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Brown Adipose Tissue Metabolism in Type 2 Diabetes

Not Applicable
Recruiting
Conditions
Type 2 Diabetes
Interventions
Other: Cold exposure
Drug: Oral Nicotinic acid
Registration Number
NCT05092945
Lead Sponsor
Université de Sherbrooke
Brief Summary

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.

Detailed Description

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.

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
40
Inclusion Criteria
  • 10 men and 10 women with T2D.
  • 10 non-diabetic men and 10 non-diabetic women (matched for sex, BMI and age to the T2D participants).
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Exclusion Criteria
  • Change in weight of more than 2 kg over the past 3 months or recent changes in lifestyle;
  • Treatment with a fibrate, thiazolidinedione, insulin, beta-blocker, GLP-1 agonist, or other drug known to affect lipid or carbohydrate metabolism, except statins, metformin, sulfonylurea, DPP-IV inhibitor and other antihypertensive agents that can be temporarily stopped safely prior to the studies, as per our approved protocols;
  • Presence of overt cardiovascular, liver, renal or other medical conditions;
  • Smoking or consumption of more than 2 alcoholic beverages per day;
  • Any other contraindication to temporarily suspending current medications for lipids or hypertension;
  • Any contraindication to MRI scanning.
  • Having participated to a research study with exposure to radiation in the last two years before the start of the study.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Subject with Type 2 Diabetes- cold exposureCold exposure3-hour cold exposure: Protocol B
Subject without Type 2 Diabetes- cold exposureCold exposure3-hour cold exposure: Protocol B
Subject without type 2 Diabetes- cold exposure and nicotinic acidCold exposure3-hour cold exposure with oral nicotinic acid: Protocol A
Subject without type 2 Diabetes- cold exposure and nicotinic acidOral Nicotinic acid3-hour cold exposure with oral nicotinic acid: Protocol A
Subject with type 2 Diabetes- cold exposure and nicotinic acidCold exposure3-hour cold exposure with oral nicotinic acid: Protocol A
Subject with type 2 Diabetes- cold exposure and nicotinic acidOral Nicotinic acid3-hour cold exposure with oral nicotinic acid: Protocol A
Primary Outcome Measures
NameTimeMethod
BAT volume180 minutes after the start of the cold exposure

Assessed using i.v. injection of 18FDG with whole-body PET/CT acquisition.

Brown Adipose Tissue (BAT) Glucose uptake150 minutes after the start of the cold exposure

Assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning

Secondary Outcome Measures
NameTimeMethod
BAT triglyceride contentat baseline and at time 180 (for CT) and 240 (for MR) after cold exposure.

Estimated by CT and MR using 1H-MRS and Dixon sequences on a 3T clinical MRI system.

Hepatic Glucose production-150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure.

Systemic appearance rate of glucose determined by perfusion of \[3-3H\]-glucose.

Substrate utilisation-150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure.

VO2 and VCO2 will be measured by indirect calorimetry to calculate carbohydrate and fatty acid oxidation rates.

Activation of BAT (oxidative metabolism)90 minutes after beginning cold exposure

Measured with 11C-acetate using dynamic PET/CT acquisition.

Fatty Acid uptake and metabolismat baseline and at time 120 minutes after beginning cold exposure

Measured with 11C-palmitate using dynamic PET/CT acquisition.

Whole-body lipolysis-150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure.

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.

Changes in insulin level and secretion-150 and 0 minutes before and 60, 120 and 180 minutes after cold exposure.

measured with ELISA and Milliplex.

Trial Locations

Locations (1)

Centre de recherche du CHUS

🇨🇦

Sherbrooke, Quebec, Canada

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