: April 4, 2022
• Est. primary completion date: April 4, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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;

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Mirabegron
Mirabegron: a single dose of 200 mg mirabegron (4 tablets of 50 mg)
• Bisoprolol Fumarate
a single dose of 10 mg (2 tablets of 5 mg)

Locations

Country	Name	City	State
Canada	Centre de recherche du CHUS	Sherbrooke	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Université de Sherbrooke	Laval University

Country where clinical trial is conducted

Canada, 

References & Publications (1)

Dumont L, Caron A, Richard G, Croteau E, Fortin M, Frisch F, Phoenix S, Dubreuil S, Guerin B, Turcotte EE, Carpentier AC, Blondin DP. The effects of the beta1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown ad — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	BAT glucose uptake	Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning	240 minutes after drug administration
Secondary	Whole-body glucose partitioning	Assessed using i.v. injection of 18FDG with static PET/CT scanning	300 minutes after drug administration
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	BAT lipolysis	Estimated by quantifying changes in tissue radiodensity with CT.	baseline and 300 minutes after drug administration
Secondary	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).