Pharmacological Activation of Brown Adipose Tissue Metabolism

NCT02811289 | Completed

• 1 other identifier: 2016-1086
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Lean tissue intracellular triglycerides (ICTG) accretion is an important marker of lean tissue lipotoxicity that significantly contributes to the development of type 2 diabetes (T2D). The mechanisms leading to excess exposure of lean tissues to fatty acids involve metabolic dysfunctions of adipose tissues and lean tissues themselves. Understanding the role of white and brown adipose tissue in this metabolic dysfunction is particularly important in predicting, preventing and treating T2D and many of its associated cardiovascular complications. A recent breakthrough has been the demonstration that the acute oral administration of a β3 adrenergic agonist, mirabegron (200 mg), significantly increases BAT glucose uptake in healthy individuals. This suggests that mirabegron could be used as a pharmacological tool to selectively activate BAT metabolism as part of the mechanistic studies on BAT. It also suggests that mirabegron could be used pharmacologically for chronic activation of BAT in clinical trials to treat obesity and T2D. However, there are some outstanding issues regarding the use of mirabegron to activate BAT. First, there has been no direct comparison of the effect of acute cold vs. mirabegron on BAT metabolism. Second, there has been no demonstration of the effect of mirabegron on BAT oxidative metabolism since glucose uptake is only a surrogate of BAT energy expenditure. Third, acute administration of mirabegron led to significant increases in blood pressure and cardiac work, suggesting that it may also enhance energy expenditure in other organs in addition to BAT, thus confounding the role of BAT in energy homeostasis. Therefore, much remains to be known about the effect of mirabegron on BAT and cardiac energy metabolism before this drug can be used as a selective activator of BAT oxidative metabolism. The purpose of this study is to directly compare BAT oxidative metabolism under cold vs. β3-adrenergic agonist stimulation in lean healthy individuals. The investigator hypothesizes that the acute oral administration of a lower dose of mirabegron (50 mg) will result in an increase in BAT oxidative metabolism and whole-body energy expenditure, to a similar extent as cold exposure, without influencing the cardiovascular responses previously seen with the higher dose (200 mg).

Conditions

Type 2 Diabetes

Outcome Measures

Primary Outcomes (4)

• BAT net glucose uptake

  will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.

  2 years

• BAT oxidative metabolism

  will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning

  2 years

• BAT volume of metabolic activity

  will be determined using a total body CT (16 mA) followed by a PET acquisition.

  2 years

• whole body organ glucose partitioning

  will be determined using a total body CT (16 mA) followed by a PET acquisition be determined using a total body CT (16 mA) followed by a PET acquisition

  2 years

Secondary Outcomes (8)

• lipolysis rate

  2 years

• Glucose appearance rate

  2 years

• Energy expenditure

  2 years

• Insulin sensitivity

  2 years

• Insulin secretion rate

  2 years

Study Arms (2)

Mirabegron

EXPERIMENTAL

Mirbetriq (Mirabegron) (50mg) will be administered orally at time 0 to activate brown adipose tissue.

Drug: Mirbetriq (Mirabegron); Radiation: injection of 18FDG; Radiation: injection of 11C-acetate; Radiation: [3-3H]-glucose; Other: [U-13C]-palmitate; Other: 2H-Glycerol

Cold exposure

ACTIVE COMPARATOR

Cold exposure protocol using a water-conditioned cooling suit will be applied

Other: cold exposure; Radiation: injection of 18FDG; Radiation: injection of 11C-acetate; Radiation: [3-3H]-glucose; Other: [U-13C]-palmitate; Other: 2H-Glycerol

Interventions

Mirbetriq (Mirabegron) DRUG

50mg of Mirabegron will be administered orally at time 0 in protocol A.

Also known as: Mirabegron

Mirabegron

cold exposure OTHER

Acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B

Cold exposure

injection of 18FDG RADIATION

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning

Cold exposure; Mirabegron

injection of 11C-acetate RADIATION

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

Cold exposure; Mirabegron

[3-3H]-glucose RADIATION

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

Cold exposure; Mirabegron

[U-13C]-palmitate OTHER

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

Cold exposure; Mirabegron

2H-Glycerol OTHER

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

Cold exposure; Mirabegron

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI \< 30 kg/m2
• normal glucose tolerance (2-hour post 75g OGTT glucose at \< 7.8 mmol/l
• HbA1c \< 5.8%

You may not qualify if:

• overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG;
• treatment with any drug known to affect lipid or carbohydrate metabolism;
• presence of liver or renal disease, uncontrolled thyroid disorder, previous pancreatitis, bleeding disorder, or other major illness;
• smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day;
• prior history or current fasting plasma cholesterol level \> 7 mmol/l or fasting TG \> 6 mmol/l.

Sponsors & Collaborators

• Université de Sherbrooke: lead

Study Sites (1)

centre de recherche du CHUS

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Related Publications (1)

• Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guerin B, Turcotte EE, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC. Human Brown Adipocyte Thermogenesis Is Driven by beta2-AR Stimulation. Cell Metab. 2020 Aug 4;32(2):287-300.e7. doi: 10.1016/j.cmet.2020.07.005.

  PMID: 32755608 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

mirabegron

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• André Carpentier, M.D.

  Centre de recherche du CHUS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Tenured professor

Study Record Dates

• First Submitted: June 14, 2016
• First Posted: June 23, 2016
• Study Start: August 5, 2016
• Primary Completion: May 24, 2018
• Study Completion: July 5, 2018
• Last Updated: August 22, 2018

Record last verified: 2018-08

Locations

CA (1)