Pharmacological Activation of Brown Adipose Tissue Metabolism
Condition: Type 2 Diabetes
Study type: Interventional

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).
    

Detailed description: 
      The first step of the study will be direct comparison of mirabegron (protocol A) vs.
      cold-induced (protocol B) BAT metabolic activation using 11C-acetate to measure BAT metabolic
      activity. The principle of this method is measurement of tissue fast disappearance of 11C, a
      marker of tissue 11CO2 production. This fast tissue 11C clearance thus gives an index of
      tissue oxidative metabolism. Ten healthy, non obese men will undergo two identical 5h
      procedures in which BAT metabolism will be stimulated with a β3-agonist (mirabegron 50mg) or
      using cold exposure, in random order. The investigator just received approval from Health
      Canada to use mirabegron as part of these metabolic investigations. In brief, baseline blood
      samples and indirect calorimetry will be performed between time -60 to -30 min followed by
      i.v. injection of 11C-acetate with 30 min dynamic PET/CT scanning at room temperature in both
      protocol A and B. Mirabegron will be administered orally at time 0 in protocol A whereas
      acute cold exposure protocol using a water-conditioned cooling suit will be applied from time
      120 to 300 min in protocol B. At time 210 min (i.e. Tmax of plasma mirabegron level or 90 min
      after the onset of cold exposure), i.v. injection of 11C-acetate will be repeated followed by
      30 min dynamic PET/CT scanning. I.v. injection of 18-fluorodeoxyglucose (18FDG) will be
      performed at time 270 min, followed by 30 min dynamic PET/CT scanning to determine BAT net
      glucose uptake and a whole-body PET/CT scan to determine BAT volume of metabolic activity and
      organ-specific glucose partitioning.
    

Intervention name(s): Mirbetriq (Mirabegron); cold exposure; injection of 18FDG; injection of 11C-acetate; [3-3H]-glucose; [U-13C]-palmitate; 2H-Glycerol
Intervention type(s): Drug; Other; Radiation; Radiation; Radiation; Other; Other
Intervention description(s): 50mg of Mirabegron will be administered orally at time 0 in protocol A.; Acute cold exposure protocol using a water-conditioned cooling suit will be applied from time 120 to 300 min in protocol B; I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed at time 270 min, followed by 30 min dynamic PET/CT scanning; i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning; i.v. administration of 1.5 uCi/min of [3-3H]-glucose; i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate; i.v. administration of 0.05 µmol/kg/min of 2H-glycerol
Other intervention name(s): Mirabegron
Intervention MeSH terms: Mirabegron; Glycerol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other