Changes in hepatic glycogen cycling during a glucose load in healthy humans

Aims/hypothesis: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen. glucose 1-phosphate --> glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested (H2O)-H-2 ( 5 ml/kg body water) and were infused with [5-H-3] glucose and acetaminophen ( paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of H-2 enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the H-3-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results: Glucose infusion rates increased ( p< 0.01) to similar to 50 mu mol kg(-1) min(-1). Plasma insulin and the insulin : glucagon ratio rose similar to 3.6- and similar to 8.3-fold ( p< 0.001), respectively. From the difference between 100% and the sum of the direct ( 2 - 4 h, 54 +/- 6%; 4 - 6h, 59 +/- 5%; 6 - 8 h, 63 +/- 4%) and indirect ( 32 +/- 3, 38 +/- 4, 36 +/- 3%) pathways, glycogen cycling was seen to be decreased ( p< 0.05) from 14 +/- 4% ( 2 - 4 h) to 4 +/- 3% ( 4 - 6 h) and 1 +/- 3% ( 6 - 8 h). Conclusions/interpretation: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.