Abstract
Cultured rat hepatocytes were used to characterize the relationship between cellular glycogen content and the basal rate, as well as response to insulin of glycogen synthesis. Depending on the concentration of medium glucose, glycogen-depleted monolayers accumulated glycogen between 24 and 48 h of culture up to the fed in vivo level. Insulin at 100 nM stimulated glycogen deposition 20-fold at 1 mM and 1.5-fold at 50 mM glucose. The rate of further glycogen storage decreased with time and increasing glycogen content. In hepatocytes preincubated with 1-50 mM glucose during 24-48 h, short-term basal and insulin-dependent incorporation of 10 mM [14C]glucose into glycogen was inversely related to the actual cellular glycogen content. This was not due to different intracellular dilution of the label, since the specific radioactivity of UDP-glucose was similar in all groups. 125I-Insulin binding indicated that insulin receptors were also not involved in this phenomenon. An inverse relationship was also found between glycogen content and the stimulation of glycogen synthase I activity by insulin, whereas the basal activity of the enzyme was dissociated from the rate of incorporation of [14C]glucose. Basal net glycogen deposition at 10 mM glucose was also inversely related to cellular glycogen; however, no such relation was evident in the presence of insulin due to the overlapping inhibition of glycogenolysis. These studies suggest that the glycogen-mediated inhibition of the activation of glycogen synthase I is operative in the cultured hepatocyte and leads to an apparent inverse relationship between the actual glycogen content and basal as well as insulin-dependent glycogenesis.
Highlights
This was not due to different intracellular dilution of the label, since thespecific radioactivity of UDP-glucose wassimilarinall groups. '261-Insulin livers of fasted rats contain larger activities of glycogen synthase I than livers of fed animals (10, ll),increased rates of glycogenesiscan only be observedafter refeeding, whichelicits the action of both glucose and insulin (11).In isolated hepatocytes, a single study reported the inability of cells derived from fed animals to accumulate glycogeneven at high ambient glucose levels (12), while others were unable to detect a correlation between the basal rate of glycogenproduction and the initial hepatocellular glycogen content (13)
Binding indicatedthat insulin receptors were not glucose into glycogen using a 2-h glycogenesis assay (14). Involved in this phenomenon. 3)An inverse relation- this evidence was not yet conclusive since these ship wasalso found between glycogen content and the cultured cells did differ in glycogen content, and stimulation of glycogen synthase I activity by insulin, in their hormonal pretreatment leading to different insulin whereas the basal activity of the enzyme was disso- receptor levels and different activities of the glycogenic key ciated from the rate of incorporation of ['4C]glucose. enzyme, glycogen synthase
These studies suggest that the glycogen-mediated inhibition of the activation of glycogen synthase I is undertaken to elucidate the relationship between cellular glycogen contentand basal, as well as insulin-dependent, glycogenesis in hepatocytes maintained in serum- and hormone-free medium to avoid any perturbationby the action of hormones
Summary
'261-Insulin livers of fasted rats contain larger activities of glycogen synthase I than livers of fed animals (10, ll),increased rates of glycogenesiscan only be observedafter refeeding, whichelicits the action of both glucose and insulin (11).In isolated hepatocytes, a single study reported the inability of cells derived from fed animals to accumulate glycogeneven at high ambient glucose levels (12), while others were unable to detect a correlation between the basal rate of glycogenproduction and the initial hepatocellular glycogen content (13) This laboratory has recently described an inverse relationship between the actual glycogen content of hepatocytes cultured under chemically defined conditions and the incorporation of ["C]. These studies suggest that the glycogen-mediated inhibition of the activation of glycogen synthase I is undertaken to elucidate the relationship between cellular glycogen contentand basal, as well as insulin-dependent, glycogenesis in hepatocytes maintained in serum- and hormone-free medium to avoid any perturbationby the action of hormones
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