scholarly journals Insulin action in cultured human myoblasts: contribution of different signalling pathways to regulation of glycogen synthesis

1996 ◽  
Vol 320 (3) ◽  
pp. 871-877 ◽  
Author(s):  
Steven J. HUREL ◽  
Justin J. ROCHFORD ◽  
Andrew C. BORTHWICK ◽  
Anne M. WELLS ◽  
Jackie R. VANDENHEEDE ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glycogen Synthase ◽  
Insulin Signalling ◽  
Protein Kinase B ◽  
Glycogen Synthesis ◽  
Experimental Systems ◽  
Extracellular Signal ◽  
Insulin Control ◽  
Metabolic Action ◽  
Stimulation Of

A key metabolic action of insulin is the stimulation of non-oxidative glucose utilization in skeletal muscle, by increasing both glucose uptake and glycogen synthesis. The molecular mechanism underlying this process has been investigated using a variety of experimental systems. We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans. In these cells insulin stimulates glycogen synthesis approx. 2.2-fold, associated with a similar activation of glycogen synthase (GS) which occurs within 5–10 min of the addition of insulin. Insulin also causes inactivation of glycogen synthase kinase-3 (GSK-3) and activation of protein kinase B, both processes being sufficiently rapid to account for the effects of insulin on GS. Activation by insulin of the protein kinases p70s6K, p90s6K and extracellular signal-regulated kinase 2 (ERK2) is observed, but is significantly slower than the activation of GS. Selective inhibitors of the p70s6K pathway (rapamycin), the ERK2/p90s6K pathway (PD98059) and phosphatidylinositol 3-kinase (wortmannin) have been used to probe the contribution of these components to insulin signalling in human muscle. Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK-3. PD98059 is without effect on these events, while rapamycin is without effect on inactivation of GSK-3 but partially blocks activation of glycogen synthesis and GS. Taken together, these findings suggest that protein kinase B is responsible for the inactivation of GSK-3, but that an additional rapamycin-sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis.

scholarly journals Glutamatergic Fate of Neural Progenitor Cells of Rats with Inherited Audiogenic Epilepsy

2020 ◽  
Vol 10 (5) ◽  
pp. 311
Author(s):  
Alexandra A. Naumova ◽  
Ekaterina A. Oleynik ◽  
Elena V. Chernigovskaya ◽  
Margarita V. Glazova
Keyword(s):  
Protein Kinase ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Glycogen Synthase ◽  
Neural Progenitor ◽  
Cell Number ◽  
Gamma Aminobutyric Acid ◽  
Audiogenic Epilepsy ◽  
Extracellular Signal ◽  
Stimulation Of

Epilepsy is associated with aberrant neurogenesis in the hippocampus and may underlie the development of hereditary epilepsy. In the present study, we analyzed the differentiation fate of neural progenitor cells (NPC), which were isolated from the hippocampus of embryos of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic epilepsy. NPCs from embryos of Wistar rats were used as the control. We found principal differences between Wistar and KM NPC in unstimulated controls: Wistar NPC culture contained both gamma-aminobutyric acid (GABA) and glutamatergic neurons; KM NPC culture was mainly represented by glutamatergic cells. The stimulation of glutamatergic differentiation of Wistar NPC resulted in a significant increase in glutamatergic cell number that was accompanied by the activation of protein kinase A. The stimulation of KM NPC led to a decrease in immature glutamatergic cell number and was associated with the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B/ glycogen synthase kinase 3 beta (Akt/GSK3β), which indicates the activation of glutamatergic cell maturation. These results suggest genetically programmed abnormalities in KM rats that determine the glutamatergic fate of NPC and contribute to the development of audiogenic epilepsy.

scholarly journals Osmotic Shock Inhibits Insulin Signaling by Maintaining Akt/Protein Kinase B in an Inactive Dephosphorylated State

1999 ◽  
Vol 19 (7) ◽  
pp. 4684-4694 ◽  
Author(s):  
Dong Chen ◽  
Raymond V. Fucini ◽  
Ann Louise Olson ◽  
Brian A. Hemmings ◽  
Jeffrey E. Pessin
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Protein Kinase B ◽  
Osmotic Shock ◽  
Glycogen Synthesis ◽  
Type I ◽  
Transport Activity ◽  
Insulin Stimulation ◽  
Stimulation Of

ABSTRACT We have previously reported that insulin and osmotic shock stimulate an increase in glucose transport activity and translocation of the insulin-responsive glucose transporter isoform GLUT4 to the plasma membrane through distinct pathways in 3T3L1 adipocytes (D. Chen, J. S. Elmendorf, A. L. Olson, X. Li, H. S. Earp, and J. E. Pessin, J. Biol. Chem. 272:27401–27410, 1997). In investigations of the relationships between these two signaling pathways, we have now observed that these two stimuli are not additive, and, in fact, osmotic shock pretreatment was found to completely prevent any further insulin stimulation of glucose transport activity and GLUT4 protein translocation. In addition, osmotic shock inhibited the insulin stimulation of lipogenesis and glycogen synthesis. This inhibition of insulin-stimulated downstream signaling occurred without any significant effect on insulin receptor autophosphorylation or tyrosine phosphorylation of insulin receptor substrate 1 (IRS1). Furthermore, there was no effect on either the insulin-stimulated association of the p85 type I phosphatidylinositol (PI) 3-kinase regulatory subunit with IRS1 or phosphotyrosine antibody-immunoprecipitated PI 3-kinase activity. In contrast, osmotic shock pretreatment markedly inhibited the insulin stimulation of protein kinase B (PKB) and p70S6 kinase activities. In addition, the dephosphorylation of PKB was prevented by pretreatment with the phosphatase inhibitors okadaic acid and calyculin A. These data support a model in which osmotic shock-induced insulin resistance of downstream biological responses results from an inhibition of insulin-stimulated PKB activation.

Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators

2004 ◽  
Vol 286 (3) ◽  
pp. R498-R504 ◽  
Author(s):  
Kyle L. Hoehn ◽  
Susan F. Hudachek ◽  
Scott A. Summers ◽  
Gregory L. Florant
Keyword(s):  
Protein Kinase ◽  
Body Mass ◽  
Large Scale ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthesis ◽  
Mass Gain ◽  
Tissue Specific ◽  
Protein Levels ◽  
Specific Regulation

Yellow-bellied marmots ( Marmota flaviventris) exhibit a circannual cycle of hyperphagia and nutrient storage in the summer followed by hibernation in the winter. This annual cycle of body mass gain and loss is primarily due to large-scale accumulation of lipid in the summer, which is then mobilized and oxidized for energy during winter. The rapid and predictable change in body mass makes these animals ideal for studies investigating the molecular basis for body weight regulation. In the study described herein, we monitored seasonal changes in the protein levels and activity of a central regulator of anabolic metabolism, the serine-threonine kinase Akt-protein kinase B (Akt/PKB), during the months accompanying maximal weight gain and entry into hibernation (June-November). Interestingly, under fasting conditions, Akt/PKB demonstrated a tissue-specific seasonal activation. Specifically, although Akt/PKB levels did not change, the activity of Akt/PKB (isoforms 1/α and 2/β) in white adipose tissue (WAT) increased significantly in July. Moreover, glycogen synthase, which lies downstream of Akt/PKB on a linear pathway linking the enzyme to the stimulation of glycogen synthesis, demonstrated a similar pattern of seasonal activation. By contrast, Akt/PKB activity in skeletal muscle peaked much later (i.e., September). These data suggest the existence of a novel, tissue-specific mechanism regulating Akt/PKB activation during periods of marked anabolism.

scholarly journals Cytosolic Protein Tyrosine Phosphatase-ε Is a Negative Regulator of Insulin Signaling in Skeletal Muscle

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 605-614 ◽  
Author(s):  
Shlomit Aga-Mizrachi ◽  
Tamar Brutman-Barazani ◽  
Avraham I. Jacob ◽  
Asia Bak ◽  
Ari Elson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Tyrosine Phosphorylation ◽  
Rna Silencing ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase 3 ◽  
Wild Type ◽  
Stimulation Of

Whereas positive regulatory events triggered by insulin binding to insulin receptor (IR) have been well documented, the mechanism by which the activated IR is returned to the basal status is not completely understood. Recently studies focused on the involvement of protein tyrosine phosphatases (PTPs) and how they might influence IR signaling. In this study, we examined the possibility that cytosolic PTPε (cytPTPε) is involved in IR signaling. Studies were performed on L6 skeletal muscle cells. cytPTPε was overexpressed by using pBABE retroviral expression vectors. In addition, we inhibited cytPTPε by RNA silencing. We found that insulin induced rapid association of cytPTPε with IR. Interestingly, this association appeared to occur in the plasma membrane and on stimulation with insulin the two proteins internalized together. Moreover, it appeared that almost all internalized IR was associated with cytPTPε. We found that knockdown of cytPTPε by RNA silencing increased insulin-induced tyrosine phosphorylation of IR and IR substrate (IRS)-1 as well as phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin-induced stimulation of glucose uptake. Moreover, overexpression of wild-type cytPTPε reduced insulin-induced tyrosine phosphorylation of IR, IRS-1, and phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin-induced stimulation of glucose uptake. Finally, insulin-induced tyrosine phosphorylation of IR and IRS-1 was greater in skeletal muscle from mice lacking the cytPTPε gene than that from wild-type control animals. We conclude that cytPTPε serves as another major candidate negative regulator of IR signaling in skeletal muscle.

scholarly journals Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells

1995 ◽  
Vol 311 (2) ◽  
pp. 595-601 ◽  
Author(s):  
S K Moule ◽  
N J Edgell ◽  
G I Welsh ◽  
T A Diggle ◽  
E J Foulstone ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Pyruvate Dehydrogenase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Signalling Pathways ◽  
Fat Cells ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Stimulation Of

We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.

Sign in / Sign up

Export Citation Format

Share Document