Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate (GB10)
Condition: Type 2 Diabetes; Obesity
Study type: Interventional

Summary: 
      One emerging, highly modifiable homeostatic mechanism for energy expenditure in humans is
      brown adipose tissue (BAT) thermogenesis. BAT is currently considered a prime target for the
      treatment of obesity and Type 2 diabetes (T2D).

      Using acetate and fluorodeoxyglucose (FDG) positron emission tomography (PET) , It has been
      demonstrated that BAT thermogenesis is inducible by chronic cold exposure.

      BAT activation through cold exposure is associated with improved glucose homeostasis and
      insulin sensitivity.

      A pharmaceutical approach, which seemed to be very promising to stimulate the activation of
      BAT, was the use of a selective beta 3-adrenergic receptor agonist, mirabegron. Nevertheless,
      in a later study, It has been demonstrated that human BAT thermogenesis is under the control
      of beta-2, not beta-3, adrenergic receptor. The most selective beta-2 adrenergic receptor
      agonist approved for clinical use in Canada is formoterol fumarate, given in inhalation for
      the treatment of asthma (Oxeze®).

      In summary, BAT contributes to cold-induced thermogenesis and is recruited by chronic cold
      exposure as well as by a growing number of food supplements and drugs. Intracellular
      triglyceride (TG) is the primary source of fuel for BAT thermogenesis under normal
      physiological conditions, as blocking intracellular TG lipolysis using nicotinic acid
      abolishes BAT thermogenesis. Beta-2 adrenergic stimulation is the pharmacological target to
      activate BAT thermogenesis in humans and may also lead to white adipose tissue lipolysis.
      Using a highly-selective beta-2 receptor agonist with and without administration of nicotinic
      acid would thus give the opportunity to quantify more precisely energy expenditure accounted
      by BAT thermogenesis and white adipose tissue metabolism in humans.
    

Detailed description: 
      Each participant will undergo three metabolic sessions with PET imaging using
      [11C]-palmitate, [11C]-acetate and [18F]-FDG:

        1. during a 3-h cold exposure (Study A, control condition)

        2. after inhalation of Formoterol with oral nicotinic acid (Study B)

        3. after inhalation of Formoterol only (Study C).
    

Intervention name(s): Formoterol Fumarate 12 micrograms Inhalation Powder; Nicotinic Acid 50 MG Oral Tablet; Acute Cold Exposure; Positron Emission Tomography (PET); Indirect calorimetry; dual-energy x-ray absorptiometry (DEXA scan); Biopsy; iv lines; Electromyogram (EMG)
Intervention type(s): Drug; Drug; Other; Diagnostic Test; Diagnostic Test; Diagnostic Test; Procedure; Procedure; Procedure
Intervention description(s): At time 60 minutes, a total of 48 micrograms will be inhaled within 3 minutes: 4 inhalations of 12 micrograms of fumarate formoterol (Oxeze® Turbuhaler®).; a total dose of 1050 MG will be ingested. From time 0 to 180 minutes, doses of 150 MG will be repeated every 30 minutes.; Participants will be fitted with a liquid-conditioned tube suit. The liquid-conditioned tube suit will be perfused with 18°C water using a temperature- and flow-controlled circulation bath from time 0 to 180 min.; PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150); will be repeated every hour, for 20 minutes, using Vmax29n.; Whole body scan; After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy; for stable tracer perfusion and blood sampling; Surface electrodes will be used to measure skeletal muscle activity and shivering intensity
Other intervention name(s): Oxeze Turbuhaler; Niacin 50 MG
Intervention MeSH terms: Niacin; Nicotinic Acids; Niacinamide; Formoterol Fumarate
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The protocol will be carried out as a within-subject, randomized, cross-over study in which each subject will serve as his/her own control
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Brown adipose tissue; formoterol fumarate; Thermogenesis