The aim of these studies was to investigate the effect of
hyperglycemia with or without
hyperinsulinemia on hepatic gluconeogenic flux, with the hypothesis that inhibition would be greatest with combined
hyperglycemia/
hyperinsulinemia. A
glycogen phosphorylase inhibitor (
BAY R3401) was used to inhibit
glycogen breakdown in the conscious overnight-fasted dog, and the effects of a twofold rise in plasma
glucose level (HI group) accompanied by 1) euinsulinemia (HG group) or 2) a fourfold rise in plasma
insulin were assessed over a 5-h experimental period.
Hormone levels were controlled using
somatostatin with portal
insulin and
glucagon infusion. In the HG group, net hepatic
glucose uptake and net hepatic
lactate output substantially increased. There was little or no effect on the net hepatic uptake of gluconeogenic precursors other than
lactate (
amino acids and
glycerol) or on the net hepatic uptake of
free fatty acids compared with the control group. Consequently, whereas
hyperglycemia had little effect on gluconeogenic flux to
glucose 6-phosphate (G-6-P), net hepatic gluconeogenic flux was reduced because of increased hepatic glycolytic flux during
hyperglycemia. Net
hepatic glycogen synthesis was increased by
hyperglycemia. The effect of
hyperglycemia on gluconeogenic flux to G-6-P and net hepatic gluconeogenic flux was similar. We conclude that, in the absence of appreciable
glycogen breakdown, the increase in glycolytic flux that accompanies
hyperglycemia results in decreased net carbon flux to G-6-P but no effect on gluconeogenic flux to G-6-P.