RESUMO
A key feature of type 2 diabetes is impairment in the stimulation of glycogen synthesis in skeletal muscle by insulin. Glycogen synthesis and the activity of the enzyme glycogen synthase (GS) have been studied in human myoblasts in culture under a variety of experimental conditions. Incubation in the absence of glucose for up to 6 h caused an approximately 50% decrease in glycogen 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 glucose concentration-dependent and essentially additive with the effects of insulin. This effect was seen only after glycogen depletion. Inhibitors of signaling pathways involved in the stimulation of glycogen synthesis by insulin were without significant effect on the stimulatory action of glucose. These results indicate that at least two distinct mechanisms exist to stimulate 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.
Assuntos
Glucose/fisiologia , Glicogênio/fisiologia , Insulina/fisiologia , Músculo Esquelético/metabolismo , Células Cultivadas , Desoxiglucose/farmacocinética , Ativação Enzimática/fisiologia , Glucose/farmacologia , Glicogênio/biossíntese , Glicogênio/deficiência , Glicogênio Sintase/metabolismo , Humanos , Insulina/farmacologia , Músculo Esquelético/citologia , Concentração Osmolar , Fatores de TempoRESUMO
Insulin and a number of metabolic factors stimulate glycogen synthesis and the enzyme glycogen synthase. Using human muscle cells we find that glycogen synthesis is stimulated by treatment of the cells with lithium ions, which inhibit glycogen synthase kinase 3. Insulin further stimulates glycogen synthesis in the presence of lithium ions, an effect abolished by wortmannin and rapamycin. We report also that amino acids stimulate glycogen synthesis and glycogen synthase, these effects also being blocked by rapamycin and wortmannin. Amino acids stimulate p70(s6k) and transiently inhibit glycogen synthase kinase 3 without effects on the activity of protein kinase B or the mitogen-activated protein kinase pathway. Thus, the work reported here demonstrates that amino acid availability can regulate glycogen synthesis. Furthermore, it demonstrates that glycogen synthase kinase 3 can be inactivated within cells independent of activation of protein kinase B and p90(rsk).
Assuntos
Aminoácidos/farmacologia , Glicogênio/biossíntese , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinases , Sequência de Aminoácidos , Androstadienos/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Glucose/metabolismo , Quinase 3 da Glicogênio Sintase , Quinases da Glicogênio Sintase , Humanos , Cinética , Lítio/farmacologia , Dados de Sequência Molecular , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Sirolimo/farmacologia , WortmaninaRESUMO
Glucose uptake into muscle and its subsequent storage as glycogen is a crucial factor in energy homeostasis in skeletal muscle. This process is stimulated acutely by insulin and is impaired in both insulin-resistant states and in type 2 diabetes mellitus. A signalling pathway involving protein kinase B and glycogen synthase kinase 3 seems certain to have a key role in stimulating glycogen synthesis but other signalling pathways also contribute, including a rapamycin-sensitive pathway stimulated by amino acids. Although glycogen synthesis is one of the classical insulin-regulated pathways, it is also regulated in an insulin-independent manner; for example glycogen synthesis in muscle is stimulated significantly after strenuous exercise, with much of this stimulation being independent of the involvement of insulin. Evidence suggests that glucose and the glycogen content of the muscle have a key role in this stimulation but the molecular mechanism has yet to be fully explained.