Impaired Insulin Suppression of VLDL-Triglyceride Kinetics in Nonalcoholic Fatty Liver Disease

Context: Nonalcoholic fatty liver disease (NAFLD) is associated with glucose and lipid metabolic abnormalities. However, insulin suppression of very low-density lipoprotein-triglyceride (VLDL-TG) kinetics is not fully understood. Objective: The objective of the study was to determine VLDL-TG, glucose, and palmitate kinetics during fasting and hyperinsulinemia in men with (NAFLD+) and without NAFLD (NAFLD+). Design: Twenty-seven nondiabetic, upper-body obese (waist to hip ratio > 0.9, body mass index > 28 kg/m(2)) men, 18 NAFLD+, and nine NAFLD- determined by magnetic resonance spectroscopy were enrolled. C-14-labeled VLDL-TG and 3H-labeled glucose and palmitate tracers were applied in combination with indirect calorimetry and breath samples to assess kinetics and substrate oxidations postabsorptively and during a hyperinsulinemic-euglycemic clamp. Dual-X-ray absorptiometry and magnetic resonance imaging assessed body composition. Results: Liver fat content was greater in NAFLD+ than NAFLD- men (21.0% vs 3.7%), even though body composition, metabolites (except triglycerides), and insulin were similar in the groups. Insulin suppression of VLDL-TG secretion (P = .0001), oxidation (P = .0003), and concentration (P = .008) as well as percentage decreases were lower in NAFLD+ than NAFLD- men (secretion: 31.9% +/- 17.2% vs 64.7% +/- 19.9%; oxidation: -9.0% +/- 24.7% vs 46.5% +/- 36.6%; concentration: 11.9% +/- 20.7% vs 56.2% +/- 22.9%, all P < .001). Likewise, lower insulin suppression of very low-density lipoprotein particle size was present in NAFLD+ than NAFLD- men (P = .0002). Conversely, insulin suppression of endogenous glucose production was similar in the groups. Conclusions: Compared with endogenous glucose production, the inability of NAFLD- men to suppress VLDL-TG kinetics to compensate for the increased liver fat content seems to be an early pathophysiological manifestation of male NAFLD+. These data suggest therapeutic targets reducing liver fat content may ameliorate metabolic abnormalities associated with NAFLD and presumably diabetes.