Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D)

Summary

Lipotoxicity-causing fatty acid overexposure and accretion in lean tissues leads to insulin resistance and impaired pancreatic β-cell function - the hallmarks of T2D - contributing to associated complications such as heart failure, kidney failure and microvascular diseases. Proper dietary fatty acid (DFA) storage in white adipose tissue (WAT) is now thought to prevent lean-tissue lipotoxicity. Using novel Positron-Emission Tomography (PET) and stable isotopic tracer methods which were developed in Sherbrooke, the investigator showed that WAT storage of DFA is impaired in people with pre-diabetes or T2D. The investigator also showed that this impairment is associated with greater cardiac DFA uptake, as well as subclinical left-ventricular systolic and diastolic dysfunction. Then, It has been found that modest weight loss in pre-diabetics, after a one-year lifestyle intervention, improved WAT DFA storage, curbed cardiac DFA uptake, and restored associated left-ventricular dysfunction. It has been also found that a 7-day low-saturated fat, low-calorie diet raised insulin sensitivity but did not restore WAT or cardiac DFA metabolism. Whether WAT DFA storage directly impacts cardiac DFA uptake is not known. Importantly, the investigator recently uncovered marked sex-specific differences in WAT DFA metabolism. These may explain, at least in part, sex-related differences in the cardiac DFA uptake, which occurs in pre-diabetes. Higher spillover of WAT DFA into circulating Non-Esterified Fatty Acid (NEFA) appears to be linked in women to greater cardiac DFA uptake, as opposed to direct cardiac chylomicron triglycerides (TG) uptake in men. Here, the investigator will isolate and compare organ-specific fatty acid uptake occurring postprandially from chylomicron-TG vs. NEFA pools, as well as the oxidative vs. non-oxidative intracellular metabolic pathways associated with increased cardiac DFA uptake in pre-diabetic men and women.

Conditions

• Impaired Glucose Tolerance

Interventions

DRUG

Nicotinic acid

oral administration of nicotinic acid (100mg at 0, 30, 60, 90, 120, 180, 240 and 300 min) to minimize WAT intracellular lipolysis

OTHER

[7,7,8,8-2H]-palmitate

using i.v. administration of \[7,7,8,8-2H\]-palmitate (in 25% human albumin) from time -60 to +360 min

OTHER

[U-13C]-palmitate

oral administration of \[U-13C\]-palmitate (0.2 g mixed into the liquid meal) at time 0 min

PROCEDURE

Biopsy

A subcutaneous abdominal 0.5-g adipose tissue biopsy will be performed at the end of protocols A0 and A1

OTHER

liquid meal

At time 0, a standard liquid meal (400 mL, 906 kcal, 33g-fat/34g-protein/101g-carbohydrates i.e. 33%/17%/50% calories) will be drunk over 20 minutes

Sponsors & Collaborators

• Université de Sherbrooke

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

45 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-01-17

Primary Completion

2020-12-31

Completion

2021-05-31

Countries

• Canada

Study Locations