Glycogen concentration and regulation of synthase activity in rat liver in vivo

The proportion of liver glycogen synthase in the active (R+I) forms is lower in the fed than in the fasted state. This has been attributed to inhibition of synthase phosphatase by the accumulated hepatic glycogen. We observed that after oral administration of glucose or galactose to fasted rats, hepatic synthase R+I activity first increased, as expected, but then decreased to a nadir significantly below the control level regardless of the maximal glycogen concentration reached. Therefore, we investigated further the relationship of hepatic synthase R+I activity and glycogen concentration in vivo in fasted rats given increasing oral glucose loads. Male rats fasted 24 h were given glucose doses of 0.1-4.0 g/kg by oral gavage (n > or = 8). Liver synthase R+I, total synthase, phosphorylase a, glucose, glycogen, glucose-6-P, and UDP glucose were measured at intervals over 20-240 min after gavage. Even the smallest glucose load elicited rapid glycogen synthesis. The maximum glycogen concentration increased linearly with the size of the glucose load, although the proportion of administered glucose accounted for by liver glycogen decreased as the glucose load increased. The proportion of synthase in the active (R+I) forms peaked at 20 min after all doses and then declined. By the time the glycogen concentration was maximal, synthase R+I activity had decreased to the control value, regardless of the glucose dose administered or the maximum glycogen concentration reached. Although the decrease in synthase R+I at the time of the glycogen peak was correlated with the increase in glycogen concentration, synthase R+I continued to decrease for another 1-2 h even though liver glycogen was stable or decreasing. The nadir reached was independent of the maximal glycogen concentration. The synthase R+I nadir also did not correlate with hepatic glucose or glucose-6-P concentrations or phosphorylase a activity. Overall, there was not a straightforward temporal or quantitative relationship between the glycogen concentration and synthase R+I activity. These data suggest a more complex mechanism than simply direct inhibition of synthase phosphatase by glycogen.