Type 2 Diabetes, Obesity
Conditions
Keywords
Brown adipose tissue, formoterol fumarate, Thermogenesis
Brief 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).
Interventions
DRUGFormoterol Fumarate 12 micrograms Inhalation Powder
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®).
DRUGNicotinic Acid 50 MG Oral Tablet
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.
OTHERAcute Cold Exposure
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.
DIAGNOSTIC_TESTPositron Emission Tomography (PET)
PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)
DIAGNOSTIC_TESTIndirect calorimetry
will be repeated every hour, for 20 minutes, using Vmax29n.
DIAGNOSTIC_TESTdual-energy x-ray absorptiometry (DEXA scan)
Whole body scan
PROCEDUREBiopsy
After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy
PROCEDUREiv lines
for stable tracer perfusion and blood sampling
PROCEDUREElectromyogram (EMG)
Surface electrodes will be used to measure skeletal muscle activity and shivering intensity
Sponsors
Université de Sherbrooke
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI of 18 to 30 kg/m2.
Exclusion criteria
* Change in weight of more than 2 kg over the past 3 months or recent changes in lifestyle; * The presence of any chronic medical condition requiring any pharmacological treatment; * Previous intolerance or allergy to lactose, formoterol, nicotinic acid or local anesthetic agent; * Any previous cardiac arrhythmia, long QT syndrome or hypokalemia; * Chronic treatment with any medication other than contraceptives; * Acute use of any drug other that acetaminophen or non-steroidal anti-inflammatory without decongestant or other stimulants; * Smoking or consumption of more than 2 alcoholic beverages per day; * Having participated to a research study with exposure to radiation in the last two years before the start of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid) | measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C) | determined using \[11C\]-acetate PET |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brown Adipose Tissue nonesterified fatty acid (NEFA) metabolism (uptake, oxidation, esterification and release rates) | measured 120 minutes after the start of acute cold exposure (A), and 60 minutes after inhalation of Fumarate Formoterol (B and C) | determined using \[11C\]-palmitate PET method |
| Change in systemic plasma NEFA turnover. | measured at baseline and every 60 minutes after the start of acute cold exposure (A) and every 60 minutes after inhalation of fumarate formoterol (B and C), for 4 hours | Determined using continuous infusion of labelled palmitate from time -60 to 180. |
| Change in systemic plasma glycerol turnover. | measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours. | Determined using continuous infusion of \[1,1,2,3,3-D2\]-glycerol from time -60 to 180 . |
| Change in systemic plasma glucose turnover. | measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 5.50 hours | Determined using continuous infusion of \[6,6 D2\]-glucose from time -150 to 180 . |
| Brown Adipose Tissue (BAT) glucose uptake | measured 150 minutes after the start of acute cold exposure (A), and 90 minutes after inhalation of Fumarate Formoterol (B and C) | determined using \[18F\]-FDG dynamic PET acquisition |
| Change in whole-body energy expenditure | measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours | Determined using indirect calorimetry |
| Muscle shivering activity | measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours | Determined using the surface electromyogram (EMG) |
| Change in insulin sensitivity | measured at baseline and every 60 minutes after the start of acute cold exposure (A) and every 60 minutes after inhalation of fumarate formoterol (B and C), for 4 hours. | Determined by measuring circulating glucose, NEFA, insulin and C-peptide |
| Protein expression of subcutaneous abdominal white adipose tissue | measured at baseline and 180 minutes after the start of the cold exposure (study A) and 120 minutes after inhalation of fumarate formoterol (study B and C) | Using biopsy |
| BAT triglyceride content | measured 180 minutes after the start of cold exposure (A) and 90 minutes after inhalation of fumarate formoterol (B and C) | Determined using the CT radio-density method |
Countries
Canada
Outcome results
None listed