Mechanism of muscle glycogen autoregulation in humans

To examine the mechanism by which muscle glycogen limits its own synthesis, muscle glycogen and glucose g-phosphate (G-6-P) concentrations were measur ed in seven healthy volunteers during a euglycemic (similar to 5.5 mM)-hype rinsulinemic (similar to 450 pM) clamp using C-13/(31)p nuclear magnetic re sonance spectroscopy before and after a muscle glycogen loading protocol. R ates of glycogen synthase (V-syn) and phosphorylase (V-phos) flux were esti mated during a [1-C-13]glucose (pulse)-unlabeled glucose (chase) infusion. The muscle glycogen loading protocol resulted in a 65% increase in muscle g lycogen content that was associated with a twofold increase in fasting plas ma lactate concentrations (P < 0.05 vs. basal) and an similar to 30% decrea se in plasma free fatty acid concentrations (P < 0.001 vs. basal). Muscle g lycogen loading resulted in an similar to 30% decrease in the insulin-stimu lated rate of net muscle glycogen synthesis (P < 0.05 vs. basal), which was associated with a twofold increase in intramuscular G-6-P concentration (P < 0.05 vs, basal). Muscle glycogen loading also resulted in an similar to 30% increase in whole body glucose oxidation rates (P < 0.05 vs. basal), wh ereas there was no effect on insulin-stimulated rates of whole body glucose uptake (similar to 10.5 mg.kg body wt(-1). min(-1) for both clamps) or gly cogen turnover (Vsyn/Vphos was similar to 23% for both clamps). In conclusi on, these data are consistent with the hypothesis that glycogen limits its own synthesis through feedback inhibition of glycogen synthase activity, as reflected by an accumulation of intramuscular G-6-P, which is then shunted into aerobic and anaerobic glycolysis.