Abstract

Objective. Insulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were to determine 1) the maximal physiologic effect of insulin, 2) the relative importance of its effects on gluconeogenic regulatory sites and to 3) correlate those changes with alterations at the cellular level.

Research Design and Methods. Conscious 60-h-fasted dogs were studied at three insulin levels (near basal, 4x, or 16x) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arterio-venous difference technique and molecular signals were assessed.

Results. Insulin reduced gluconeogenic flux to G6P but only at the near maximal physiological level (16x basal). The effect was modest compared to its inhibitory effect on net hepatic glycogenolysis, it occurred within 30 min, and was associated with a marked decrease in hepatic fat oxidation, increased liver fructose-2,6-bisphosphate level, and reductions in lactate, glycerol and amino acid extraction. No further diminution in gluconeogenic flux to G6P occurred over the remaining 4.5-h of the study, despite a marked decrease in PEPCK content, suggesting poor control strength for this enzyme in gluconeogenic regulation in the dog.

Conclusions. Gluconeogenic flux can be rapidly inhibited by high insulin levels in the dog. Initially decreased hepatic lactate extraction is important and later reduced gluconeogenic precursor availability plays a role. Changes in PEPCK appear to have little or no acute effect on gluconeogenic flux.