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New Insights Into the Role and Mechanism of Glycogen Synthase Activation by Insulin
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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“GSK-3 phosphorylates these sites, which are the most important for regulation of glycogen synthase activity [11]”
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Cusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7535 · Cited by 1,139
“Therefore, even though it is possible to increase glucose uptake by overexpressing glycogen synthase in transgenic mice (45), it seems that an increase in glycogen synthase activity alone is insufficient to increase glucose disposal in humans.”
BackgroundChan, T. O., Rittenhouse, S. E., & Tsichlis, P. N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.965 · Cited by 737
Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling
SHEPHERD, P. R., WITHERS, D. J., & SIDDLE, K. (1998) · Biochemical Journal · doi:10.1042/bj3330471 · Cited by 953
Coghlan, M. P., Culbert, A. A., Cross, D. A. E., Corcoran, S. L., Yates, J. W., Pearce, N. J., Rausch, O., Murphy, G. J., Carter, P. S., Cox, L. R., et al. (2000) · Chemistry & Biology · doi:10.1016/s1074-5521(00)00025-9 · Cited by 906
“It is likely that in this case insulin acts through stimulating the MAPK/MAPKAPK-1L/PP1G pathway, rather than through inhibition of GSK-3, to stimulate glycogen synthase and hence glycogen synthesis [40,44].”
BackgroundGlycogen and its metabolism: some new developments and old themes
Roach, P. J., DePaoli-Roach, A. A., Hurley, T. D., & Tagliabracci, V. S. (2012) · Biochemical Journal · doi:10.1042/bj20111416 · Cited by 728
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Metadata
- 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
- 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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