Short-Term Exercise Improves Hepatic Insulin Extraction in Individuals with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD), the hepatic component of insulin resistance syndrome, is pathophysiologically associated with lower hepatic insulin clearance, lower fat oxidation and increased carbohydrate oxidation in a post-absorptive state. Aerobic exercise is purported to be beneficial in NAFLD. To better understand the mechanisms through which short-term, moderate intensity aerobic exercise training could exert these benefits, 13 obese, sedentary adults (age: 58±3.4 years, BMI: 34.3±1.1 kg/m²; means±SEM) with NAFLD (>5% Intra-hepatic lipid content assessed by ¹H MR spectroscopy) were recruited into a 7-day exercise training program (treadmill walking for 60 mins, 5 days per week, at 80-85% maximum heart rate). Participants maintained their normal dietary patterns. Pre- and post-intervention assessments included a 75-gm OGTT, CT scans, VO_2max and indirect calorimetry. Insulin sensitivity (ISI) was estimated using Soonthorpun model. Hepatic Insulin Extraction (HIE) was calculated as the molar difference in AUCs for insulin and C-peptide (HIE=1-(AUC_Insulin÷AUC_C-Pep)). The intervention yielded an ∼9% increase in VO_2max and HIE (P<0.01). Whole-body insulin sensitivity increased by ∼43% (P<0.05). There was a significant increase in basal fat oxidation (pre vs. post: 47±6 vs. 65±6 mg/min, P<0.05) and decrease in basal carbohydrate oxidation (160±20 vs. 112±15 mg/min, P<0.05). After the intervention, HIE was positively correlated with adiponectin (r=0.56, P<0.05) and negatively correlated with TNF-α (r=-0.78, P<0.001). The change in ISI was negatively correlated with change in subcutaneous abdominal fat depot (r=-0.55, P=0.05). These data suggest that exercise may quickly reverse the pathophysiology of NAFLD by improving

HIE and fasting substrate oxidation. The cardio-metabolic benefit of exercise in individuals with NAFLD is potentially mediated through changes in HIE.