Investigation of the mechanism of glycogen rebound in the liver of 72-hour fasted rats.

We have investigated the mechanism of the rebound of glycogen stores in the liver of 72-h fasted rats. The liver of 72- and 96-h fasted rats contains significant amounts of glycogen (about 5 mg/g, wet weight) as compared to the liver of 24- and 48-h fasted rats, which contains less than 2 mg of glycogen/g of liver, wet weight. Rebound of glycogen does not involve glycogen synthase activation or glycogen phosphorylase inhibition. It could be dependent on the concentration of the precursor substrate of glycogenesis, i.e. glucose 6-phosphate (Glc-6-P), which is higher by about 45% in the liver of 72- and 96-h fasted rats than in the liver of 48-h fasted rats. The 72-h increase of Glc-6-P compared with the 48-h values could not be explained either by late modifications of the total activities of glucokinase, hexokinases, Glc-6-P dehydrogenase, and glucose-6-phosphatase (Glc-6-Pase) or by changes in plasma glucose and insulin/glucagon ratio. In agreement with the fact that total glucose output tends to decrease upon prolonged fasting, the increase of Glc-6-P concentration in the liver of 72-h fasted rats suggests the involvement of a metabolite inhibition of Glc-6-Pase. The increase of the alpha-ketoglutarate concentration in the 72- and 96-h fasted liver with regard to the 48-h fasted liver (about three times) might account for such an inhibition since we show here that Glc-6-Pase is inhibited in vitro in the presence of relevant concentrations of alpha-ketoglutarate, Glc-6-P, and Mg2+ ions.