Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D)
Condition: Impaired Glucose Tolerance
MeSH terms: Glucose Intolerance
Study type: Interventional

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.
    


Intervention name(s): Nicotinic acid; [7,7,8,8-2H]-palmitate; [U-13C]-palmitate; Biopsy; liquid meal
Intervention type(s): Drug; Other; Other; Procedure; Other
Intervention description(s): oral administration of nicotinic acid (100mg at 0, 30, 60, 90, 120, 180, 240 and 300 min) to minimize WAT intracellular lipolysis; using i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to +360 min; oral administration of [U-13C]-palmitate (0.2 g mixed into the liquid meal) at time 0 min; A subcutaneous abdominal 0.5-g adipose tissue biopsy will be performed at the end of protocols A0 and A1; 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
Other intervention name(s): Niacin
Intervention MeSH terms: Niacin; Nicotinic Acids; Niacinamide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science