The relative contribution of the direct and indirect pathways to liver glycogen formation was assessed in humans by using a combined tracer-hepatic vein catheterization technique. An oral glucose load (75 g) labelled with 1-14C-glucose was administered to five subjects (control group) and 4.5 h later hepatic glycogen was flushed with glucagon and analysed to determine the randomization of 14C. The specific activity (SA) of the glycogen derived glucose (1-14C-glucose SA+recycled 14C-glucose SA) was 61 +/- 7% of the mean blood glucose SA of the interval 0-180 min after the oral glucose load. The relative values due to 1-14C-glucose and recycled 14C-glucose were 33 +/- 7 and 28 +/- 3%, respectively. The data indicate that the indirect pathway of glycogen formation is not only active in humans but contributes substantially (at least 50%) to liver glycogen formation. In order to investigate whether the basal adrenergic tone plays a role in the maintenance of the indirect pathway, the same protocol was also performed in a second group of subjects (n = 5) who received propranolol before the oral glucose load (propranolol group). The SA of the glycogen-derived glucose was considerably smaller than that of the control group (18 +/- 5 vs. 61 +/- 7%, P < 0.001), suggesting lesser glycogen formation. However, the ratio of 1-14C to recycled-14C in the glucose molecule was similar in the control (1.3 +/- 0.4) and propranolol group (1.9 +/- 1.2). We conclude that the basal adrenergic tone does not play any role in the operation of the indirect pathway of liver glycogen synthesis.