Brown Adipose Tissue Metabolism in Type 2 Diabetes (GB8)

Quantifying Brown Adipose Tissue Thermogenesis in Type 2 Diabetes

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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Other: Cold exposure; Drug: Oral Nicotinic acid

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Frédérique Frisch; Phone Number: 12394 819-346-1110; Email: frederique.frisch@Usherbrooke.ca

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Recruiting
      • Centre de recherché du CHUS
      • Contact: Frédérique Frisch; Phone Number: 12394 819-346-1110; Email: frederique.frisch@Usherbrooke.ca
      • Sub-Investigator: Eric Turcotte
      • Sub-Investigator: Denis Blondin
      • Sub-Investigator: Martin Lepage
      • Principal Investigator: Andre Carpentier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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).

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Subject with Type 2 Diabetes- cold exposure; 3-hour cold exposure: Protocol B	Other: Cold exposure; 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.
Experimental: Subject with type 2 Diabetes- cold exposure and nicotinic acid; 3-hour cold exposure with oral nicotinic acid: Protocol A	Other: Cold exposure; 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.; Drug: Oral 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: one dose of 150 mg at time 0 and 60 minutes, one dose of 100 mg at time 120 minutes and 180 minutes.; Other Names: Niacin 500 (Jamp Pharma) NPN 00557412
Active Comparator: Subject without Type 2 Diabetes- cold exposure; 3-hour cold exposure: Protocol B	Other: Cold exposure; 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.
Experimental: Subject without type 2 Diabetes- cold exposure and nicotinic acid; 3-hour cold exposure with oral nicotinic acid: Protocol A	Other: Cold exposure; 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.; Drug: Oral 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: one dose of 150 mg at time 0 and 60 minutes, one dose of 100 mg at time 120 minutes and 180 minutes.; Other Names: Niacin 500 (Jamp Pharma) NPN 00557412

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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.	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.

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Investigators: Principal Investigator: André Carpentier, Université de Sherbrooke

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: May 19, 2021
• First Submitted That Met QC Criteria: October 12, 2021
• First Posted (Actual): October 26, 2021

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2019-2990

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No