Short-term metformin and exercise training effects on strength, aerobic capacity, glycemic control, and mitochondrial function in children with burn injury

Severely burned children experience a chronic state of sympathetic nervous system activation that is associated with hyper-metabolic/cardiac stress and muscle wasting. Metformin, a diabetes medication, helps control hyperglycemia in obese diabetic populations, and exercise has been shown to improve exercise strength and aerobic exercise capacity after severe burns. However, whether exercise improves glycemic control in burned children and whether combining exercise and metformin improves outcomes to a greater degree than exercise alone are unknown. We tested the hypothesis that a 6-wk exercise program combined with short-term metformin administration (E + M) improves aerobic and strength exercise capacity to a greater degree than exercise and placebo (E), while improving glucose tolerance and muscle metabolic function. We found that, before exercise training, the metformin group compared with the placebo group had attenuated mitochondrial respiration (pmol·s ^-1 ·mg ^-1 ) for each state: state 2 (-22.5 ± 3), state 3 (-42.4 ± 13), and oxphos (-58.9 ± 19) (P ≤ 0.02, M vs. E + M group for each state). However, in the E + M group, exercise increased mitochondrial respiration in each state (P ≤ 0.05), with respiration being comparable to that in the E group (each P > 0.05). In both groups, exercise induced comparable improvements Vin strength (change from preexercise, ∆1.6 ± 0.6 N-M·kg ^L BM) and _O2peak (∆9 ± 7 mlO ₂ ·kg ^L BM) as well as fasting glucose (∆19.3 ± 13 mg·dl) and glucose AUC (∆3402 ± 3674 mg·dl ^-1 ·min ^-1 ), as measured by a 75-g OGTT (all P ≤ 0.03). Exercise reduced resting energy expenditure in E + M (∆539 ± 480 kcal/24 h, P < 0.01) but not E subjects (P = 0.68). Both groups exhibited reduced resting heart rate (∆30 ± 23 beats/min, P ≤ 0.02). These data indicate that short-term metformin combined with exercise provides no further improvement beyond that of exercise alone for strength, exercise capacity, and glycemic control.