Glycogen: its mode of formation and contribution to hepatic glucose output in postabsorptive humans

Summary To assess the relative contributions of gluconeogenesis and glycogenolysis to overall hepatic glucose output in postabsorptive normal humans and those of the indirect and direct pathways for glycogen synthesis, we studied six normal volunteers, who had been fasted for 16 h to reduce their hepatic glycogen stores, and then ingested glucose (250 g over 10 h) enriched with 6-³H] glucose to replenish and label their hepatic glycogen. After a 10-h overnight fast, release of the 6-³H] glucose into the circulation was traced with 2-³H] glucose to estimate breakdown of glycogen that had been formed via the direct pathway while gluconeogenesis was simultaneously estimated by incorporation of infused ¹⁴C] lactate into plasma glucose. We found that release of 6-³H] glucose into plasma (6.79±0.69 mol · kg^–1 · min^–1) accounted for 46±5% of hepatic glucose output (15.0±0.7 mol · kg^–1· min^–1) while glucose formed from lactate (2.71±0.28 mol · kg^–1 · min^–1) accounted for 19±2% of hepatic glucose output. Since these determinations underestimate direct pathway glycogenolysis and overall gluconeogenesis, a maximal estimate for the contribution of indirect pathway glycogenolysis to hepatic glucose output is obtained by subtracting the sum of direct pathway glycogenolysis and lactate gluconeogenesis from hepatic glucose output. This amounted to a maximum of 36±5 % of hepatic glucose output and 44±6% of overall glycogenolysis. Assuming that the relative proportions of direct and indirect pathway glycogen breakdown would reflect the relative contributions of these pathways to glycogen formation, we conclude that under our experimental conditions the direct pathway is the predominant route for glycogen formation in man and that in overnight fasted humans, hepatic glucose output is mainly the result of glycogenolysis.