Brown Adipose Tissue Metabolism in Type 2 Diabetes (GB8)

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.

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.

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.

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.

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.

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

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.