Visual Abstract

Insulin resistance is a key characteristic in the development of nonalcoholic fatty liver disease (NAFLD) and NASH. The present study tested the effects of lifestyle intervention (9 months, energy restriction, high intensity interval training) on glucose utilization and liver disease in patients with NASH. Before and after treatment, subjects underwent histologically-graded liver biopsies and two-step, labeled (13C6 glucose), hyperinsulinemic-euglycemic clamps. Glucose appearance (Ra) and glucose disposal (Rd) were measured in eight subjects (mean±SD, age 38.9±8.3y, BMI 38.8±5.4 kg/m2) with a NAFLD activity score (ranging from NAS 1-8) of 5.3±1.2. Following the intervention, BMI (5%, P=0.045), liver fat (35%, P=0.017), plasma glucose (15%, P=0.043), and NAS (28%, P=0.035) were significantly reduced. VO2 max increased 25% (P=0.046) and the change correlated positively with Rd (r=0.925, P=0.001). Absolute changes in Ra and Rd were associated with the individual changes in NAS (Figure 1A-B). Further, absolute change in hepatocyte lobular inflammation and Ra (Figure 1C) and change in hepatocellular ballooning and Rd were correlated (Figure 1D). These data demonstrate improvements in liver health may be driven by enhancing hepatic and peripheral insulin sensitivity through weight loss and exercise. The rerouting of substrates away from the liver may reduce nutrient toxicity and contribute to improvement in NASH.


J. M. Mucinski: None. N. S. Nallapeta: None. M. P. Moore: None. J. A. Ibdah: None. R. Rector: None. E. J. Parks: Advisory Panel; Self; Atkins Nutritionals, Inc., Consultant; Self; Genentech, Inc.


National Institutes of Health (R01DK113701)

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