Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle (original) (raw)
Related papers
American Journal of Physiology-Endocrinology and Metabolism, 2005
Insulin-stimulated glucose uptake and incorporation of glucose into skeletal muscle glycogen contribute to physiological regulation of blood glucose concentration. In the present study, glucose handling and insulin signaling in isolated rat muscles with low glycogen (LG, 24-h fasting) and high glycogen (HG, refed for 24 h) content were compared with muscles with normal glycogen (NG, rats kept on their normal diet). In LG, basal and insulin-stimulated glycogen synthesis and glycogen synthase activation were higher and glycogen synthase phosphorylation (Ser645, Ser649, Ser653, Ser657) lower than in NG. GLUT4 expression, insulin-stimulated glucose uptake, and PKB phosphorylation were higher in LG than in NG, whereas insulin receptor tyrosyl phosphorylation, insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, and GSK-3 phosphorylation were unchanged. Muscles with HG showed lower insulin-stimulated glycogen synthesis and glycogen synthase activation than NG de...
Regulation of glycogen synthesis in human muscle cells
Biochemical Society Transactions, 2001
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.
Regulation of glycogen synthase in muscle and its role in Type 2 diabetes
Diabetes Management, 2013
Type 2 diabetic patients exhibit reduced insulin-stimulated glucose disposal rates along with impaired muscle glycogen synthase (GS) activity and glycogen synthesis. After a meal, muscle is an important glucose sink and a large proportion of glucose entering muscle is converted to glycogen. It is, therefore, a clinically relevant question to ask whether impaired GS activation and glycogen storage in muscle are defects responsible for reduced glucose disposal in Type 2 diabetes. This short review first provides a brief mechanistic background on regulation of GS activity and then presents evidence from human and rodent Glycogen synthase (GS) is regulated covalently via multiple phosphorylation sites and allosterically by glucose-6-phosphate.
Archives of Biochemistry and Biophysics, 2007
The aim of this study was to investigate the effect of insulin resistance on glycogen concentration and glycogen synthase activity in the red and white gastrocnemius muscles and to determine whether the inverse relationship existing between glycogen concentration and enzyme activity is maintained in insulin resistant state. These questions were addressed using 3 models that induce various degrees of insulin resistance: sucrose feeding, dexamethasone administration, and a combination of both treatments (dex+sucrose). Sucrose feeding raised triglyceride levels without affecting plasma glucose or insulin concentrations whereas dexamethasone and dex+sucrose provoked severe hyperinsulinemia, hyperglycemia and hypertriglyceridemia. Sucrose feeding did not alter muscle glycogen concentration but provoked a small reduction in the glycogen synthase activity ratio (À/+ glucose-6-phosphate) in red but not in white gastrocnemius. Dexamethasone administration augmented glycogen concentration and reduced glycogen synthase activity ratio in both muscle fiber types. In contrast, dex+sucrose animals showed decreased muscle glycogen concentration compared to dexamethasone group, leading to levels similar to those of control animals. This was associated with lower glycogen synthase activity compared to control animals leading to levels comparable to those of dexamethasone-treated animals. Thus, in dex+sucrose animals, the inverse relationship observed between glycogen levels and glycogen synthase activity was not maintained, suggesting that factors other than the glycogen concentration modulate the enzyme's activity. In conclusion, while insulin resistance was associated with a reduced glycogen synthase activity ratio, we found no correlation between muscle glycogen concentration and insulin resistance. Furthermore, our results suggest that sucrose treatment may modulate dexamethasone action in skeletal muscle.
Journal of Clinical Investigation, 1996
To determine whether glycogen synthase (GS) activity remains impaired in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients or can be normalized after prolonged culture, needle biopsies of vastus lateralis were obtained from 8 healthy nondiabetic control (ND) and 11 NIDDM subjects. After 4-6 wk growth and 4 d fusion in media containing normal physiologic concentrations of insulin (22 pM) and glucose (5.5 mM), both basal (5.21 Ϯ 0.79 vs 9.01 Ϯ 1.25%, P Ͻ 0.05) and acute insulinstimulated (9.35 Ϯ 1.81 vs 16.31 Ϯ 2.39, P Ͻ 0.05) GS fractional velocity were reduced in NIDDM compared to ND cells. Determination of GS kinetic constants from muscle cells of NIDDM revealed an increased basal and insulinstimulated K m 0.1 for UDP-glucose, a decreased insulin-stimulated V max 0.1 and an increased insulin-stimulated activation constant (A 0.5 ) for glucose-6-phosphate. GS protein expression, determined by Western blotting, was decreased in NIDDM compared to ND cells (1.57 Ϯ 0.29 vs 3.30 Ϯ 0.41 arbitrary U/mg protein, P Ͻ 0.05). GS mRNA abundance also tended to be lower, but not significantly so (0.168 Ϯ 0.017 vs 0.243 Ϯ 0.035 arbitrary U, P ϭ 0.08), in myotubes of NIDDM subjects. These results indicate that skeletal muscle cells of NIDDM subjects grown and fused in normal culture conditions retain defects of basal and insulin-stimulated GS activity that involve altered kinetic behavior and possibly reduced GS protein expression. We conclude that impaired regulation of skeletal muscle GS in NIDDM patients is not completely reversible in normal culture conditions and involves mechanisms that may be genetic in origin. ( J. Clin. Invest. 1996Invest. . 98:1231Invest. -1236
Control of Glycogen Synthesis by Glucose, Glycogen, and Insulin in Cultured Human Muscle Cells
Diabetes, 2001
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 ∼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 leas...
Diabetes, 2002
Glycogen synthase kinase (GSK)-3 has been implicated in the regulation of multiple cellular physiological processes in skeletal muscle. Selective cell-permeable reversible inhibitors (INHs) of GSK-3 (CT98014 and CHIR98023 [Chiron, Emeryville, CA] and LiCl) were used to evaluate the role of GSK-3 in controlling glucose metabolism. Acute treatment (30 min) of cultured human skeletal muscle cells with either INH resulted in a dose-dependent activation of glycogen synthase (GS) with a maximally effective concentration of ∼2 μmol/l. The maximal acute effect of either INH on GS (103 ± 25% stimulation over basal) was greater than the maximal insulin response (48 ± 9%, P < 0.05 vs. INH); LiCl was as effective as insulin. The GSK-3 inhibitor effect, like that of insulin, was on the activation state (fractional velocity [FV]) of GS. Cotreatment of muscle cells with submaximal doses of INH and insulin resulted in an additive effect on GS FV (103 ± 10% stimulation, P < 0.05 vs. either age...
Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase
Diabetes, 2005
Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5–10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals ...