Molecular Characterization of Insulin-Mediated Suppression of Hepatic Glucose Production In Vivo

OBJECTIVE—Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular sig-naling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression. We determined, for the first time, the time course and relevance (to metabolic flux) of these molecular events during physiological hyperinsulinemia in vivo in a large animal model. RESEARCH DESIGN AND METHODS—24 h fasted dogs were infused with somatostatin, while insulin (basal or 8 basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, 2H2O, and arterio-venous difference techniques. Studies were terminated at different time points to evaluate insulin signaling and enzyme regulation in the liver. RESULTS—Hyperinsulinemia reduced HGP due to a rapid tran