Cited by 311Metabolism, Diabetes, and CancerGlycogen Storage Diseases and MyoclonusProtein Kinase Regulation and GTPase Signaling

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New Insights Into the Role and Mechanism of Glycogen Synthase Activation by Insulin

Lawrence, John C, Roach, Peter J·1997·Diabetes

DOI 10.2337/diab.46.4.541

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Abstract

The metabolism of the storage polysaccharide glycogen is intimately linked with insulin action and blood glucose homeostasis. Insulin activates both glucose transport and glycogen synthase in skeletal muscle. The central issue of a long-standing debate is which of these two effects determines the rate of glycogen synthesis in response to insulin. Recent studies with transgenic animals indicate that, under appropriate conditions, each process can contribute to determining the extent of glycogen accumulation. Insulin causes stable activation of glycogen synthase by promoting dephosphorylation of multiple sites in the enzyme. A model linking this action to the mitogen-activated protein kinase signaling pathway via the phosphorylation of the regulatory subunit of glycogen synthase phosphatase gained widespread acceptance. However, the most recent evidence argues strongly against this mechanism. A newer model, in which insulin inactivates the enzyme glycogen synthase kinase-3 via the protein kinase B pathway, has emerged. Though promising, this model still does not completely explain the molecular basis for the insulin-mediated activation of glycogen synthase, which remains one of the many unknowns of insulin action.

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RETRACTED: Role of the PDK1–PKB–GSK3 pathway in regulating glycogen synthase and glucose uptake in the heart
Mora, A., Sakamoto, K., McManus, E. J., & Alessi, D. R. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.05.040 · Cited by 90
“Thus, the similar levels of glycogen observed in the wild type and GSK3 knockin mice might be ex- plained, if activation of GS by G6P can compensate for the failure of insulin to induce the dephosphorylation of GS, in the skeletal muscle of knockin mice expressing GSK3 mutants that cannot be inactivated by insulin.”
BackgroundInfluential
Retracted
Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice
Parker, G. J., Taylor, R. P., Jones, D., & McClain, D. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312139200 · Cited by 84
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“Concomitantly, insulin also failed to down-regulate hepatic gluconeogenesis and could no longer inhibit GSK3β and induce expression of lipogenic genes.”
BackgroundInfluential
Regulation of glycogen synthase in skeletal muscle during exercise
Nielsen, J. N., & Richter, E. A. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01165.x · Cited by 81
p38 Mitogen-Activated Protein Kinase: A Critical Node Linking Insulin Resistance and Cardiovascular Diseases in Type 2 Diabetes Mellitus
Liu, Z., & Cao, W. (2009) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153009787582397 · Cited by 80
“GS activity is determined by complex multisite phosphorylation as well as allosteric factors [19, 20].”
Background
Dysregulation of Glycogen Synthase COOH- and NH2-Terminal Phosphorylation by Insulin in Obesity and Type 2 Diabetes Mellitus
Højlund, K., Birk, J. B., Klein, D. K., Levin, K., Rose, A. J., Hansen, B. F., Nielsen, J. N., Beck‐Nielsen, H., & Wojtaszewski, J. F. P. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0897 · Cited by 77
Glucose transport rate and glycogen synthase activity both limit skeletal muscle glycogen accumulation
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“glycogen synthase activity, the two driving forces for net glycogen synthesis ( 19 , 30).”
BackgroundInfluential
Differential regulation of MAP kinase by contraction and insulin in skeletal muscle: metabolic implications
Wojtaszewski, J. F. P., Lynge, J., Jakobsen, A. B., Goodyear, L. J., & Richter, E. A. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.4.e724 · Cited by 75
“This, in turn, leads to dephosphorylation and activation of glycogen synthase (12, 30).”
Background
Insulin resistance and antidiabetic drugs
Bailey, C. J. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00191-4 · Cited by 73
Expression of a Dominant Negative SHP-2 in Transgenic Mice Induces Insulin Resistance
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Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid
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“Palmitate (C16:0; saturated FFA) has been shown to reduce insulin-stimulated phosphorylation of AKT (pAKT—a key signalling molecule in the pathway from insulin stimulation to glucose uptake (Lawrence and Roach, 1997; Bevan, 2001)) in murine C2C12 myotubes (Schmitz-Peiffer et al., 1999).”
Background
Drosophila melanogasteras a Model for Diabetes Type 2 Progression
Álvarez-Rendón, J. P., Salceda, R., & Riesgo‐Escovar, J. R. (2018) · BioMed Research International · doi:10.1155/2018/1417528 · Cited by 69
Troglitazone Regulation of Glucose Metabolism in Human Skeletal Muscle Cultures from Obese Type II Diabetic Subjects1
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Insulin‐like actions of vanadium: Potential as a therapeutic agent
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“Activity of glycogen synthase, the key enzyme in glycogen synthesis, is regulated by both glycogen synthase kinase-3 (GSK-3), a downstream enzyme of PKB, which inactivates (phosphorylates) glycogen synthase and by protein phosphatase-1 (PP-1), which activates (dephosphorylates) the enzyme [69,70].”
Background
Antihyperglycemic and hypolipidemic effects of Costus speciosus in alloxan induced diabetic rats
Bavarva, J. H., & Narasimhacharya, A. V. R. L. (2008) · Phytotherapy Research · doi:10.1002/ptr.2302 · Cited by 66
“An increase in hepatic glycogen content in CSREt administered animals suggests the activation of glycogen synthase for which the substrate glucose-6phosphate could have been readily provided by an increased hexokinase activity (Lawrence and Roach, 1997; Bouche et al., 2004).”
Background
Glucose 6-Phosphate Regulates Hepatic Glycogenolysis Through Inactivation of Phosphorylase
Aiston, S., Andersen, B., & Agius, L. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1333 · Cited by 67
“Glycogen synthase is regulated by multisite phosphorylation, which results in inactivation (2,3).”
Background
Impaired Muscle Glycogen Synthase in Type 2 Diabetes Is Associated with Diminished Phosphatidylinositol 3-Kinase Activation
Nikoulina, S. E., Ciaraldi, T. P., Carter, L., Mudaliar, S. R. D., Park, K. S., & Henry, R. R. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.9.7872 · Cited by 67
“Evidence has accumulated to support a key role for PI 3-kinase in mediating insulin action on glucose transport and GS (44, 45).”
Control of Glycogen Synthesis in Cultured Human Muscle Cells
Halse, R., Rochford, J. J., McCormack, J. G., Vandenheede, J. R., Hemmings, B. A., & Yeaman, S. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.776 · Cited by 62
Genetics of type 2 diabetes mellitus: status and perspectives
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Use of lithium and SB‐415286 to explore the role of glycogen synthase kinase‐3 in the regulation of glucose transport and glycogen synthase
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“GSK3 is one of several kinases that phosphorylate glycogen synthase (GS), an event that helps to maintain the enzyme in an inactive state [16].”
Background
Fasting-Induced Protein Phosphatase 1 Regulatory Subunit Contributes to Postprandial Blood Glucose Homeostasis via Regulation of Hepatic Glycogenesis
Luo, X., Zhang, Y., Ruan, X., Jiang, X., Zhu, L., Wang, X., Ding, Q., Liu, W., Pan, Y., Wang, Z., et al. (2011) · Diabetes · doi:10.2337/db10-1663 · Cited by 60
“In addition, the postprandial increase of insulin stimulates GS by reducing its phosphorylation and inactivation by GSK3, at least in muscle (12).”
Background
Control of Glycogen Synthesis by Glucose, Glycogen, and Insulin in Cultured Human Muscle Cells
Halse, R., Bonavaud, S. M., Armstrong, J. L., McCormack, J. G., & Yeaman, S. J. (2001) · Diabetes · doi:10.2337/diabetes.50.4.720 · Cited by 61
“in [1]).”
Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers
Azpiazu, I., Manchester, J., Skurat, A. V., Roach, P. J., & Lawrence, J. C. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.2.e234 · Cited by 59
“Insulin activates both glucose transport and glycogen synthase in skeletal muscle, thereby affecting the initial as well as the final step in the pathway leading from extracellular glucose to glycogen (24).”
BackgroundSelf-citation
Regulation of Glycogen Synthase in Rat Hepatocytes
Lavoie, L., Band, C. J., Kong, M. S., Bergeron, J. J. M., & Posner, B. I. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.40.28279 · Cited by 59
Signalling pathways involved in the stimulation of glycogen synthesis by insulin in rat hepatocytes
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“The activation of glycogen synthase by insulin results from dephosphorylation of sites (3a + 3b + 3c) and (2a + 2 b) [30].”
Background
Muscle-Specific Deletion of the Glut4 Glucose Transporter Alters Multiple Regulatory Steps in Glycogen Metabolism
Kim, Y., Peroni, O. D., Aschenbach, W. G., Minokoshi, Y., Kotani, K., Zisman, A., Kahn, C. R., Goodyear, L. J., & Kahn, B. B. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9713-9723.2005 · Cited by 60
“, glycogen synthase and phosphorylase, respectively (32, 44), we investigated the activities of these two enzymes in muscle of muscle-G4KO mice.”
BackgroundInfluential

Authors: Lawrence, J. C., & Roach, P. J.
Affiliations: University of Virginia (US)
Indiana University Indianapolis (US)
Venue: Diabetes
Publisher: American Diabetes Association
Published: 1997-04-01
Volume: 46
Issue: 4
Pages: 541-547
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diab.46.4.541
OpenAlex: W2140664543
Cited by: 311
References: 0
Citations by year: 2026: 1 · 2025: 4 · 2024: 8 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 4 · 2014: 10 · 2013: 3 · 2012: 14
FWCI: 7.00
Type: journal article
Language: en
Open access: closed
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1zicar041189-01)
National Institute of Diabetes and Digestive and Kidney Diseases (DK28312, DK 27221, R01DK028312)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR41189)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Glycogen Storage Diseases and Myoclonus
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: glycogen synthase, insulin signaling, glycogen synthesis, glycogen synthase kinase-3, Akt, mitogen-activated protein kinase, glycogen synthase phosphatase, glucose transport, skeletal muscle, blood glucose homeostasis
MeSH terms: Animals, Enzyme Activation, Glycogen, Glycogen Synthase, Humans, Insulin, Muscle, Skeletal

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New Insights Into the Role and Mechanism of Glycogen Synthase Activation by Insulin

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