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Activation of brown adipose tissue (BAT) by cold exposure.
BAT thermogenesis and BAT volume of metabolic activity will be assessed by Positron-Emitting-Tomography (PET/CT) and MRI/MRS imaging and new pharmacological methods to modulate BAT thermogenesis.
All previous data on the functioning of Brown Adipose Tissue (BAT) were obtained by Positron-Emitting-Tomography (PET) imaging studies using fluorodeoxyglucose F18 ( [18F]- FDG). This approach underestimates the actual activity of the BAT. In this study, the investigator is going to use a new PET tracer (C11-palmitate) which is a fat molecule. This will allow to quantify more accurately the activity of brown fat.
The study protocol includes three visits: the screening visit (V1) and two PET/MRI imaging studies (V2 and V3) performed in random order at an interval of 7 to 14 days.
PET/ MRI studies will be performed with and without nicotinic acid. A total of 500 mg of nicotinic acid will be given orally, at a rate of 2 doses of 150 mg and 2 doses of 100 mg, through V2 (protocol A): one dose at time 0, 60 minutes, 120 minutes and 180 minutes.
During V2 and V3, participants will undergo Acute Cold Exposure to stimulate brown adipose tissue.
The morning of each PET imaging study, the participants will follow an MRI acquisition to determine hepatic, pancreatic, visceral and BAT lipid content, followed by an MRS acquisition in the hepatic and cervico-thoracic region. MRI and MRS acquisition of the hepatic and cervico-thoracic region will be repeated again at the end of the day.
The radioactive PET tracers used in this study are the [11C]-acetate, [11C]-palmitate and [18F]-FDG followed by dynamic and whole-body scans.
Stable isotopes such as [U-13C]-palmitate (0.08 umol/kg/min), 5D-glycérol (0.1 µmol/kg/min,) and tritiated glucose (of 1.5 uCi/min) will be perfused from the start of the day until time 180 min.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Subject with Type 2 Diabetes- cold exposure | Active Comparator | 3-hour cold exposure: Protocol B |
|
| Subject with type 2 Diabetes- cold exposure and nicotinic acid | Experimental | 3-hour cold exposure with oral nicotinic acid: Protocol A |
|
| Subject without Type 2 Diabetes- cold exposure | Active Comparator | 3-hour cold exposure: Protocol B |
|
| Subject without type 2 Diabetes- cold exposure and nicotinic acid | Experimental | 3-hour cold exposure with oral nicotinic acid: Protocol A |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cold exposure | Other | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| BAT volume | Assessed using i.v. injection of 18FDG with whole-body PET/CT acquisition. | 180 minutes after the start of the cold exposure |
| Brown Adipose Tissue (BAT) Glucose uptake | Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning | 150 minutes after the start of the cold exposure |
| Measure | Description | Time Frame |
|---|---|---|
| Activation of BAT (oxidative metabolism) | Measured with 11C-acetate using dynamic PET/CT acquisition. | 90 minutes after beginning cold exposure |
| Fatty Acid uptake and metabolism | Measured with 11C-palmitate using dynamic PET/CT acquisition. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| André Carpentier | Université de Sherbrooke | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de recherche du CHUS | Sherbrooke | Quebec | J1H 5N4 | Canada |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D009525 | Niacin |
| ID | Term |
|---|---|
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
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Two groups in parallel (with and without Type 2 diabetes). In each group, 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.
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| Oral Nicotinic acid | Drug | A total of 500 mg of nicotinic acid will be given orally, at a rate of 2 doses of 150 mg and 2 doses of 100 mg: one dose of 150 mg at time 0 and 60 minutes, one dose of 100 mg at time 120 minutes and 180 minutes. |
|
|
| at baseline and at time 120 minutes after beginning cold exposure |
| BAT triglyceride content | Estimated by CT and MR using 1H-MRS and Dixon sequences on a 3T clinical MRI system. | at baseline and at time 180 (for CT) and 240 (for MR) after cold exposure. |
| Whole-body lipolysis | Systemic appearance rate of glycerol and fatty acid determined by perfusion of [1,1,2,3,3-2H]-glycerol, [U-13C]-palmitate tracers and concentration of total NEFA, triglycerides, palmitate, oleate, linoleate, glycerol. | -150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure. |
| Hepatic Glucose production | Systemic appearance rate of glucose determined by perfusion of [3-3H]-glucose. | -150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure. |
| Substrate utilisation | VO2 and VCO2 will be measured by indirect calorimetry to calculate carbohydrate and fatty acid oxidation rates. | -150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure. |
| Changes in insulin level and secretion | measured with ELISA and Milliplex. | -150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure. |
| D004700 | Endocrine System Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |