Liver glycogen formation can occur via the direct (glucose----glucose-6-phosphate----glycogen) or indirect (glucose----C3 compounds----glucose-6-phosphate----glycogen) pathways. In the present study we have examined the effect of
hyperglycemia on the pathways of hepatic glycogenesis, estimated from liver
uridine diphosphoglucose (UDPglucose) specific activities, and on peripheral (muscle)
glucose metabolism in awake, unstressed control and 90% pancreatectomized, diabetic rats. Under identical conditions of
hyperinsulinemia (approximately 550 microU/ml), 2-h euglycemic (6 mM) and hyperglycemic (+5.5 mM and +11 mM) clamp studies were performed in combination with [3-3H,U-14C]
glucose, [6-3H,U-14C]
glucose, or [3-3H]
glucose and [U-14C]
lactate infusions under postabsorptive conditions. Total body
glucose uptake and muscle
glycogen synthesis were decreased in diabetic vs. control rats during all the clamp studies, whereas glycolytic rates were similar. By contrast,
hyperglycemia determined similar rates of
liver glycogen synthesis in both groups. Nevertheless, in diabetic rats, the contribution of the direct pathway to
hepatic glycogen repletion was severely decreased, whereas the indirect pathway was markedly increased. After
hyperglycemia, hepatic
glucose-6-phosphate concentrations were increased in both groups, whereas UDPglucose concentrations were reduced only in the control group. These results indicate that in the diabetic state, under hyperinsulinemic conditions,
hyperglycemia normally stimulates
liver glycogen synthesis through a marked increase in the indirect pathway, which in turn may compensate for the reduction in the direct pathway. The increase in the hepatic concentrations of both
glucose-6-phosphate and UDPglucose suggests the presence, in this diabetic rat model, of a compensatory "push" mechanism for
liver glycogen repletion.