In-depth Studies of Glucagon Resistance on Hepatic Glucose, Fatty Acid and Triglyceride Kinetics and Generation of Toxic Lipid Intermediates in NAFLD and NASH.

The investigators propose that the sensitivity to glucagon in hepatic lipid metabolism is impaired in subjects with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Moreover, they propose a dys-coordinated, reduced glucagon sensitivity in hepatic lipid metabolism and endogen glucose production in patients with NAFLD and NASH compared with healthy subjects and patients with simple steatosis. This reduced sensitivity may be the basis of a more severe dyslipidemia and the production of increased concentrations of toxic lipid intermediates in plasma and muscle tissue. The study will include healthy subjects with obesity and subjects with simple steatosis and NASH, tested at basal glucagonemia and moderate hyperglucagonemia to mimic insulin resistant levels during simultaneous somatostatin infusion and replacement doses of insulin and growth hormone. Infusion of palmitate, VLDL-triglyceride and glucose tracers in combination with indirect calorimetry as well as skeletal and adipose tissue biopsies will be employed to assess free fatty acid and VLDL-triglyceride kinetics (turnover, and oxidation) and hepatic fatty acid-esterification.