726-P: Impaired Glucose Tolerance Blunts Exercise-Training Induced Improvements in Aerobic Exercise Capacity

Abstract

Background: Low aerobic exercise capacity independently and strongly predicts metabolic disease and mortality. While aerobic exercise training can increase exercise capacity and reduce health risks, people with impaired glucose tolerance (IGT; i.e., prediabetes, T1D and T2D) have lower exercise capacity than glucose-tolerant subjects, even when exercise training “dose” is matched. We tested the hypothesis that low exercise capacity in IGT is caused by blunted exercise training-induced improvements in exercise capacity. Methods: IGT was induced in CD-1 mice by a) diet-induced insulin resistance (Western Diet, WD; 40% kcal from fat), or b) streptozotocin injection (STZ; 2x 40 mg/kg) to reduce circulating insulin. Control and STZ mice consumed standard chow (10% fat). Eight weeks following treatment, mice were partitioned into sedentary or exercise-trained (voluntary wheel running) groups. Exercise capacity (meters, m) was measured before and after a 3-week training intervention, and the change (Δ) in exercise capacity was calculated. Body composition was measured (DEXA) and tissues were harvested to measure metabolic health outcomes. Results: Baseline exercise capacity and total running distance were similar among Control, WD and STZ groups. Mice from all treatment groups displayed metabolic benefits from training, including increased muscle GLUT4 and mitochondrial content, and reduced adiposity. In contrast, exercise capacity only improved with training in Control mice (Δ124.82±40.25 m), whereas WD-trained (Δ29.69±24.11 m) and STZ-trained (Δ37.10±25.76 m) animals had no significant increase in exercise capacity. These data demonstrate that IGT can prevent improvements in exercise capacity with exercise training, despite the induction of other beneficial metabolic health outcomes. Conclusions: Our data identify IGT as a negative regulator of improved exercise capacity with training and a novel mechanism underlying low exercise capacity in diabetes. Disclosure T. MacDonald: None. P. Pathak: None. S. Lessard: None. Funding American Heart Association (1-19-PDF-168)