Postprandial Fatty Acid Metabolism in the Natural History of Type 2 Diabetes (T2D)
Status:
Completed
Trial end date:
2021-05-01
Target enrollment:
Participant gender:
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.