Effects of Insulin on the Metabolic Control of Hepatic Gluconeogenesis In Vivo

OBJECTIVE—Insulin represses the expression of gluconeo-genic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alter-ations at the cellular level. RESEARCH DESIGN AND METHODS—Conscious 60-h fasted canines were studied at three insulin levels (near basal, 4, or 16) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arteriovenous difference technique, and molecular signals were assessed. RESULTS—Insulin reduced gluconeogenic flux to glucose-6