Increased hepatic fructose 2,6-bisphosphate after an oral glucose load does not affect gluconeogenesis

The generally accepted metabolic concept that fructose 2,6-bisphosphate (Fru-2,6-P₂) inhibits gluconeogenesis by directly inhibiting fructose 1,6-bisphosphatase is based entirely on in vitro observations. To establish whether gluconeogenesis is indeed inhibited by Fru-2,6-P₂ in intact animals, a novel NMR method was developed using [U-¹³C]glucose and ²H₂O as tracers. The method was used to estimate the sources of plasma glucose from gastric absorption of oral [U-¹³C]glucose, from gluconeogenesis, and from glycogen in 24-h fasted rats. Liver Fru-2,6-P₂ increased ∼10-fold shortly after the glucose load, reached a maximum at 60 min, and then dropped to base-line levels by 150 min. The gastric contribution to plasma glucose reached ∼50% at 30 min after the glucose load and gradually decreased thereafter. Although the contribution of glycogen to plasma glucose was small, glucose formed from gluconeogenesis was substantial throughout the study period even when liver Fru-2,6-P₂ was high. Liver glycogen replstion was also brisk throughout the study period, reaching ∼30 μmol/g at 3 h. These data demonstrate that Fru-2,6-P₂ does not inhibit gluconeogenesis significantly in vivo.