Depletion of Liver Fat in Type 2 Diabetes

The aim of this randomized trial is to determine whether liver fat depletion via a short-term (i.e., two weeks) very-low calorie diet will restore the normal exercise-induced secretion of a signaling protein (fibroblast growth factor 21) from the liver in people living with type 2 diabetes. Participants will have their liver fat, body composition, and various markers of metabolic health assessed and then will be randomized to either the very-low calorie diet intervention or a free-living control group for two weeks. Upon completion of the two-week intervention period, participants will redo all of the pre-intervention assessments. The changes in the assessments from before vs. after the intervention period will be compared between the two intervention groups (i.e., the very-low calorie diet group vs. the free living control group).

Fibroblast growth factor 21 (FGF21) is a hepatokine that confers multiple beneficial effects when signaling to other tissues in the body. This is particularly true in adipose tissue, where it improves insulin sensitivity and leads to adiponectin production/secretion. In healthy individuals, FGF21 secretion is induced by exercise: however, this effect is absent in people living with type 2 diabetes (T2D). Aberrant secretion of FGF21 and other hepatokines is associated with increases in ectopic fat in the liver, but it is unknown if depletion of ectopic liver fat ameliorate this effect. 42 participants living with T2D will be recruited for this parallel randomized controlled trial. At baseline, participants will have their liver fat assessed via magnetic resonance imaging, exercise-induced FGF21 incremental area under the curve (following \~1 hour of exercise on a cycle ergometer at a workload equivalent to 60% VO2peak) as well as anthropometrics and outcomes relating to cardiometabolic health. Participants will then be randomized to either 1) two weeks of a very-low calorie diet (VLCD; \~800 kcal/day) or 2) two weeks of free living control (CON). Following the two week intervention period, participants will repeat the baseline outcome assessment. The primary objective of this trial is to determine whether diet-induced liver fat depletion will restore exercise-induced FGF21 secretion in people living with T2D. Secondary objectives include determining the effect of diet-induced liver fat depletion on fasting levels of circulating FGF21 and expression of FGF21 receptor/co-receptors and downstream signals in adipose tissue, as well as other cardiometabolic outcomes.