Clinical trial NCT04823442: Activation of Brown Adipose Tissue Metabolism Using Mirabegron
Official title: Sympathomimetics and Sympatholytics in Type 2 Diabetes: Teaching Old Drugs New Tricks
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Laval University
First posted: 2021-03-30
Enrollment: 9
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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;

Primary outcomes:
measure: Change in activation of Brown Adipose Tissue (BAT) (oxidative metabolism and blood flow)
timeFrame: 30 minutes before and 210 minutes after drug administration
measure: BAT glucose uptake
timeFrame: 240 minutes after drug administration
Secondary outcomes:
measure: Whole-body glucose partitioning
timeFrame: 300 minutes after drug administration
measure: Whole-body lipolysis
timeFrame: 150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
measure: Hepatic Glucose production
timeFrame: 150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
measure: Substrate utilisation
timeFrame: 150 minutes before and mean of time 210 and 270 minutes after drug administration (steady state).
measure: BAT lipolysis
timeFrame: baseline and 300 minutes after drug administration
measure: Changes in pancreatic and gut hormones
timeFrame: 150 minutes before and mean of time 180, 240 and 300 minutes after drug administration (steady state).
Other outcomes:
Locations:
city: Sherbrooke
country: Canada
facility: Centre de recherche du CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: Denis Blondin
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 adipose tissue thermogenesis. Acta Physiol (Oxf). 2024 May;240(5):e14127. doi: 10.1111/apha.14127. Epub 2024 Mar 19.