Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells

A key feature of type 2 diabetes is impairment in the stimulation of glycog en synthesis in skeletal muscle by insulin. Glycogen synthesis and the acti vity of the enzyme glycogen synthase (GS) have been studied in human myobla sts in culture under a variety of experimental conditions. Incubation in th e absence of glucose for up to 6 h caused an similar to 50% decrease in gly cogen content, which was associated with a small decrease in the fractional activity of GS, Subsequent reincubation with physiological concentrations of glucose led to a dramatic increase in the rate of glycogen synthesis and in the fractional activity of GS, an effect which was both time- and gluco se concentration-dependent and essentially additive with the effects of ins ulin. This effect was seen only after glycogen depletion. Inhibitors of sig naling pathways involved in the stimulation of glycogen synthesis by insuli n were without significant effect on the stimulatory action of glucose, The se results indicate that at least two distinct mechanisms exist to stimulat e glycogen synthesis in human muscle: one acting in response to insulin and the other acting in response to glucose after glycogen depletion, such as that which results from exercise or starvation.