An endogenous glycogen-associated compound modulates glucose-6-phosphatase activity in rat liver microsomes

Liver glycogen is closely associated with the endoplasmic reticulum, which contains the glucose-6-phosphatase enzyme system that catalyses the final step of hepatic glucose production. To examine whether this structural association has functional consequences, microsomes were isolated from 48 h fasted (n = 6) and ad lib fed rats (n = 3). Microsomes from fed rats had a higher glycogen content and lower enzyme activity than fasted rats. Overall, glucose-6-phosphatase activity was inversely proportional to microsomal glycogen content. Partially purified rabbit or rat liver glycogen, at physiological relevant concentrations (10-100 mM glucose equivalents), added directly to either intact or Triton-disrupted microsomes from fasted rats significantly decreased glucose-6-phosphatase activity. Inhibitory activity was present in native liver glycogen prepared by sedimentation and could be dissociated from glycogen by ion-exchange and ultrafiltration. These findings suggest that a low molecular weight (< 5000 D) compound closely associated with glycogen can modulate glucose-6-phosphatase and may have a physiologic role in the regulation of hepatic glucose production.